FLAGELLIN COMPOSITIONS AND USES

Abstract

The present invention relates to compositions comprising improved flagellin derived constructs and methods of using the same in the treatment of various diseases.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation application of U.S. patent application Ser. No. 16/802,859 (now U.S. Pat. No. 11,034,733), filed on Feb. 27, 2020, which is a continuation application of U.S. patent application Ser. No. 16/226,909 (now U.S. Pat. No. 10,669,316), filed on Dec. 20, 2018, which is a continuation application of U.S. patent application Ser. No. 15/329,870 (now U.S. Pat. No. 10,202,426), filed on Oct. 9, 2017, which is a 371 national stage entry of International Application No. PCT/US2015/042684, filed on Jul. 29, 2015, which claims the benefit of U.S. Provisional Patent Application Nos. 62/031,116, filed Jul. 30, 2014; 62/110,744, filed Feb. 2, 2015; and 62/117,366, filed Feb. 17, 2015 the entire contents of which are herein incorporated by reference.

FIELD OF THE INVENTION

[0002] This invention relates to methods and compositions that are useful for the treatment, prevention, and/or diagnosis, of various diseases, including cancer and radiation-related ailments.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0003] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: CLE-016PC-SequenceListing.txt; date recorded: Jul. 28, 2015; file size: 245 KB).

BACKGROUND

[0004] Toll-like receptors (TLRs) are type I membrane glycoproteins that are key receptors in innate immunity. The 10 TLRs known in humans recognize different microbial antigens, and when activated by ligand binding, mediate rapid production of cytokines and chemokines. In addition to their role in host defense, TLRs play a role in cancer progression and development and cell protection.

[0005] TLR5 binds flagellin, a globular protein that arranges itself in a hollow cylinder to form the filament in bacterial flagella. Binding of flagellin to TLR5 initiates a cascade of pro-inflammatory molecules, notably NF-.kappa.B and its targets. TLR5 agonists derived from flagellin have been developed as therapies various diseases. However, these molecules may suffer from specific limitations, including for example, unsatisfactory binding and signaling. Additionally, many possible hosts already produce anti-flagellin antibodies that also target the TLR5 agonist derivatives, thereby clearing the therapeutics from the body and limiting their efficacy. Moreover, as intrinsically immunogenic bacterial proteins flagellin derivatives may possess disadvantageous antigenicity and immunogenicity, and therefore warrant improvement.

SUMMARY OF THE INVENTION

[0006] Accordingly, the present invention provides flagellin-related compositions and methods that overcome limitations observed among this group of biologies.

[0007] The present invention is based, in part, of the discovery that minimized constructs of flagellin-related compositions can exhibit reduced immunogenicity and improve pharmacokinetics while still retaining the ability to active TLR5 signaling.

[0008] In one aspect, the invention provides a flagellin-related composition that retains the ability to activate TLR5 signaling. In a further embodiment, the flagellin-related composition comprises mutations that decrease the antigenicity and immunogenicity of the construct. In a further embodiment, the flagellin-related composition is not recognized by flagellin (FliC) neutralizing antibodies. In yet a further embodiment, the flagellin-related composition activates TLR5 signaling at a level the same as or similar to that of a full-length flagellin-related composition. In a further embodiment, the flagellin-related composition demonstrates improved pharmacokinetics compared with a full length flagellin-related composition. In yet a further embodiment, the flagellin-related composition demonstrates increased retention in the host.

[0009] In some embodiments, the flagellin-related composition is derived from CBLB502 (SEQ ID NO: 2). In a further embodiment, the flagellin-related composition comprises a truncation in one or more domains. In a further embodiment, the flagellin-related composition comprises a deletion in a N-terminal domain. In yet a further embodiment, the flagellin-related composition comprises a deletion in the ND0 domain. In yet a further embodiment, the flagellin-related composition comprises a deletion of the entire ND0 domain. In a further embodiment, the flagellin-related composition comprises a deletion in a C-terminal domain. In yet another embodiment, the flagellin-related composition comprises a deletion in the CD0 domain. In yet another embodiment, the flagellin-related composition retains amino acids 470-485 of the CD0 domain. In yet a further embodiment, the flagellin-related composition is CBLB502-S33 (SEQ ID NO: 17).

[0010] In some embodiments, the flagellin-related composition comprises mutations in epitopes recognized by neutralizing anti-CBLB502 antibodies. In some embodiments, the flagellin-related composition comprises one or more mutations in the epitopes recognized by neutralizing anti-CBLB502 antibodies which inhibit the ability of the antibodies to neutralize the composition. In yet a further embodiment, the flagellin-related composition comprises a truncation and mutations in one or more epitopes recognized by anti-CBLB502 neutralizing antibodies. In a further embodiment, the mutations comprise replacement of the epitope residues with alanine. In a further embodiment, the mutations are selected from one or more of D42A, A45G, N68A, N100A, T102A, S104A, S106A, D107A, S110A, D113A, Q117A, E120A, R124A, N127A, Q128A, F131A, N132A, G133A, Q142A, K144A, D151A, G152A, E153A, T154A, Q439A, N440A, R441A, D443A, S444A, T447A, N448A, N451A, N455A, N457A, R460A, Y468A; A469G; T470A; S473A, and N474Q. In a further embodiment, the mutated epitopes comprise one or more of the following residues: E153, S444, T154, N440, Q142, F131, D443, N68, T447, S110, Q117, R124, D113, E120, N127, and Q128. In a further embodiment, the flagellin-related composition is CBLB502-S33MX/"CBLB543" (SEQ ID NO: 150). In yet a further embodiment, the flagellin-related composition is CBLB502-485CT/"BCLB533" (SEQ ID NO: 71).

[0011] In some embodiments, the flagellin-related composition comprises a tag. In yet a further embodiment, the tag is attached to the N-terminus of the flagellin-related composition. In yet another embodiment, the tag is attached to the C-terminus of the flagellin-related composition.

[0012] In some embodiments, the flagellin-related composition comprises a flexible linker. In a further embodiment, the flexible linker comprises SEQ ID NO: 16. In yet a further embodiment, the flexible linker comprises SEQ ID NO: 242.

[0013] In some embodiments, the flagellin-related composition is encoded by any one of the nucleotide sequences listed in Table 1. In a further embodiment, the flagellin-related composition comprises any one of the polypeptides listed in Table 1.

[0014] In some embodiments, the flagellin-related composition activates TLR5 signaling. In a further embodiment, the flagellin-related composition induces expression of NF-.kappa.B. In yet a further embodiment, the minimized flagellin-related composition induces expression of one or more of cytokines. In yet a further embodiment, the cytokines are selected from IL-6, IL-12, keratinocyte chemoattractant (KC), IL-10, G-CSF, MCP-1, TNF-.alpha., MIG, and MIP-2.

[0015] In one aspect, the invention provides a pharmaceutical composition comprising the flagellin-related composition of the invention with a pharmaceutically accepted carrier.

[0016] In one aspect, the invention provides a method of stimulating TLR5 signaling comprising administering a flagellin-related composition of the invention to a subject in need thereof. In some embodiments, the subject has cancer. In a further embodiment, the tumor expresses TLR5. In a further embodiment, the tumor does not express TLR5. In yet a further embodiment, the cancer is selected from breast cancer, lung cancer, colon cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lymphatic system cancer, rectal cancer, pancreatic cancer, esophageal cancer, stomach cancer, cervical cancer, thyroid cancer, skin cancer, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burkett's lymphoma, acute and chronic myelogenous leukemias, myelodysplastic syndrome, myeloid leukemia, promyelocytic leukemia, astrocytoma, neuroblastoma, glioma, schwannomas, fibrosarcoma, rhabdomyosarcoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, seminoma, thyroid follicular cancer, teratocarcinoma, and cancers of the gastrointestinal tract or the abdominopelvic cavity.

[0017] In some embodiments, the subject suffers from radiation-induced damage. In a further embodiment, the subject has been subjected to a lethal dose of radiation. In yet a further embodiment, the subject is undergoing radiation treatment. In another embodiment, the flagellin-related composition is administered prior to exposure to radiation. In yet another embodiment, the flagellin-related composition is administered during exposure to radiation. In yet another embodiment, the flagellin-related composition is administered after exposure to radiation.

[0018] In some embodiments, the subject suffers from reperfusion injury. In a further embodiment the reperfusion is caused by an injury. In a further embodiment, the injury is ischemia or hypoxia. In a further embodiment, the flagellin-related composition is administered prior to the influx of oxygen. In a further embodiment, the flagellin-related composition is administered during the influx of oxygen. In a further embodiment, the flagellin-related composition is administered after the influx of oxygen.

[0019] In various embodiments, the flagellin-related composition is administered in conjunction with other therapeutics and/or treatments. In a further embodiment, the flagellin-related composition is administered in conjunction with chemotherapy. In a further embodiment, the flagellin-related composition is administered with radiation treatment. In a further embodiment, the flagellin-related composition is administered in conjunction with an antioxidant. In a further embodiment, the flagellin-related composition is administered in conjunction with amifostine and/or vitamin E. In some embodiments, the flagellin-related composition is administered prior to administration of other therapeutics and/or treatments. In further embodiments, the flagellin-related composition is administered at the same time as other therapeutics and/or treatments. In yet further embodiments, the flagellin-related composition is administered after administration of other therapeutics and/or treatments.

[0020] In one aspect, the invention provides a method of treating cancer comprising administering a flagellin-related composition of the invention to a subject in need thereof.

[0021] In one aspect, the invention provides a method of treating radiation-induced damage comprising administering a flagellin-related composition of the invention to a subject in need thereof.

[0022] In one aspect, the invention provides a method of treating reperfusion injury comprising administering a flagellin-related composition of the invention to a subject in need thereof.

[0023] The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

BRIEF DESCRIPTION OF THE FIGURES

[0024] FIGS. 1A and 1B show the 13 conserved amino acids of flagellin that may be important for TLR5 activity. FIGS. 1A and 1B show a comparison of amino acid sequences of the conserved amino (FIG. 1A) and carboxy (FIG. 1B) terminus from 21 species of bacteria. The 13 conserved amine acids important for TLR5 activity are shown with shading. The amino acid sequences are identified by their accession numbers from TrEMBL (first letter=Q) or Swiss-Prot (first letter=P).

[0025] FIG. 2 shows early structure-activity relationship analysis (SAR) data reflecting the contribution of individual segments and entire domains of CBLB502 to the efficiency of binding and signaling. Relative binding and signaling affinities were obtained using FP biochemical assay and cell-based reporter assay respectively and normalized to CBLB502. Analyses were performed for a series of mutations within predicted primary and secondary dimerization interfaces (A) as well as for a deletion of larger segments or entire domains D0 or D1 (B) as diagrammatically shown above the graph.

[0026] FIG. 3 shows the structural regions involved in interactions between TLR5 ectodomain and CBLB502 (FliC) domain D1. Note a contribution of loops LRR7 and 9 (characteristic of TLR5 family) to high-affinity primary interactions.

[0027] FIG. 4, panels A-E show the signaling efficiency of CBLB502 mutants in NF-.kappa.B luciferase reporter mice. The graphs show the NF-.kappa.B luciferase activity in reporter mice after subcutaneous administration of the (A) CBLB502, (B) DIM2, (C) DIM 1, (D) PIM, and (E) SY3 constructs. The activity was measured in the mouse liver, spleen, large intestine, and bladder.

[0028] FIG. 5 shows the iterative minimization of the flagellin-related composition, CBLB502. The constructs S33 and 33ML retain nearly full signaling activity in vitro. The schematic shows domain organization including spacer and tag.

[0029] FIG. 6 panels A and B show that a minimized variant CBLB502-S33 shows substantially higher signaling activity in vivo compared to CBLB502. NF-kB-luciferase reporter mice were injected (s.c) with 0.1 .mu.g of CBLB502 (A) or S33 (B) and imaged 3 hours later. The measurements in individual organs are illustrated in FIG. 4.

[0030] FIG. 7 panels A-H show that a minimized variant CBLB502-S33 shows substantially higher signaling activity in vivo compared to CBLB502, and the effect was particularly strong in bladder and large intestine. Signaling efficiency of the CBLB502 and CBLB502-S33 in NF-kB luciferase reporter mice (s.c. injection at indicated doses and collection of organs 3 hours later) was established by the analysis of luciferase activity in collected organs.

[0031] FIG. 8 panels A and B show that a minimized variant CBLB502-S33 shows higher potency in protection against lethal irradiation in mice, as compared to CBLB502. Panel A. Kaplan-Meyer plot showing survival dynamics in C57/BL6 mice injected with CBLB502 or CBLB502-S33, 30 min prior to total body irradiation at 9.5 Gy (compared with vehicle control. Panel B. Dose dependence for the 30-day % survival.

[0032] FIG. 9 shows the higher signaling and radioprotective activity of CBLB502-S33 correlates with higher cytokine production (PD analysis) in mice compared to CBLB502, including mechanistically essential biomarkers G-CSF and IL-6. Mice were injected with either 1 .mu.g/kg or 2 .mu.g/kg of CBLB502 or S33.

[0033] FIG. 10 shows that the minimized variant CBLB502-S33 displays better PK (higher levels in plasma) in mice compared to CBLB502.

[0034] FIG. 11 shows the suppression of luciferase activity in murine liver lysates as a measurement of the in vivo neutralization of CBLB502 by injection of antisera and antibodies (neutralizing and not neutralizing) in reporter mice (3 mice/group). PBS, non-neutralizing human serum, neutralizing serum (D15), the non-neutralizing monoclonal antibody 7C, or the neutralizing monoclonal antibody 11D were administered to the mice intravenously. An hour after, the CBLB502 construct was administered subcutaneously. The amount of luciferase activity was measured three hours after administration of CBLB502. Murine serum samples were collected before administration of CBLB502. Human sera were diluted 10-fold with PBS for injections. Both monoclonal antibodies, 7C and 11D were injected at a concentration of 2 mg/ml in PBS.

[0035] FIG. 12 panels A and B show schematic diagrams of the constructs (A) 445 (SEQ ID NO: 54) and (B) 467 (SEQ ID NO: 62).

[0036] FIG. 13 panels A-C show examples of predicted, without wishing to be bound by theory, structural epitopes used for the design of CBLB502 derivatives.

[0037] FIG. 14 shows that the construct CBLB502-33MX demonstrates substantial elimination of neutralizing antigenicity. The graph shows a profile of CBLB502-33MX versus CBLB502 and its truncated variant CBLB502-ML over a panel of human sera with the appreciable titer of CBLB502-neutralizing antibodies.

[0038] FIG. 15 shows quantification of CBLB502 and CBLB502-33MX in mouse plasma samples. BLQ--below the limit of quantification. Panel A shows raw data while panel B shows a graphical representation of the data in panel A. CBLB502-33MX has very similar PK properties as that of parental CBLB502, i.e. it clears from circulation at approximately the same rate.

[0039] FIG. 16 shows cytokine profiling for the analysis of PD properties of CBLB502-33MX as compared to CBLB502. CBLB502-33MX has a very similar PD profile to the parental CBLB502

[0040] FIG. 17 shows luciferase activity in mouse organs after treatment with CBLB502, CBLB502-S33 and CBLB502-33MX.

[0041] FIG. 18 shows injury scores for a 33MX dose range as compared to a dose of CBLB502

DETAILED DESCRIPTION OF THE INVENTION

[0042] The present invention is based, in part, on the discovery of certain mutations of flagellin that improve pharmacologically relevant properties of this biologic and related agents. Such mutations yield various flagellin-related compositions that, by way of non-limiting example, have altered antigenicity and immunogenicity relative to those without the mutations. The flagellin-related compositions retain the ability to active TLR5 signaling at levels the same as, or similar to, that of a full length flagellin-related composition.

Flagellin-Related Compositions

[0043] The present invention is based, in part, of the discovery that minimized constructs of flagellin-related compositions can exhibit reduced immunogenicity while still retaining the ability to active TLR5 signaling at levels the same as, or similar to, that of a full length flagellin-related composition. The reduced immunogenicity allows the construct to persist in the host longer than full length flagellin-related compositions. It is possible to eliminate at least half of the endogenous C_D0 segment, leaving only its N-terminal half (470-485) capped by the C-terminal His-tag and still retain most of the molecule's ability to activate TLR5 signaling. The presence of the cap may be essential for activity as the variant 33-485 loses about 90% of signaling activity. These observations taken together suggest that the D_0 domain has only minor (if any) contribution to direct interactions with TLR5, and its role may be limited by maintaining structural integrity of the D1 domain. Conversely, the residual C_D0 segment (470-485) cannot be removed or replaced by the C-terminal half of C_D0 (485-504) or other sequences.

[0044] In various embodiments, the present invention provides flagellin-related compositions. In some embodiments, the present invention provides for flagellin-related compositions that have (1) improved pharmacological properties, including reduced antigenicity and immunogenicity, which, for example, allow for use in wide variety of disease states and patient types and/or (2) improved functional properties which, for example, allow for improved medical effects.

[0045] The flagellin-related compositions may be a flagellin-related polypeptide. The flagellin-related compositions may be from various sources, including a variety of Gram-positive and Gram-negative bacterial species. In some embodiments, the flagellin-related compositions may have an amino acid sequence that is derived from any of the flagellins from bacterial species that are depicted in FIG. 7 of U.S. Patent Publication No. 2003/0044429, the contents of which are incorporated herein by reference in their entirety. The flagellin-related compositions may have nucleotide sequences related to those encoding the flagellin polypeptides listed in FIG. 7 of U.S. 2003/0044429, which are publicly available at sources including the NCBI Genbank database.

[0046] The flagellin-related compositions may be the major component of bacterial flagellum. The flagellin-related compositions may be composed of one, or two, or three, or four, or five, or six, or seven domains or fragments thereof (see, e.g. FIG. 10 of U.S. Pat. No. 8,324,163, the contents of which are incorporated herein by reference in their entirety). The domains may be selected from ND0, ND1, ND2, D3, CD2, CD1, and CD0. Domains 0 (D0), 1 (D1), and 2 (D2) may be discontinuous and may be formed when residues in the amino terminus and carboxy terminus are juxtaposed by the formation of a hairpin structure. The amino and carboxy terminus comprising the D1 and D2 domains may be most conserved, whereas the middle hypervariable domain (D3) may be highly variable. The non-conserved D3 domain may be on the surface of the flagellar filament and may contain the major antigenic epitopes. The potent proinflammatory activity of flagellin may reside in the highly conserved ND1, ND2, CD1, and CD2 regions.

[0047] The flagellin-related compositions may be from a species of Salmonella, representative examples of which are S. typhimurium and S. dublin (encoded by GenBank Accession Number M84972). The flagellin related-polypeptide may be a fragment, variant, analog, homolog, or derivative of wild type flagellin (SEQ ID NO: 1), or combination thereof. A fragment, variant, analog, homolog, or derivative of flagellin may be obtained by rational-based design based on the domain structure of flagellin and the conserved structure recognized by TLR5.

[0048] The flagellin-related compositions may be related to a flagellin polypeptide from any Gram-positive or Gram-negative bacterial species including, but not limited to, the flagellin polypeptides disclosed in U.S. Pat. Pub. 2003/000044429, the contents of which are incorporated herein, and the flagellin peptides corresponding to the Accession numbers listed in the BLAST results shown in FIG. 7 (panels A-F) of U.S. Patent Pub. 2003/000044429, or variants thereof.

[0049] Flagellin and previously described variants suffer from high antigenicity and immunogenicity in large part, without wishing to be bound by theory, because they are intrinsically immunogenic bacterial proteins (e.g. flagellin or "FliC"). A practical limitation in preexisting flagellin constructs is that many subjects have high titers of pre-existing antibodies capable of neutralizing the TLR5-stimulating activity of these constructs. These individuals would be desensitized (or completely resistant) to flagellin-derived treatment, sometimes even in case of single-injections and, without wishing to be bound by theory, more likely upon recurrent treatment. Moreover, the titer of such pre-existing antibodies, even if initially present at lower levels, may be rapidly boosted by a single flagellin-derived injection thereby compromising even a larger group of individuals for the purpose of multi-dose regimen as projected for medical applications. The widespread preexistence of anti-FliC antibodies (including neutralizing Abs) in a population likely reflects humanity's life-long exposure to numerous species of flagellated enterobacteria (e.g. Salmonella spp., E. coli) colonizing (and infecting) the human body. In some embodiments, the presently described flagellin-related compositions comprise alterations of epitopes for various antibodies that neutralize flagellin activity.

[0050] In some embodiments, the flagellin-related composition comprises mutations in epitopes recognized by neutralizing anti-CBLB502 antibodies. The flagellin-related composition may comprise one or more mutations in the epitopes recognized by neutralizing anti-CBLB502 antibodies which inhibit or abrogate the ability of the antibodies to neutralize the composition. In yet a further embodiment, the flagellin-related composition comprises a truncation and mutations in one or more epitopes. In a further embodiment, the mutations comprise replacement of the epitope residues with alanine. In a further embodiment, the mutated epitopes comprise one or more of the following residues: E153, S444, T154, N440, Q142, F131, D443, N68, T447, S110, Q117, R124, D113, E120, N127, and Q128.

[0051] The flagellin-related compositions may comprise insertions, deletions, transposon insertions, and changes to any one of the D0, D1, D2, and the variable D3 domains. The D3 domain may be substituted in part, or in whole, with a hinge or linker polypeptide that allows the D1 and D2 domains to properly fold such that the variant stimulates TLR5 activity.

[0052] In some embodiments, the present invention relates to the development of a minimal functional core of a flagellin, for example, deleting residues relative to the already shortened CBLB502 molecule. In some embodiments, the present invention relates to the development of a flagellin-related composition that has altered amino acid identity relative to wild type, including deletions, additions and substitutions, that provide for improved activity. In some embodiments, the flagellin-related composition is derived from CBLB502 (SEQ ID NO: 2). In some embodiments, the flagellin-related composition comprises a truncation in one or more domains. In a further embodiment, the flagellin-related composition comprises a deletion in a N-terminal domain. In yet a further embodiment, the flagellin-related composition comprises a deletion in the ND0 domain. In yet a further embodiment, the flagellin-related composition comprises a deletion of the entire ND0 domain. In a further embodiment, the flagellin-related composition comprises a deletion in a C-terminal domain. In yet another embodiment, the flagellin-related composition comprises a deletion in the CD0 domain. In yet another embodiment, the flagellin-related composition retains amino acids 470-485 of the CD0 domain. In yet a further embodiment, the minimized flagellin-related composition is CBLB502-S33 (SEQ ID NO: 17).

[0053] The flagellin-related compositions may comprise at least 10, 11, 12, or 13 of the 13 conserved amino acids shown in FIG. 1A and FIG. 1B (positions 89, 90, 91, 95, 98, 101, 115, 422, 423, 426, 431, 436 and 452). The flagellin-related compositions may be at least 30-99% identical to amino acids 1-174 and 418-505 of SEQ ID NO: 1.

[0054] In some embodiments, the flagellin-related compositions have improved functional and pharmacological properties which, for example, allow for improved medical effects. In some embodiments, the flagellin-related compositions have improved NF-kB activation and radioprotection relative to CBLB502. In some embodiments, the flagellin-related compositions have improved pharmacokinetics leading to a proportionally stronger pharmacodynamic response (as detected by, for example, cytokine assays).

[0055] In some embodiments, the flagellin-related compositions have improved pharmacological properties, including reduced antigenicity and immunogenicity, which, for example, allows for use in wide variety of disease states and patient types. A reduced antigenicity and immunogenicity expands the medical applications for which the flagellin-related compositions of the invention can be used including, for example, medical applications requiring recurrent administration. In some embodiments, the decreased antigenicity translates to improved resistance against the neutralizing action of preexisting human antibodies (e.g. anti-flagellin) as well as those induced in response to CBLB502 injection. In further embodiments, the flagellin-related compositions have longer retention times in vivo. A longer retention time may allow the composition to be effective with fewer doses or with doses spaced further apart.

[0056] In some embodiments, the flagellin-related composition comprises a tag. In yet a further embodiment, the tag is attached to the N-terminus of the flagellin-related composition. In yet another embodiment, the tag is attached to the C-terminus of the flagellin-related composition.

[0057] In some embodiments, the flagellin-related composition comprises a flexible linker. In a further embodiment, the flexible linker comprises SEQ ID NO: 16. In yet a further embodiment, the flexible linker comprises SEQ ID NO: 242.

[0058] In some embodiments, the flagellin-related compositions comprise or consist of any of the polypeptides or nucleic acids encoding said polypeptides listed in Table 1. In some embodiments, the flagellin-related composition is encoded by the nucleotide sequences listed in Table 1. In a further embodiment, the flagellin-related composition comprises the polypeptides listed in Table 1. In some embodiments, the flagellin-related compositions comprise or consist of polypeptides encoded by either SEQ ID NOs: 69 or 70. In some embodiments, the flagellin-related compositions comprise or consist of the polypeptides of SEQ ID NO: 71, "CBLB543". In some embodiments, the flagellin-related compositions comprise or consist of polypeptides encoded by either SEQ ID NOs: 149 or 151. In some embodiments, the flagellin-related compositions comprise or consist of the polypeptides of SEQ ID NO: 150, "CBLB533". In some embodiments, the flagellin-related compositions may be at least 30-99% identical to the sequences listed in Table 1, for instance, about 50%, or about 60%, or about 70%, or about 805, or about 90%, or about 95%, or about 97%, or about 98%, or about 99%, or about 100% identical to the sequences listed in Table 1.

TABLE-US-00001 TABLE 1 Illustrative Flagellin Compositions SEQ DNA/ ID Construct Name PRT Species Sequence 0001 Wild type PRT Salmonella MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRN dublin ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQ- FNG VKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNGPKEATVGDLKSSFKNVTGYDTYAA GADKYRVDINSGAVVTDAAAPDKVYVNAANGQLTTDDAENNTAVDLFKTTKSTAGTAEAKAIAGAIK GGKEGDTFDYKGVTFTIDTKTGDDGNGKVSTTINGEKVTLTVADIATGAADVNAATLQSSKNVYTSV VNGQFTFDDKTKNESAKLSDLEANNAVKGESKITVNGAEYTANATGDKITLAGKTMFIDKTASGVST LINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADY ATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0002 CBLB502 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSS Sequence GLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATN GTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSL GLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFD SAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0003 T7 Promoter DNA Artificial TAATACGACTCACTATAGGGG (forward) Sequence 0004 FliC AA74-80 DNA Artificial ATTGCGCAGACCACTGAAGG (forward) Sequence 0005 Thrombin PRT Artificial LVPRGS cleavage site Sequence 0006 Enterokinase Artificial DDDDK cleavage site Sequence 0007 NS (N-terminal PRT Artificial SSGLRINSAKDDA spoke region; Sequence Ser32-Ala44) 0008 CS (C-terminal PRT Artificial EDADYA spoke region; Sequence Glu464 to Ala469) 0009 linker PRT Artificial AASAGAGQGGGGSG Sequence 0010 linker PRT Artificial EGKSSGSGSESKST Sequence 0011 linker PRT Artificial GGGRTSSSAASAGAGQGGGGSG Sequence 0012 linker PRT Artificial GPSG Sequence 0013 linker PRT Artificial GSAGSAAGSGEF Sequence 0014 linker PRT Artificial GSPG Sequence 0015 linker PRT Artificial KESGSVSSEQLAQFRSLD Sequence 0016 linker PRT Artificial SPGISGGGGGILDSMG Sequence 0017 Mutant 33-485 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIKGLTQ Mutant S33 Sequence ASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQT QFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINE DAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEV SNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0018 Mutant 33-485 DNA Artificial GCAGATTCTGCAGCAGGCTGGTTGATAATCTGGCGCAGGCTAACCAGG Forward Primer Sequence CBLB485 0019 Mutant 33-485 DNA Artificial TCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTT 502 template Sequence sequence 0020 Mutant 33-485 DNA Artificial CCTGGTTAGCCTGCGCCAGATTATCAACCAGCCTGCTGCAGAATCTGC Reverse Primer Sequence CBLB485 0021 Mutant 33-485 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGAC of 485 Mutant TGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGTCT (T7 Promoter GGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTA to Stop) ATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAAC GGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCG ATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAAT CCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTT GGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCA TGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAAT TGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGAT TCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATG CTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTTGATAA 0022 Mutant 33-485 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIKGLTQ Expressed Sequence ASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQT Mutant 33-485 QFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINE DAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEV SNMSKAQILQQAG 0023 Mutant 45CT PRT Artificial MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRN Mutant 506T Sequence ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNG VKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAA AKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMS KAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDP 0024 Mutant 45CT DNA Artificial ATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGT Mutant 506T Sequence CCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGC GGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAAC GCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGC AGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTAT CCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGT GTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTA CCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGG AATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCA GCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAAC CAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCT AAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACG TCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGG TGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGTAAGTCGACAAGCTTGCG 0025 Mutant 45CT DNA Artificial CGAAAGACCATATGGCAGGCCAGGCGATTGC Forward F45CT Sequence 0026 Mutant 45CT DNA Artificial CGCAAGCTTGTCGACTTACGGATCCTTATCGTC Reverse R45CT Sequence 0027 Mutant 45CT DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTTTAA Sequence of Sequence CTTTAAGAAGGAGATATACATATGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAG 45CT construct GTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCT GAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAAC TCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTT CTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGG TGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGAT GGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACAT TAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGC ATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATT ACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATG CAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCA GGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCAT CATGGTATGGCTAGCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGG ATCCGTAAGTCGAC 0028 Mutant 45CT PRT Artificial MAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKS Expressed Sequence IQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSP Mutant 45CT GISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTV TNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHGMASMT GGQQMGRDLYDDDDKDP 0029 Mutant 33GPS DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Expressed Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC Mutant 33ML CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCGGACCATCAGGTCAGGATGAAATTCAGC AACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCA GGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAA ATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCAC TGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAA CCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGT ATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTG GTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGG TTCTCATCATCATCATCATCATGGTTAA 0030 Mutant 33GPS PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Expressed Sequence TNGTNSDSDLKSIGPSGQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQK Mutant 33ML IDVKSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSR IEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0031 Mutant 33GPS DNA Artificial GATATACATATGAGCGGGTTACGGATCAACAG Forward primer Sequence FSY3CT 0032 Mutant 33GPS DNA Artificial AGATCTCCCGGGGAATTAACATTGAACCC Reverse primer Sequence RMIMxN 0033 Mutant 33GPS DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of mutant GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC 33GPS GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT- GC GTGAGTTGTCTGTTCAGGCCACTGGACCATCAGGTGAAATTCAGCAACGTCTGGAAGAAATCGATCG CGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAG GTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCC TTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATT GTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACC AACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAA CGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGC TAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCAT GGTTAAGTCGAC 0034 Mutant 33GPS PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Expressed Sequence TGPSGEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVN Mutant 33GPS SPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMS KAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0035 Mutant 33ML PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant 33CT Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK (Fixed A) SLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNR FDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGS HHHHHHG 0036 Mutant 33ML DNA Artificial

ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Mutant 33CT Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC (Fixed A) CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAG ACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGC TTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGC TTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCG AAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTAC TTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCT CATCATCATCATCATCATGGTTAA 0037 Mutant 33ML DNA Artificial TCTAGACCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG Forward Sequence primer F502ML 0038 Mutant 33ML DNA Artificial CCAGTCATGTCGACTTAACCATGATGATGATGATGATGAG Reverse Sequence primer R33CT 0039 Mutant 33ML DNA Artificial CTCATCATCATCATCATCATGGTTAAGTCGACAAGCTTGCGGCCGCAGAGCTCGC 502 template Sequence sequence 0040 Mutant 33ML DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC 33ML Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0041 Mutant 33ML DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Expressed Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC Mutant CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAG- GCC 33ML ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAA- G AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTC TGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCA TCATCATCATGGTTAA 0042 Mutant 33ML PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant 33ML Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0043 Mutant 37CT DNA Artificial ATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGT delta ND0 Sequence CCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACGGCGCGAAAGACGATGC mutant GGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG- TAAC based on GCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGC CBLB506T AGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTAT CCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGT GTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTA CCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGG AATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCA GCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAAC CAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCT AAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACG TCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGG TGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGTAAGTCGACAAGCTTGCG 0044 Mutant 37CT PRT Artificial MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINGAKDDAAGQAIANRFTSNIKGLTQASRN delta ND0 Sequence ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNG mutant VKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINE- DAAA based on AKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMS CBLB506T KAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDP 0045 Mutant 37CT DNA Artificial CTCTGGTCATATGATCAACAGCGCGAAAGACGATGC Forward F37CT Sequence 0046 Mutant 37CT DNA Artificial TCTAGAGTCGACTATTAAGCCATACCATGATGATGATGATGATGAG Reverse R37CT Sequence 0047 Mutant 37CT DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTTTAA 37CT Sequence CTTTAAGAAGGAGATATACATATGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTA construct ACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTAT TGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCT GTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAAC GTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGA CAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATT GATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTG GAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAA CCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATT CAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTA GCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCA GGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCG CGGGGTTCTCATCATCATCATCATCATGGTATGGCTTAATAGTCGAC 0048 Mutant 37CT PRT Artificial MINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGT Mutant 37CT Sequence NSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGL DGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSA ITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHH HHGMA 0049 Mutant 445 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIE 502-SY1 Sequence RLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSV QATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKID VKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQ NRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0050 Mutant 445 DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATGGGTC 502-SY1 Sequence GGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGATGGCACAAGTCATTAATACAAA CAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGAG CGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGC GCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTT CAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTC TGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAA CCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGAT GTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAA TTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCC ACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAA AACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCC GTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGC TGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0051 Mutant 445 DNA Artificial GGCAATTCAAAACCGTTTTGATTAAGCCATTACCAACCTTGG Forward Primer Sequence CBLB445 0052 Mutant 445 DNA Artificial CCAAGGTTGGTAATGGCTTAATCAAAACGGTTTTGAATTGCC Reverse Primer Sequence CBLB445 0053 Mutant 445 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC mutant 445 Sequence TTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGAC TGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGATG GCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCT CACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGC AGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCT AACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGC GTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCA GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTT AAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCA TCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAT TTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCC AAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTT CTTCTCTGGGGGCAATTCAAAACCGTTTTGATTAA 0054 Mutant 445 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIE mutant 445 Sequence RLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSV QATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKID VKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQ NRFD 0055 Mutant 461 DNA Artificial CAATCTGAACTCCGCGCGTTGACGTATCTAAGATGCTGACTATGC Forward Primer Sequence CBLB461 0056 Mutant 461 DNA Artificial GCATAGTCAGCATCTTAGATACGTCAACGCGCGGAGTTCAGATTG Reverse Primer Sequence CBLB461 0057 Mutant 461 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Mutant 461 Sequence TTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGAC TGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGATG GCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCT CACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGC AGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCT AACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGC GTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCA GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTT AAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCA TCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAT TTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCC AAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTT CTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAA TCTGAACTCCGCGCGTTGACGTATCTAA 0058 Mutant 461 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIE Mutant 461 Sequence RLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSV QATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKID VKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQ NRFDSAITNLGNTVTNLNSAR 0059 Mutant 467 DNA Artificial CGTAGCCGTATCGAAGATGCTTAATAGGCAACGGAAGTTTCTAATATG Forward Primer Sequence CBLB467 0060 Mutant 467 DNA Artificial CATATTAGAAACTTCCGTTGCCTATTAAGCATCTTCGATACGGCTACG Reverse Primer Sequence CBLB467 0061 Mutant 467 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Mutant 467 Sequence TTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGAC TGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGATG GCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCT CACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGC AGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCT AACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGC GTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCA

GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTT AAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCA TCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAT TTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCC AAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTT CTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAA TCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTTAATAG 0062 Mutant 467 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIE Mutant 467 Sequence RLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSV QATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKID VKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQ NRFDSAITNLGNTVTNLNSARSRIEDA 0063 Mutant 470CT DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATGGGTC CBLB502 Sequence GGGATCTGTACGACGATGACGATAAGGATCCGATGGCACAAGTCATTAATACAAACAGCCTGTCGCT GTTGACCCAGAATAACCTGAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCT GGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTA ATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAAC GGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCG ATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAAT CCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTT GGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCA TGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAAT TGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGAT TCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATG CTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGT TCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0064 Mutant 470CT DNA Artificial CGATAAGGATCATATGGCACAAGTCATTAATAC Forward Primer Sequence F470CT 0065 Mutant 470CT DNA Artificial AGATCTGTCGACTTAACCATGATGATGATGATGATGAGAACCCCGCGGAACCAGTGCATAGTCAGCA Reverse Primer Sequence TCTTCGATACG R470CT 0066 Mutant 470CT DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Mutant 470CT Sequence TTTAAGAAGGAGATATACATATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAA TAACCTGAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATC AACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTC TGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAA TGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCT GATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTA ATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGC TAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGG TTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAA TCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATT GTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACC AACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAC TGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0067 Mutant 470CT PRT Artificial MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRN Mutant 470CT Sequence ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNG VKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAA AKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYALVPRGSH HHHHHG 0068 Mutant 485CT DNA Artificial AGATCTCCGCGGAACCAGACCAGCCTGCTGCAGAATCTGC Reverse primer Sequence R485MC 0069 Mutant 485CT DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of 485CT GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0070 Mutant 485CT DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Mutant 485CT Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCTGGTTCCGC GGGGTTCTCATCATCATCATCATCATGGTTAA 0071 Mutant 485CT PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant 485CT Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGLVPRGSHHHHHHG 0072 Mutant 485D DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAA DNA template Sequence TTCAAAACCGTTTTGATTCAGCCATTACCGCCCTTGGCAATACGGTAACCAAT for deletion mutations from Mutant 485CT variant 0073 Mutant 485D PRT Artificial NPLASIDSALSKVDAVRSSLGAIQNRFDSAITALGNTVTN PRT sequence Sequence for deletion mutations from Mutant 485CT variant 0074 Mutant 485D DNA Artificial GTTCGTTCTTCTCTGGGGGCAATTGATTCAGCCATTACCGCCCTTG Forward Primer Sequence F485D 0075 Mutant 485D DNA Artificial CAAGGGCGGTAATGGCTGAATCAATTGCCCCCAGAGAAGAACGAAC Reverse Primer Sequence R485D 0076 Mutant 485D DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC 485CT_Delta GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC construct GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTGATTCAGCCATTACCGCCCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCG AAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCT GGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0077 Mutant 485D PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant 485D Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK (CT_Delta SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIDSAITALGNTVTNLNSARSRIEDADYAT 439-442) EVSNMSKAQILQQAGLVPRGSHHHHHHG 0078 Mutant CGD1 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Mutant SY3CT Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0079 Mutant CGD1 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant SY3CT Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYALVPRGSHHHHHHG 0080 Mutant CGD1 DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGATGTTA GFPuv4 Sequence ATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTTACCCTTAA ATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTCTGACGTATGGT GTTCAATGCTTTTCCCGTTATCCGGATCATATGAAACGGCATGACTTTTTCAAGAGTGCCATGCCCG AAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACTACAAGACGCGTGCTGAAGT CAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTATTGATTTTAAAGAAGATGGA AACATTCTCGGACACAAACTCGAGTACAACTATAACTCACACAATGTATACATCACGGCAGACAAAC AAAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCACAACATTGAAGATGGATCCGTTCAACTAGC AGACCATTATCAACAAAATACTCCAATTGGCGATGGCCCTGTCCTTTTACCAGACAACCATTACCTG TCGACACAATCTGCCCTTTTGAAAGATCCCAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTTG TAACTGCTGCTGGGATTACACATGGCATGGATGAACTATACAAA 0081 Mutant CGD1 PRT Artificial MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTYG GFPuv4 Sequence VQCFSRYPDHMKRHDFFKSAMPEGYVQERTISFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDG NILGHKLEYNYNSHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYL STQSALLKDPNEKRDHMVLLEFVTAAGITHGMDELYK 0082 Mutant CGD1 DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGATGTTA GFPuv4 Sequence ATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTTACCCTTAA mutation ATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTCTGACGTATGGT of wt GTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTTTTTCAAGAGTGCCATGC- CCG NdeI site AAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACTACAAGACGCGTGCTGAAGT CAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTATTGATTTTAAAGAAGATGGA AACATTCTCGGACACAAACTCGAGTACAACTATAACTCACACAATGTATACATCACGGCAGACAAAC AAAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCACAACATTGAAGATGGATCCGTTCAACTAGC AGACCATTATCAACAAAATACTCCAATTGGCGATGGCCCTGTCCTTTTACCAGACAACCATTACCTG TCGACACAATCTGCCCTTTTGAAAGATCCCAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTTG TAACTGCTGCTGGGATTACACATGGCATGGATGAACTATACAAATAA 0083 Mutant CGD1 DNA Artificial TCTAGACGGCCGATCTCAGGTAAGAATGGAATCAAAGCTAACTTCAAAATTCGC Forward primer Sequence FCGFP 0084 Mutant CGD1 PRT Artificial NVYIPISGKNGIKANFKIRH PRT altered Sequence GFPuv4 sequence 0085 Mutant CGD1 DNA Artificial AGATCTCCGCGGTTTGTATAGTTCATCCATGCCATGTGTAATCCC Reverse RCGFP Sequence 0086 Mutant CGD1 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of CGD1 GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCCGATCTCAGGTAAGAATGGAATCAAAGC TAACTTCAAAATTCGCCACAACATTGAAGATGGATCCGTTCAACTAGCAGACCATTATCAACAAAAT ACTCCAATTGGCGATGGCCCTGTCCTTTTACCAGACAACCATTACCTGTCGACACAATCTGCCCTTT TGAAAGATCCCAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTAC ACATGGCATGGATGAACTATACAAACCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC

0087 Mutant CGD1 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Expressed Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC Mutant CGD1 CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCACTGGTTCCGCCGATCTCAGGTAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCACA ACATTGAAGATGGATCCGTTCAACTAGCAGACCATTATCAACAAAATACTCCAATTGGCGATGGCCC TGTCCTTTTACCAGACAACCATTACCTGTCGACACAATCTGCCCTTTTGAAAGATCCCAACGAAAAG CGTGACCACATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTACACATGGCATGGATGAACTAT ACAAACCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0088 Mutant CGD1 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Expressed Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK Mutant CGD1 SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYALVPPISGKNGIKANFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQSALLKDPNEK RDHMVLLEFVTAAGITHGMDELYKPRGSHHHHHHG 0089 Mutant CPM194 DNA Artificial ATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTT Mutant CPM194 Sequence CTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCT GAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCATCCCCGGGAAGCGGGTTACGGATCAAC AGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGA CTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGA AATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGAT TCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAA CGATGGTCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0090 Mutant CPM194 PRT Artificial MSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYASPGSGLRIN Mutant CPM194 Sequence SAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSD SDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGLVPRGSHHHHHHG 0091 Mutant CPM194 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Mutant CPM194 Sequence TTTAAGAAGGAGATATACATATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAA AGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTT GGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCATCCCCGG GAAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCAC TTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACC ACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCA CTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGA AATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATG AAAATCCAGGTTGGTGCTAACGATGGTCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTT AAGTCGAC 0092 Mutant CPM194 DNA Artificial TCTAGACATATGAGTACCGCTAACCCACTGGCTTCAATTG Forward primer Sequence FCD1 0093 Mutant CPM194 DNA Artificial GCTTCCCGGGGATGCATAGTCAGCATCTTCGATACGGC Reverse primer Sequence RCD1J 0094 Mutant CPM194 DNA Artificial GCATCCCCGGGAAGCGGGTTACGGATCAACAGCG Forward primer Sequence FND1J 0095 Mutant CPM194 DNA Artificial AGATCTCCGCGGAACCAGACCATCGTTAGCACCAACCTGGATTTTCATCT Reverse primer Sequence RND1 0096 Mutant CPM217 DNA Artificial ATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTT Mutant CPM217 Sequence CTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCT GAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCATCCCCGGGAAGCGGGTTACGGATCAAC AGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGA CTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGA AATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGAT TCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAA CGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTC AATGTTAATCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0097 Mutant CPM217 PRT Artificial MSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYASPGSGLRIN Mutant CPM217 Sequence SAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSD SDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGF NVNLVPRGSHHHHHHG 0098 Mutant CPM217 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Mutant CPM217 Sequence TTTAAGAAGGAGATATACATATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAA AGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTT GGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCATCCCCGG GAAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCAC TTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACC ACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCA CTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGA AATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATG AAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAA GCCTTGGCCTTGATGGGTTCAATGTTAATCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGG TTAAGTCGAC 0099 Mutant CPM217 DNA Artificial AGATCTCCGCGGAACCAGATTAACATTGAACCCATCAAGGCCAAG Reverse primer Sequence RCPM217 0100 Mutant GD1G DNA Artificial CCCGTTATCCGGATCACATGAAACGGCATGACTTTTTC Forward Primer Sequence FGFP77 0101 Mutant GD1G DNA Artificial GAAAAAGTCATGCCGTTTCATGTGATCCGGATAACGGG Reverse Primer Sequence RGFP77 0102 Mutant GD1G DNA Artificial CTGTTCCATGGCCAACACTTG FGFP54 Sequence 0103 Mutant GD1G DNA Artificial TCTAGACATATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCC Forward primer Sequence FNGFP 0104 Mutant GD1G DNA Artificial GGCCTATGCGGCCGCAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAA altered GFP Sequence DNA sequence 0105 Mutant GD1G DNA Artificial AGATCTATTAATGCGGCCTGATAGGCCTTGTTTGTCTGCCGTGATGTATACATTGTG Reverse RNGFP Sequence 0106 Mutant GD1G PRT Artificial SHNVYITADKQGLSGRNM altered GFP Sequence PRT sequence 0107 Mutant GD1G DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGT of GD1G TGAATTAGATGGTGATGTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACA construct TACGGAAAACTTACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTG TCACTACTCTGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTT TTTCAAGAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAAC TACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTA TTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGTACAACTATAACTCACACAATGT ATACATCACGGCAGACAAACAAGGCCTATCAGGCCGCATTATGAGCGGGTTACGGATCAACAGCGCG AAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGG CTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAA CAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGAT CTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTC AATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGG TGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTT AATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAG TTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGT AACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCCGATCTCA GGTAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCACAACATTGAAGATGGATCCGTTCAACTAG CAGACCATTATCAACAAAATACTCCAATTGGCGATGGCCCTGTCCTTTTACCAGACAACCATTACCT GTCGACACAATCTGCCCTTTTGAAAGATCCCAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTT GTAACTGCTGCTGGGATTACACATGGCATGGATGAACTATACAAACCGCGGGGTTCTCATCATCATC ATCATCATGGTTAAGTCGAC 0108 Mutant GD1G DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGATGTTA Expressed Sequence ATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTTACCCTTAA Mutant GD1G ATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTCTGACGTATGGT GTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTTTTTCAAGAGTGCCATGCCCG AAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACTACAAGACGCGTGCTGAAGT CAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTATTGATTTTAAAGAAGATGGA AACATTCTCGGACACAAACTCGAGTACAACTATAACTCACACAATGTATACATCACGGCAGACAAAC AAGGCCTATCAGGCCGCATTATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCCGATCTCAGGTAAGAATGGAATCAAAGC TAACTTCAAAATTCGCCACAACATTGAAGATGGATCCGTTCAACTAGCAGACCATTATCAACAAAAT ACTCCAATTGGCGATGGCCCTGTCCTTTTACCAGACAACCATTACCTGTCGACACAATCTGCCCTTT TGAAAGATCCCAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTAC ACATGGCATGGATGAACTATACAAACCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0109 Mutant GD1G PRT Artificial MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTYG Expressed Sequence VQCFSRYPDHMKRHDFFKSAMPEGYVQERTISFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDG Mutant GD1G NILGHKLEYNYNSHNVYITADKQGLSGRIMSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAND GISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKV LSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGA IQNRFDSAITNLGNTVTNLNSARSRIEDADYALVPPISGKNGIKANFKIRHNIEDGSVQLADHYQQN TPIGDGPVLLPDNHYLSTQSALLKDPNEKRDHMVLLEFVTAAGITHGMDELYKPRGSHHHHHHG 0110 Mutant MF227C DNA Artificial CTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTACATTAA mutant 470CT Sequence TCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTG template 0111 Mutant MF227C PRT Artificial LGLDGFNVNSPGISGGGGGITLINEDAAAAKKSTANPLASI mutant 470CT Sequence template 0112 Mutant MF227C DNA Artificial AGATCTCCGCGGAACCAGTAAAGAGAGGACGTTTTGCGGAACCTGGTTTGCATAGTCAGCATCTTCG Reverse Primer Sequence ATACG R2YY 0113 Mutant MF227C DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of Mutant GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC MF227C GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTG- TGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCC GCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0114 Mutant MF227C DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Mutant MF227C Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT

GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATC ATCATCATGGTTAA 0115 Mutant MF227C PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant MF227C Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYANQVPQNVLSLLVPRGSHHHHHHG 0116 Mutant MF227N DNA Artificial AGATCTCCCGGGGAACCATCGTTAGCACCAACCTGGATTTTC Reverse Primer Sequence RMF227N 0117 Mutant MF227N DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of mutant GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC MF227N GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTG- TGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTTCCCCGGGAAGTACCGCTA ACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAAT TCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGT AGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGC AGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCC GCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0118 Mutant MF227N DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA mutant MF227N Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGAT TCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAG CCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGA CTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTG GCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATC ATCATCATGGTTAA 0119 Mutant MF227N PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA mutant MF227N Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGSPGSTANPLASID SALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVL AQANQVPQNVLSLLVPRGSHHHHHHG 0120 Mutant MF233 DNA Artificial AGATCTCCGCGGAACCAGCAGGTTATTCTGGGTCAACAGCGACAGGCTGTTTGTATTAATGACTTGT Reverse primer Sequence GCATAGTCAGCATCTTCGATACG RMF233 0121 Mutant MF233 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC MF233 GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT- GC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCA GAATAACCTGCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0122 Mutant MF233 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA MF233 Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGCTGGTTCCGC GGGGTTCTCATCATCATCATCATCATGGTTAA 0123 Mutant MF233 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA MF233 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYAQVINTNSLSLLTQNNLLVPRGSHHHHHHG 0124 Mutant MF471 DNA Artificial GCTGACTATGCAACGGCAGTTTCTGCTATGTCTGCAGCGCAGATTCTGC Forward primer Sequence F471-77 0125 Mutant MF471 DNA Artificial GCAGAATCTGCGCTGCAGACATAGCAGAAACTGCCGTTGCATAGTCAGC Reverse Primer Sequence R471-77 0126 Mutant MF471 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC MF471 GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT- GC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGCAGTTTCTGCTATGTCTGCAGCGCAGATTCTGCA GCAGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0127 Mutant MF471 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA MF471 Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGCAGTTTCTGCTATGTCTGCAGCGCAGATTCTGCAGCAGGCTGGTCTGGTTCCGC GGGGTTCTCATCATCATCATCATCATGGTTAA 0128 Mutant MF471 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA MF471 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATAVSAMSAAQILQQAGLVPRGSHHHHHHG 0129 Mutant MF479 DNA Artificial GTTTCTAATATGTCTAAAGCGGCGATTCTGGGAGCGGCTGGTCTGGTTCCGCGG Forward primer Sequence F479-83 0130 Mutant MF479 DNA Artificial CCGCGGAACCAGACCAGCCGCTCCCAGAATCGCCGCTTTAGACATATTAGAAAC Reverse Primer Sequence R479-83 0131 Mutant MF479 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC MF479 GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT- GC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGGCGATTCTGGG AGCGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0132 Mutant MF479 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Mutant MF479 Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGGCGATTCTGGGAGCGGCTGGTCTGGTTCCGC GGGGTTCTCATCATCATCATCATCATGGTTAA 0133 Mutant MF479 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant MF479 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAAILGAAGLVPRGSHHHHHHG 0134 Mutant N45 DNA Artificial TCTAGAGGATCCGGCAGGCCAGGCG Forward Sequence primer N45_F 0135 Mutant N45 DNA Artificial CGCAAGCTTGTCGACTTAACGC Reverse Sequence R502D0 0136 Mutant N45 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGAC of Mutant TGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGGCA N45 GGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTA ACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCG TGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAG GATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTA AAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCAT CGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATT TCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCA AGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTC TTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAAT CTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAG CGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCT CTCTTTACTGCGTTAAGTCGACAAGCTTGCGG 0137 Mutant N45 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPAGQAIANRFTSNIKGLTQASRNANDGISIA Mutant N45 Sequence QTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDN QMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANP LASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQA GTSVLAQANQVPQNVLSLLR 0138 Mutant NGD1 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGT of NGD1 TGAATTAGATGGTGATGTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACA construct TACGGAAAACTTACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTG TCACTACTCTGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTT TTTCAAGAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAAC TACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTA TTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGTACAACTATAACTCACACAATGT ATACATCACGGCAGACAAACAAGGCCTATCAGGCCGCATTATGAGCGGGTTACGGATCAACAGCGCG AAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGG CTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAA CAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGAT CTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTC AATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGG TGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTT

AATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAG TTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGT AACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCGGGGTTCT CATCATCATCATCATCATGGTTAAGTCGAC 0139 Mutant NGD1 DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGATGTTA Expressed Sequence ATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTTACCCTTAA Mutant ATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTCTGACGTA- TGGT SY3-GFP GTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTTTTTCAAGAGTGCCATG- CCCG AAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACTACAAGACGCGTGCTGAAGT CAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAGGTATTGATTTTAAAGAAGATGGA AACATTCTCGGACACAAACTCGAGTACAACTATAACTCACACAATGTATACATCACGGCAGACAAAC AAGGCCTATCAGGCCGCATTATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGG TTAA 0140 Mutant NGD1 PRT Artificial MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTYG Expressed Sequence VQCFSRYPDHMKRHDFFKSAMPEGYVQERTISFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFKEDG Mutant SY3- NILGHKLEYNYNSHNVYITADKQGLSGRIMSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAND GFP/Mutant GISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKV NGD1 LSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLG- A IQNRFDSAITNLGNTVTNLNSARSRIEDADYALVPRGSHHHHHHG 0141 Mutant S33 DNA Artificial TCTAGAGGATCCGTCTGGTCTGCGTATCAACAGCGC Forward Sequence F502_S33 0142 Mutant S33 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGAC of Mutant TGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGTCT S33 GGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTA ATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAAC GGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCG ATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAAT CCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTT GGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCA TGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAAT TGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGAT TCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATG CTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGT TCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAAGTCGAC 0143 Mutant S33 DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATGGGTC Mutant S33 Sequence GGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGTCTGGTCTGCGTATCAACAGCGC GAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAG GCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCA ACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGA TCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACT CAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATG GTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGT TAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAA GACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAG TGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGG CAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTT TCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGG TTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0144 Mutant S33 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIKGLTQ Mutant S33 Sequence ASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQT QFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINE DAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEV SNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0145 Mutant SY3CT DNA Artificial AGATCTCCGCGGAACCAGTGCATAGTCAGCATCTTCGATACGGC Reverse primer Sequence RSY3CT 0146 Mutant SY3CT DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of SY3CT GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGG TTAAGTCGAC 0147 Mutant SY3CT DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Expressed Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC Mutant CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAG- GCC SY3CT ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGA- AG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0148 Mutant SY3CT PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Expressed Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK Mutant SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRI- EDA SY3CT DYALVPRGSHHHHHHG 0149 Mutant 33MX DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Mutant 33MX Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGACGGCATTTCTATTGCGCAGAC CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTCAGCAGACTCAAGCTGCCGCTGTTAAAGTCCTGTCTCAGGACAACGCAAT GGCAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTC TGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCA TCATCATCATGGTTAA 0150 Mutant 33MX PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAADGISIAQTTEGALNEINNNLQRVRELSVQA Mutant 33MX Sequence TAGANADAALKAIQAEIQQRLEEIDRVSQQTQAAAVKVLSQDNAMAIQVGANDGAAITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSQMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0151 Mutant 33MX DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of 33MX GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGC- AGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTCAGCAGACTCAAGCTGCCGCTGTTAAAGTC CTGTCTCAGGACAACGCAATGGCAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0152 Mutant 485MX DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA Sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of 485MX GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTCAGCAGACTCAAGCTGCCGCTGTTAAAGTC CTGTCTCAGGACAACGCAATGGCAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0153 Mutant 485MX DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA 485MX Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGACGGCATTTCTATTGCGCAGAC construct CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTCAGCAGACTCAAGCTGCCGCTGTTAAAGTCCTGTCTCAGGACAACGCAAT GGCAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCTGGTTCCGC GGGGTTCTCATCATCATCATCATCATGGTTAA 0154 Mutant 485MX PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAADGISIAQTTEGALNEINNNLQRVRELSVQA 485MX Sequence TAGANADAALKAIQAEIQQRLEEIDRVSQQTQAAAVKVLSQDNAMAIQVGANDGAAITIDLQKIDVK construct SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSQMSKAQILQQAGLVPRGSHHHHHHG 0155 Mutant MIM4 DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATGGGTC CBLB502 Sequence GGGATCTGTACGACGATGACGATAAGGATCCGATGGCACAAGTCATTAATACAAACAGCCTGTCGCT variant GTTGACCCAGAATAACCTGCAGAAATCTCAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTC- CTCT GGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTA ATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTCAA GGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCG ATCGCGTTTCTCAGCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAAT CCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTT GGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCA TGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAAT TGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGAT TCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATG CTGACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGT TCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0156 Mutant MIM4 DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAA Primers design Sequence TTCAAAACCGTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGCCTCCGCGCG (for deletion TAGCGCTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATG aa Gln439; Asn440; Arg441; Phe442): 0157 Mutant MIM4 PRT Artificial NPLASIDSALSKVDAVRSSLGAIQNRFDSAITALGATVTALASARSAIEDADYATEVSNM Primers design Sequence (for deletion aa Gln439; Asn440; Arg441; Phe442): 0158 Mutant MIM4 DNA Artificial GCAGTTCGTTCTTCTCTGGGGGCAATTGATTCAGCCATTACCGCCCTTGG

Forward Primer Sequence MIM4 0159 Mutant MIM4 DNA Artificial CCAAGGGCGGTAATGGCTGAATCAATTGCCCCCAGAGAAGAACGAACTGC Reverse Primer Sequence MIM4 0160 Mutant MIM4 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTTTAA MIM4 Sequence CTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGA CTGGTGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGATGGCACAAGTCAT TAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCTCACTGAGTTCC GCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGA TTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCAT TTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTC AGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTC TCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAA AAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTG GTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTAC CGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGG GCAATTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGCCTCCGCGGCTAGCCGTA TCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGG TACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0161 Mutant MIM4 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSS MIM4 Sequence GLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATN GTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSL GLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIDSAIT ALGATVTALASAASRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0162 Mutant MIM5 DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAA Primers design Sequence TTGCAAAGGCTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGCCTCCGCGCG (mutations TAGCGCTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATG Gln439Ala; Asn440Lys; Arg441Ala): 0163 Mutant MIM5 PRT Artificial NPLASIDSALSKVDAVRSSLGAIAKAFDSAITALGATVTALASARSAIEDADYATEVSNM Primers design Sequence (mutations Gln439Ala; Asn440Lys; Arg441Ala): 0164 Mutant MIM5 DNA Artificial CGTTCTTCTCTGGGGGCAATTGCAAAGGCTTTTGATTCAGCCATTACCGC Forward Primer Sequence MIM5 0165 Mutant MIM5 DNA Artificial GCGGTAATGGCTGAATCAAAAGCCTTTGCAATTGCCCCCAGAGAAGAACG Reverse Primer Sequence MIM5 0166 Mutant MIM5 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTTTAA MIM5 Sequence CTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGA CTGGTGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGATGGCACAAGTCAT TAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCTCACTGAGTTCC GCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGA TTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCAT TTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTC AGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTC TCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAA AAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTG GTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTAC CGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGG GCAATTGCAAAGGCTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGCCTCCG CGGCTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCT GCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTG CGTTAA 0167 Mutant MIM5 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSS MIM5 Sequence GLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATN GTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSL GLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIAKAFD SAITALGATVTALASAASRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0168 Mutant MIMX DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATGGGTC Mutant 33MIMX Sequence GGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGTCTGGTCTGCGTATCAACAGCGC GAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAG GCTTCCCGTAACGCTGCAGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCA ACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGA TCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACT CAAGCTAACGGTGTTAAAGTCCTGTCTCAGGACAACGCAATGAAAATCCAGGTTGGTGCTAACGATG GTGCCGCTATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGT TAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAA GACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAG TGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAGCTCGTTTTGCCGCGGCCATTGCTAACCTTGG CAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTT TCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGG TTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0169 Mutant MIMX PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIKGLTQ MIMx Sequence ASRNAADGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQT QANGVKVLSQDNAMKIQVGANDGAAITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINE DAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQARFAAAIANLGNTVTNLNSARSRIEDADYATEV SNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0170 Mutant MIMX DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGAC of 33MIMx TGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGTCT GGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTA ATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAAC GGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCG ATCGCGTTTCTAATCAGACTCAAGCTAACGGTGTTAAAGTCCTGTCTCAGGACAACGCAATGAAAAT CCAGGTTGGTGCTAACGATGGTGCCGCTATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTT GGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCA TGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAAT TGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAGCTCGTTTTGCC GCGGCCATTGCTAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATG CTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGT TCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAAGTCGAC 0171 Mutant MIXC DNA Artificial AGATCTGTCGACTTAACCATGATGATGATGATGATGAGAACCCCGCGGAACCAGTAAAGAGAGGACG Reverse primer Sequence TTTTGCGGAACC RMIXC 0172 Mutant MIXC DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of MIXC GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAA- CGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAGCTCGTTTTGCCGCGGCCATTGCTAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0173 Mutant MIXC PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA MIXC Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQARFAAAIANLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0174 Mutant MIXN DNA Artificial AGATCTCATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGC Forward primer Sequence FMIMxN 0175 Mutant MIXN DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC DNA sequence Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA of MIX.N GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAAGCTAACGGTGTTAAAGTC CTGTCTCAGGACAACGCAATGAAAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0176 Mutant MIXN PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAADGISIAQTTEGALNEINNNLQRVRELSVQA Expressed Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQANGVKVLSQDNAMKIQVGANDGAAITIDLQKIDVK Mutant SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRI- EDA MIX.N DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0177 Mutants MIM1; DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAA MIM2 and MIM3 Sequence TTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCG 502 Mutants TAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCAG MIM1; MIM2 and CAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTT MIM3 C- AA terminal part of CBLB502 0178 Mutants MIM1; DNA Artificial ATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGAT MIM2 and MIM3 Sequence Primers design (mutant MIM1) 0179 Mutants MIM1; PRT Artificial ITNLGNTVTNLNSARSRIED MIM2 and MIM3 Sequence Primers design (mutant MIM1) 0180 Mutants MIM1; DNA Artificial CCTTGGCAATACGGTAACCGCTCTGGCCTCCGCGCGTAGCCGTATC MIM2 and MIM3 Sequence Forward Primer 455-57 0181 Mutants MIM1; DNA Artificial GATACGGCTACGCGCGGAGGCCAGAGCGGTTACCGTATTGCCAAGG MIM2 and MIM3 Sequence Reverse Primer 455-57 0182 Mutants MIM1; DNA Artificial ACGGTAACCGCTCTGGCCTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAA MIM2 and MIM3 Sequence Primers design (mutant MIM2_MIM1 plus R460A) 0183 Mutants MIM1; PRT Artificial TVTALASARSRIEDADYATE MIM2 and MIM3 Sequence Primers design (mutant MIM2_MIM1 plus R460A) 0184 Mutants MIM1; DNA Artificial GCTCTGGCCTCCGCGGCTAGCCGTATCGAAGATG MIM2 and MIM3 Sequence Forward Primer 460 0185 Mutants MIM1; DNA Artificial CATCTTCGATACGGCTAGCCGCGGAGGCCAGAGC MIM2 and MIM3 Sequence Reverse Primer

460 0186 Mutants MIM1; DNA Artificial CAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCGCTCTGGCCTCC MIM2 and MIM3 Sequence Primers design (mutant MIM3_MIM2 plus N448A; N451A) 0187 Mutants MIM1; PRT Artificial QNRFDSAITNLGNTVTALAS MIM2 and MIM3 Sequence Primers design (mutant MIM3_MIM2 plus N448A; N451A) 0188 Mutants MIM1; DNA Artificial GTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGG MIM2 and MIM3 Sequence Forward Primer 448-51 0189 Mutants MIM1; DNA Artificial CCAGAGCGGTTACCGTAGCGCCAAGGGCGGTAATGGCTGAATCAAAAC MIM2 and MIM3 Sequence Reverse Primer 448-51 0190 Mutant ME42 DNA Artificial CAACAGCGCGAAAGCCGATGCGGGAGGCCAGGCGATTGC Forward Primer Sequence ME42 0191 Mutant ME42 DNA Artificial GCAATCGCCTGGCCTCCCGCATCGGCTTTCGCGCTGTTG Reverse Primer Sequence ME42 0192 Mutant ME42 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGCCGATGCGGGAGGCCA ME42 construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0193 Mutant ME42 PRT Artificial MSGLRINSAKADAGGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME42 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0194 Mutant ME110 DNA Artificial GTCTGTTCAGGCCACTGCCGGGGCTAACTCTGATTCCGATCTG Forward Primer Sequence ME100 0195 Mutant ME110 DNA Artificial CAGATCGGAATCAGAGTTAGCCCCGGCAGTGGCCTGAACAGAC Reverse Primer Sequence ME100 0196 Mutant ME110 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME100 GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAAC- GAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0197 Mutant ME110 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME110 Sequence TAGANSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0198 Mutant DNA Artificial CTGATTCCGATCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTC ME100/110 Sequence Forward Primer ME110 0199 Mutant DNA Artificial GACGTTGCTGAATTTCAGCCTGGATAGCTTTCAGATCGGAATCAG ME100/110 Sequence Reverse Primer ME110 0200 Mutant DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC ME100/110 Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA Sequence of GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC ME100/110 GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC construct GTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACTCTGATTCCGATCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0201 Mutant ME104N DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Intermediate Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC Mutant CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCA- GGCC ME100/110 ACTGCCGGGGCTAACTCTGATTCCGATCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAG AAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTC TGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCA TCATCATCATGGTTAA 0202 Mutant PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA ME100/110 Sequence TAGANSDSDLKAIQAEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK Mutant SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSR- IEDA ME110/110 DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0203 Mutant ME104 DNA Artificial GCCACTAACGGGACTAACGCTGATGCCGCTCTGAAATCTATCCAG Forward Primer Sequence ME104 0204 Mutant ME104 DNA Artificial CTGGATAGATTTCAGAGCGGCATCAGCGTTAGTCCCGTTAGTGGC Reverse Primer Sequence ME104 0205 Mutant ME104 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME104 GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAAC- GAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACGCTGATGCCGCTCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0206 Mutant ME104 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME104 Sequence TNGTNADAALKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0207 Mutant ME104N DNA Artificial GCCACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAG Primer Sequence FME104New 0208 Mutant ME104N DNA Artificial CTGGATAGCTTTCAGAGCGGCATCAGCGTTAGCCCCGGCAGTGGC Primer Sequence RME104New 0209 Mutant ME104N DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC ME104New GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0210 Mutant ME104N PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME104N Sequence TAGANADAALKAIQAEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0211 Mutant ME110 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME110 GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAAC- GAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0212 Mutant ME110 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME110 Sequence TNGTNSDSDLKAIQAEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0213 Mutant ME117 DNA Artificial CTATCCAGGATGAAATTCAGGCACGTCTGGCAGAAATCGATCGCG Forward Primer Sequence ME117

0214 Mutant ME117 DNA Artificial CGCGATCGATTTCTGCCAGACGTGCCTGAATTTCATCCTGGATAG Reverse Primer Sequence ME117 0215 Mutant ME117 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA 33ML construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC (should this GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC say ME117?) GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGGCACGTCTGGCAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0216 Mutant ME117 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME117 Sequence TNGTNSDSDLKSIQDEIQARLAEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0217 Mutant ME124 DNA Artificial GGAAGAAATCGATGCCGTTTCTGCTGCGACTCAATTTAACGGTGTTAAAGTCCTGTCTC Forward Primer Sequence ME104 0218 Mutant ME124 DNA Artificial GAGACAGGACTTTAACACCGTTAAATTGAGTCGCAGCAGAAACGGCATCGATTTCTTCC Reverse Primer Sequence ME104 0219 Mutant ME124 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME124 construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATGCCGTTTCTGCTGCGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0220 Mutant ME124 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME124 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDAVSAATQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0221 Mutant ME124P DNA Artificial CAGCAACGTCTGGAAGAAATCGATGCCGTTTCTAATCAGACTCAATTTAACGG Forward Primer Sequence ME124P 0222 Mutant ME124P DNA Artificial CCGTTAAATTGAGTCTGATTAGAAACGGCATCGATTTCTTCCAGACGTTGCTG Reverse Primer Sequence ME124P 0223 Mutant ME124 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCA Expressed Sequence CTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGAC Mutant ME124P CACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCC ACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAG AAATCGATGCCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGAT GAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAA AGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG ATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTC AGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTC TGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCA TCATCATCATGGTTAA 0224 Mutant ME124P DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC ME124P Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATGCCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0225 Mutant ME124P PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA ME124P Sequence TNGTNSDSDLKSIQDEIQQRLEEIDAVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0226 Mutant ME132 DNA Artificial CGTTTCTAATCAGACTCAATTTGCCGCTGTTAAAGTCCTGTCTCAGGACAACC Forward Primer Sequence ME132 0227 Mutant ME132 DNA Artificial GGTTGTCCTGAGACAGGACTTTAACAGCGGCAAATTGAGTCTGATTAGAAACG Reverse Primer Sequence ME132 0228 Mutant ME132 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME132 construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTGCCGCTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0229 Mutant ME132 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME117 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFAAVKVLSQDNQMKIQVGANDGETITIDLQKIDVK (ME132?) SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0230 Mutant ME142 DNA Artificial GTTAAAGTCCTGTCTCAGGACAACGCGATGGCAATCCAGGTTGGTGCTAACG Forward Primer Sequence ME142 0231 Mutant ME142 DNA Artificial CGTTAGCACCAACCTGGATTGCCATCGCGTTGTCCTGAGACAGGACTTTAAC Reverse Primer Sequence ME142 0232 Mutant ME142 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME142 construct GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGAC GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACGCGATGGCAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0233 Mutant ME142 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME142 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNAMAIQVGANDGETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0234 Mutant ME150 DNA Artificial GATGAAAATCCAGGTTGGTGCTAGCGCTGCTGAAACCATTACCATCGATCTGC Forward Primer Sequence ME150 0235 Mutant ME150 DNA Artificial GCAGATCGATGGTAATGGTTTCAGCAGCGCTAGCACCAACCTGGATTTTCATC Reverse Primer Sequence ME150 0236 Mutant ME150 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME150 GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAAC- GAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAGCGCTGCTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0237 Mutant ME150 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME150 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGASAAETITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0238 Mutant ME468 DNA Artificial GCCGTATCGAAGATGCTGACGCTGGAGCGGAAGTTGCTAATATGTCTAAAGCGCAG Forward Primer Sequence ME468 0239 Mutant ME468 DNA Artificial CTGCGCTTTAGACATATTAGCAACTTCCGCTCCAGCGTCAGCATCTTCGATACGGC Reverse Primer Sequence ME468 0240 Mutant ME468 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTTAAC Sequence of Sequence TTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA ME468 GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAAC- GAC construct GGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGC GTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTC CTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGC TAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCA ATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGC GTAGCCGTATCGAAGATGCTGACGCTGGAGCGGAAGTTGCTAATATGTCTAAAGCGCAGATTCTGCA GCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0241 Mutant ME468 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQA Mutant ME468 Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVK

SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DAGAEVANMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0242 Linker PRT Artificial SPG Sequence

Uses of Flagellin-Related Compositions

[0059] In some embodiments, the flagellin-related compositions may stimulate Toll-like receptor activity (e.g. TLR1, and/or TLR2, and/or TLR3, and/or TLR4, and/or TLR5, and/or TLR6, and/or TLR7, and/or TLR8, and/or TLR9, and/or TLR10, and/or TLR11, and/or TLR12, and/or TLR13). The TLR family is composed of at least 10 members and is essential for innate immune defense against pathogens. The innate immune system recognizes conserved pathogen-associated molecular patterns (PAMPs). TLR may recognize a conserved structure that is particular to bacterial flagellin which may be composed of a large group of residues that are somewhat permissive to variation in amino acid content. Smith et al., Nat. Immunol. 4:1247-53 (2003) have identified 13 conserved amino acids in flagellin that are part of the conserved structure recognized by TLR5. The 13 conserved amino acids of flagellin that may be important for TLR5 activity are shown in FIGS. 1A and 1B.

[0060] In some embodiments, the flagellin-related composition activates TLR5 signaling. In some embodiments, the flagellin-related composition activates TLR5 at the same levels, or levels similar to, CBLB502. Activation of TLR5 induces expression of the nuclear factor NF-.kappa.B, which in turn activates numerous inflammatory-related cytokines. In further embodiments, the flagellin-related compositions induce expression of proinflammatory cytokines. In further embodiments, the flagellin-related compositions induce expression of anti-inflammatory molecules. In another embodiment, the flagellin-related compositions induce expression of anti-apoptotic molecules. In yet a further embodiment, the flagellin-related compositions induce expression of anti-bacterial molecules. The targets of NF-.kappa.B, include, but are not limited to, IL-.beta., TNF-.alpha., IL-6, IL-8, IL-18, G-CSF, TNFSF13B, keratinocyte chemoattractant (KC), BLIMP1/PRDM1, CCL5, CCL15, CCL17, CCL19, CCL20, CCL22, CCL23, CXCL1, CCL28, CXCL11, CXCL10, CXCL3, CXCL1, GRO-beta, GRO-gamma, CXCL1, ICOS, IFNG, IL-1A, IL-1B, IL1RN, IL-2, IL-9, IL-10, IL-11, IL-12, IL-12B, IL-12A, IL-13, IL-15, IL-17, IL-23A, IL-27, EBI3, IFNB1, CXCL5, KC, liGp1, CXCL5, CXCL6, LTA, LTB, CCL2, CXCL9, MCP-1/JE, CCL3, CCL4, CXCL3, CCL20, CXCL10, CXCL5, CCL5, CCL1, TNFbeta, TNFSF10, TFF3, TNFSF15, CD86, complement component 8a, CCL27, defensin-.beta.3, MIG, MIP-2, and/or NOD2/CARD15.

[0061] In some embodiments, activating TLR5 signaling may regulate CD4.sup.+ T-cell immune function by increasing the generation of regulatory T-cells (T.sub.regS), decreasing LPS-induced ERK1/2 activation, and/or activating Natural Killer (NK) T-cells.

Diseases and Methods of Treatment/Prevention

[0062] In various embodiments, the flagellin-related compositions (and/or additional agents) and methods described herein are applicable to variety of disease states. In one aspect, the invention provides a method of stimulating TLR5 signaling comprising administering a flagellin-related composition of the invention to a subject in need thereof. Activating TLR5 signaling may have broad therapeutic applications, including, but not limited to treating cancer, protecting from radiation-induced or reperfusion-induced damage, acting as adjuvant in vaccines, or protecting cells from cytotoxic compounds.

[0063] In some embodiments, the flagellin-related compositions of the invention, or fragments thereof may be provided as adjuvants to viral vaccines. In one embodiment, the flagellin-related compositions or fragments thereof may be administered in conjunction with an influenza vaccine or antigen to elicit a greater host immune response to the influenza antigens. In yet a further embodiment, the flagellin-related compositions of the invention, or fragments thereof may be provided as adjuvants to vaccines against parasites. In one embodiment, the flagellin-related compositions or fragments thereof may be administered in conjunction with an Plasmodium vaccine or antigen to elicit a greater host immune response to the Plasmodium antigen.

[0064] In some embodiments, the flagellin-related compositions of the invention may be administered to protect cells from toxic conditions. In some embodiments, the flagellin-related compositions may prevent liver cells from Fas-mediated injury. The flagellin-related compositions of the invention may cause a decrease in liver enzymes in the peripheral blood and caspase activation.

[0065] Cancers

[0066] In various embodiments, the present invention pertains to cancers and/or tumors; for example, the treatment or prevention of cancers and/or tumors. As used herein, "cancer" or "tumor" refers to an uncontrolled growth of cells and/or abnormal increased cell survival and/or inhibition of apoptosis which interferes with the normal functioning of the bodily organs and systems. Included are benign and malignant cancers, polyps, hyperplasia, as well as dormant tumors or micrometastases. Also, included are cells having abnormal proliferation that is not impeded by the immune system (e.g. virus infected cells). A subject that has a cancer or a tumor is a subject having objectively measurable cancer cells present in the subject's body. Cancers which migrate from their original location and seed vital organs can eventually lead to the death of the subject through the functional deterioration of the affected organs. Hematopoietic cancers, such as leukemia, are able to out-compete the normal hematopoietic compartments in a subject, thereby leading to hematopoietic failure (in the form of anemia, thrombocytopenia and neutropenia) ultimately causing death.

[0067] The cancer may be a primary cancer or a metastatic cancer. The primary cancer may be an area of cancer cells at an originating site that becomes clinically detectable, and may be a primary tumor. In contrast, the metastatic cancer may be the spread of a disease from one organ or part to another non-adjacent organ or part. The metastatic cancer may be caused by a cancer cell that acquires the ability to penetrate and infiltrate surrounding normal tissues in a local area, forming a new tumor, which may be a local metastasis.

[0068] The cancer may also be caused by a cancer cell that acquires the ability to penetrate the walls of lymphatic and/or blood vessels, after which the cancer cell is able to circulate through the bloodstream (thereby being a circulating tumor cell) to other sites and tissues in the body. The cancer may be due to a process such as lymphatic or hematogenous spread. The cancer may also be caused by a tumor cell that comes to rest at another site, re-penetrates through the vessel or walls, continues to multiply, and eventually forms another clinically detectable tumor. The cancer may be this new tumor, which may be a metastatic (or secondary) tumor.

[0069] The cancer may be caused by tumor cells that have metastasized, which may be a secondary or metastatic tumor. The cells of the tumor may be like those in the original tumor. As an example, if a breast cancer or colon cancer metastasizes to the liver, the secondary tumor, while present in the liver, is made up of abnormal breast or colon cells, not of abnormal liver cells. The tumor in the liver may thus be a metastatic breast cancer or a metastatic colon cancer, not liver cancer.

[0070] The cancer may have an origin from any tissue. The cancer may originate from, for example, melanoma, colon, breast, or prostate, and thus may be made up of cells that were originally skin, colon, breast, or prostate, respectively. The cancer may also be a hematological malignancy, which may be lymphoma. The cancer may invade a tissue such as liver, lung, bladder, or intestinal. The invaded tissue may express a TLR, while the cancer may or may not express a TLR.

[0071] Also provided herein is a method of reducing cancer recurrence, comprising administering to a mammal in need thereof a flagellin-related composition of the invention. The cancer may be or may have been present in a tissue that either does or does not express TLR, such as TLR5. The method may also prevent cancer recurrence. The cancer may be an oncological disease. The cancer may be a dormant tumor, which may result from the metastasis of a cancer. The dormant tumor may also be left over from surgical removal of a tumor. The cancer recurrence may be tumor regrowth, a lung metastasis, or a liver metastasis.

[0072] Representative cancers and/or tumors of the present invention may or may not express TLR5, and may include, but are not limited to, a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

[0073] The flagellin-related compositions (and/or additional agents) and methods described herein are applicable metastatic diseases, including cancers and/or tumors. "Metastasis" refers to the spread of cancer from a primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.

[0074] Metastases may be detected through the sole or combined use of magnetic resonance imaging (MRI) scans, computed tomography (CT) scans, blood and platelet counts, liver function studies, chest X-rays and bone scans in addition to the monitoring of specific symptoms.

[0075] In some embodiments, the invention relates to a method of treating a mammal suffering from a constitutively active NF-.kappa.B cancer comprising administering to the mammal a composition comprising a therapeutically effective amount of an agent that induces NF-.kappa.B activity, including the flagellin-related compositions (and/or additional agents) described herein. The agent that induces NF-.kappa.B activity may be administered in combination with a cancer treatment.

[0076] In some embodiments, the present invention includes methods for treatment of side effects from cancer treatment comprising administering the flagellin-related composition (and/or additional agents) described herein. In some embodiments, the side effects from cancer treatment include alopecia, myelosuppression, renal toxicity, weight loss; pain, nausea, vomiting, diarrhea, constipation, anemia, malnutrition, hair loss, numbness, changes in tastes, loss of appetite, thinned or brittle hair, mouth sores, memory loss, hemorrhage, cardiotoxicity, hepatotoxicity, ototoxicity, and post-chemotherapy cognitive impairment.

[0077] In some embodiments, the present invention relates to a method of treating a mammal suffering from damage to normal tissue attributable to treatment of cancer, including but not limited to a constitutively active NF-.kappa.B cancer, comprising administering to the mammal a composition comprising a therapeutically effective amount of the flagellin-related composition (and/or additional agents) described herein.

[0078] Ageing and Stress

[0079] In some embodiments, the present invention includes methods for modulation of cell aging comprising administering the flagellin-related composition (and/or additional agents) described herein.

[0080] In some embodiments, the present invention includes methods for treatment of stress comprising administering the flagellin-related composition (and/or additional agents) described herein. This invention also relates to a method of treating a subject suffering from damage to normal tissue attributable to stress, comprising administering to the mammal a composition comprising a therapeutically effective amount of a flagellin-related composition (and/or additional agents). The stress may be attributable to any source including, but not limited to, radiation, wounding, poisoning, infection, and temperature shock.

[0081] In some embodiments, the flagellin-related composition (and/or additional agents) may be administered at any point prior to exposure to the stress including, but not limited to, about 48 hr, about 46 hr, about 44 hr, about 42 hr, about 40 hr, about 38 hr, about 36 hr, about 34 hr, about 32 hr, about 30 hr, about 28 hr, about 26 hr, about 24 hr, about 22 hr, about 20 hr, about 18 hr, about 16 hr, about 14 hr, about 12 hr, about 10 hr, about 8 hr, about 6 hr, about 4 hr, about 3 hr, about 2 hr, or about 1 hr prior to exposure. In some embodiments, the flagellin-related composition may be administered at any point after exposure to the stress including, but not limited to, about 1 hr, about 2 hr, about 3 hr, about 4 hr, about 6 hr, about 8 hr, about 10 hr, about 12 hr, about 14 hr, about 16 hr, about 18 hr, about 20 hr, about 22 hr, about 24 hr, about 26 hr, about 28 hr, about 30 hr, about 32 hr, about 34 hr, about 36 hr, about 38 hr, about 40 hr, about 42 hr, about 44 hr, about 46 hr, or about 48 hr after exposure.

[0082] Mitigation and Prevention of Radiation Damage

[0083] In still other embodiments, the present invention relates to treatment of radiation related diseases or damage. In specific embodiments, the present invention relates to mitigation of or prevention and/or protection from radiation related diseases.

[0084] In one embodiment, the present invention relates to the protection of cells from the effects of exposure to radiation. In some embodiments, the present invention pertains to a method of protecting a subject from radiation comprising administering a flagellin-related composition (and/or additional agents) described herein. In some embodiments, the radiation is ionizing radiation. In some embodiments, the ionizing radiation is sufficient to cause gastrointestinal syndrome or hematopoietic syndrome. In some embodiments, the flagellin-related composition (and/or additional agents) described herein is administered in combination with a radioprotectant e.g. an antioxidant (e.g. amifostine and vitamin E), a cytokine (e.g. a stem cell factor), etc. In some embodiments, the flagellin-related composition (and/or additional agents) described herein is administered prior to, together with, or after radiation. In some embodiments, the flagellin-related composition (and/or additional agents) described herein is administered in combination with a growth factor (e.g. keratinocyte growth factor), a steroid (e.g. 5-androstenediol), ammonium triohloro(dioxoethylene-O,O')tellurate, thyroid protecting agents (e.g. Potassium iodide (KI)), anti-nausea agents, anti-diarrhea agents, analgesics, anxiolytics, sedatives, cytokine therapy, antibiotics, antifungal agents, and/or antiviral agents.

[0085] In some embodiments, the present invention pertains to a method of treating and/or mitigating apoptosis-mediated tissue damage in a subject, comprising administering to a subject in need thereof a composition comprising a flagellin-related composition (and/or additional agents) described herein. In some embodiments the apoptosis is attributable to cellular stress. In some embodiments, the flagellin-related composition (and/or additional agents) described herein is administered prior to, together with, or after the tissue damage. In some embodiments, the cellular stress is radiation. In some embodiments, the flagellin-related composition (and/or additional agents) is administered in combination with a radioprotectant (e.g. an antioxidant (e.g. amifostine and vitamin E), a cytokine (e.g. a stem cell factor), etc.

[0086] Injury and death of normal cells from ionizing radiation is a combination of a direct radiation-induced damage to the exposed cells and an active genetically programmed cell reaction to radiation-induced stress resulting in a suicidal death or apoptosis. Apoptosis plays a key role in massive cell loss occurring in several radiosensitive organs (e.g., hematopoietic and immune systems, epithelium of digestive tract, etc.), the failure of which determines general radiosensitivity of the organism. In some embodiments, administration of the flagellin-related compositions of the invention to a subject in need thereof suppresses apoptosis in cells. In some embodiments, the flagellin-related compositions of the invention are administered to a subject undergoing cancer radiotherapy treatment to protect healthy cells from the damaging effects of the radiation treatment.

[0087] Exposure to ionizing radiation (IR) may be short- or long-term, and/or it may be applied as a single or multiple doses and/or it may be applied to the whole body or locally. The present invention, in some embodiments, pertains to nuclear accidents or military attacks, which may involve exposure to a single high dose of whole body irradiation (sometimes followed by a long-term poisoning with radioactive isotopes). The same is true (with strict control of the applied dose), for example, for pretreatment of patients for bone marrow transplantation when it is necessary to prepare hematopoietic organs for donor's bone marrow by "cleaning" them from the host blood precursors. Cancer treatment may involve multiple doses of local irradiation that greatly exceeds lethal dose if it were applied as a total body irradiation. Poisoning or treatment with radioactive isotopes results in a long-term local exposure to radiation of targeted organs (e.g., thyroid gland in the case of inhalation of .sup.125I). Further, there are many physical forms of ionizing radiation differing significantly in the severity of biological effects.

[0088] At the molecular and cellular level, radiation particles are able to produce breakage and cross-linking in the DNA, proteins, cell membranes and other macromolecular structures. Ionizing radiation also induces the secondary damage to the cellular components by giving rise to the free radicals and reactive oxygen species (ROS). Multiple repair systems counteract this damage, such as, several DNA repair pathways that restore the integrity and fidelity of the DNA, and antioxidant chemicals and enzymes that scavenge the free radicals and ROS and reduce the oxidized proteins and lipids. Cellular checkpoint systems detect the DNA defects and delay cell cycle progression until damage is repaired or decision to commit cell to growth arrest or programmed cell death (apoptosis) is reached

[0089] Radiation can cause damage to mammalian organism ranging from mild mutagenic and carcinogenic effects of low doses to almost instant killing by high doses. Overall radiosensitivity of the organism is determined by pathological alterations developed in several sensitive tissues that include hematopoietic system, reproductive system and different epithelia with high rate of cell turnover.

[0090] Acute pathological outcome of gamma irradiation leading to death is different for different doses and may be determined by the failure of certain organs that define the threshold of organism's sensitivity to each particular dose. Thus, lethality at lower doses occurs, for example, from bone marrow aplasia, while moderate doses kill faster, for example, by inducing a gastrointestinal (GI) syndrome. Very high doses of radiation can cause almost instant death eliciting neuronal degeneration.

[0091] Organisms that survive a period of acute toxicity of radiation can suffer from long-term remote consequences that include radiation-induced carcinogenesis and fibrosis developing in exposed organs (e.g., kidney, liver or lungs) in the months and years after irradiation.

[0092] Cellular DNA is a major target of IR that causes a variety of types of DNA damage (genotoxic stress) by direct and indirect (e.g. free radical-based) mechanisms. All organisms maintain DNA repair system capable of effective recovery of radiation-damaged DNA; errors in DNA repair process may lead to mutations.

[0093] In some embodiments, the radiation exposure experienced by the subject is a consequence of cancer radiotherapy treatment. Tumors are generally more sensitive to gamma radiation and can be treated with multiple local doses that cause relatively low damage to normal tissue. Nevertheless, in some instances, damage of normal tissues is a limiting factor in application of gamma radiation for cancer treatment. The use of gamma-irradiation during cancer therapy by conventional, three-dimensional conformal or even more focused BeamCath delivery has also dose-limiting toxicities caused by cumulative effect of irradiation and inducing the damage of the stem cells of rapidly renewing normal tissues, such as bone marrow and gastrointestinal (GI) tract. Administration of the flagellin-related compositions of the invention may protect the patient's healthy cells from radiation damage without affecting the radiosensitivity of the tumor cells.

[0094] In some embodiments, the subject has been exposed to lethal doses of radiation. At high doses, radiation-induced lethality is associated with so-called hematopoietic and gastrointestinal radiation syndromes. Hematopoietic syndrome is characterized by loss of hematopoietic cells and their progenitors making it impossible to regenerate blood and lymphoid system. Death usually occurs as a consequence of infection (result of immunosuppression), hemorrhage and/or anemia. GI syndrome is caused by massive cell death in the intestinal epithelium, predominantly in the small intestine, followed by disintegration of intestinal wall and death from bacteremia and sepsis. Hematopoietic syndrome usually prevails at the lower doses of radiation and leads to the more delayed death than GI syndrome.

[0095] In the past, radioprotectants were typically antioxidants-both synthetic and natural. More recently, cytokines and growth factors have been added to the list of radioprotectants; the mechanism of their radioprotection is considered to be a result of facilitating the effects on regeneration of sensitive tissues. There is no clear functional distinction between both groups of radioprotectants, however, since some cytokines induce the expression of the cellular antioxidant proteins, such as manganese superoxide dismutase (MnSOD) and metallothionein.

[0096] The measure of protection for a particular agent may be expressed by dose modification factor (DMF or DRF). DMF is determined by irradiating the radioprotector treated subject and untreated control subjects with a range of radiation doses and then comparing the survival or some other endpoints. DMF is commonly calculated for 30-day survival (LD50/30 drug-treated divided by LD50/30 vehicle-treated) and quantifies the protection of the hematopoietic system. In order to estimate gastrointestinal system protection, LD50 and DMF are calculated for 6- or 7-day survival.

[0097] The flagellin-related compositions described herein possess strong pro-survival activity at the cellular level and on the organism as a whole. In response to super-lethal doses of radiation, the flagellin-related compositions described herein may inhibit both gastrointestinal and hematopoietic syndromes, which are major causes of death from acute radiation exposure. As a result of these properties, the flagellin-related compositions described herein may be used to treat the effects of natural radiation events and nuclear accidents. Moreover, the flagellin-related compositions described herein can be used in combination with other radioprotectants, thereby, dramatically increasing the scale of protection from ionizing radiation.

[0098] As opposed to conventional radioprotective agents (e.g., scavengers of free radicals), anti-apoptotic agents may not reduce primary radiation-mediated damage but may act against secondary events involving active cell reaction on primary damage, therefore complementing the existing lines of defense. Pifithrin-alpha, a pharmacological inhibitor of p53 (a key mediator of radiation response in mammalian cells), is an example of this new class of radioprotectants. However, the activity of p53 inhibitors is limited to protection of the hematopoietic system and has no protective effect in digestive tract (gastrointestinal syndrome), therefore reducing therapeutic value of these compounds.

[0099] The flagellin-related compositions described herein may be used as a radioprotective agent to extend the range of tolerable radiation doses by increasing radioresistance of humans beyond the levels achievable by currently available measures (shielding and application of existing bioprotective agents) and drastically increase the chances of crew survival in case of nuclear accidents or large-scale solar particle events, for example.

[0100] The flagellin-related compositions described herein are also useful for treating irreplaceable cell loss caused by low-dose irradiation, for example, in the central nervous system and reproductive organs. The flagellin-related compositions described herein may also be used during cancer chemotherapy to treat the side effects associated with chemotherapy, including alopecia, myelosuppression, renal toxicity, weight loss, pain, nausea, vomiting, diarrhea, constipation, anemia, malnutrition, hair loss, numbness, changes in tastes, loss of appetite, thinned or brittle hair, mouth sores, memory loss, hemorrhage, cardiotoxicity, hepatotoxicity, ototoxicity, and post-chemotherapy cognitive impairment.

[0101] In one embodiment, a mammal is treated for exposure to radiation, comprising administering to the mammal a composition comprising a therapeutically effective amount of a flagellin-related composition. The flagellin-related composition may be administered in combination with one or more radioprotectants. The one or more radioprotectants may be any agent that treats the effects of radiation exposure including, but not limited to, antioxidants, free radical scavengers and cytokines.

[0102] The flagellin-related compositions described herein may inhibit radiation-induced programmed cell death in response to damage in DNA and other cellular structures. In some embodiments, the flagellin-related compositions described herein may not deal with damage at the cellular and may not prevent mutations. Free radicals and reactive oxygen species (ROS) are the major cause of mutations and other intracellular damage. Antioxidants and free radical scavengers are effective at preventing damage by free radicals. The combination of a flagellin-related composition and an antioxidant or free radical scavenger may result in less extensive injury, higher survival, and improved health for mammals exposed to radiation. Antioxidants and free radical scavengers that may be used in the practice of the invention include, but are not limited to, thiols, such as cysteine, cysteamine, glutathione and bilirubin; amifostine (WR-2721); vitamin A; vitamin C; vitamin E; and flavonoids such as Indian holy basil (Ocimum sanctum), orientin and vicenin.

[0103] The flagellin-related compositions described herein may also be administered in combination with a number of cytokines and growth factors that confer radioprotection by replenishing and/or protecting the radiosensitive stem cell populations. Radioprotection with minimal side effects may be achieved by the use of stem cell factor (SCF, c-kit ligand), Flt-3 ligand, and interleukin-1 fragment IL-1 b-rd. Protection may be achieved through induction of proliferation of stem cells (all mentioned cytokines), and prevention of their apoptosis (SCF). The treatment allows accumulation of leukocytes and their precursors prior to irradiation thus enabling quicker reconstitution of the immune system after irradiation. SCF efficiently rescues lethally irradiated mice with DMF in range 1.3-1.35 and is also effective against gastrointestinal syndrome. Flt-3 ligand also provides strong protection in mice and rabbits.

[0104] Several factors, while not cytokines by nature, stimulate the proliferation of the immunocytes and may be used in combination with the flagellin-related compositions described herein. For example, 5-AED (5-androstenediol) is a steroid that stimulates the expression of cytokines and increases resistance to bacterial and viral infections. Synthetic compounds, such as ammonium tri-chloro(dioxoethylene-O,O'-) tellurate (AS-101), may also be used to induce secretion of numerous cytokines and for combination with the flagellin-related compositions described herein.

[0105] Growth factors and cytokines may also be used to provide protection against the gastrointestinal syndrome. Keratinocyte growth factor (KGF) promotes proliferation and differentiation in the intestinal mucosa, and increases the post-irradiation cell survival in the intestinal crypts. Flematopoietic cytokine and radioprotectant SCF may also increase intestinal stem cell survival and associated short-term organism survival.

[0106] The flagellin-related compositions described herein may offer protection against both gastrointestinal (GI) and hematopoietic syndromes. Such compositions may be used in combination with one or more inhibitors of GI syndrome (including, but are not limited to, cytokines such as SCF and KGF).

[0107] The flagellin-related composition may be administered at any point prior to exposure to radiation including, but not limited to, about 48 hr, about 46 hr, about 44 hr, about 42 hr, about 40 hr, about 38 hr, about 36 hr, about 34 hr, about 32 hr, about 30 hr, about 28 hr, about 26 hr, about 24 hr, about 22 hr, about 20 hr, about 18 hr, about 16 hr, about 14 hr, about 12 hr, about 10 hr, about 8 hr, about 6 hr, about 4 hr, about 3 hr, about 2 hr, or about 1 hr prior to exposure. The flagellin-related composition may be administered at any point after exposure to radiation including, but not limited to, about 1 hr, about 2 hr, about 3 hr, about 4 hr, about 6 hr, about 8 hr, about 10 hr, about 12 hr, about 14 hr, about 16 hr, about 18 hr, about 20 hr, about 22 hr, about 24 hr, about 26 hr, about 28 hr, about 30 hr, about 32 hr, about 34 hr, about 36 hr, about 38 hr, about 40 hr, about 42 hr, about 44 hr, about 46 hr, or about 48 hr after exposure to radiation.

[0108] In various embodiments, the present methods and compositions provide treatment or prevention of radiation-related disorders, such as ARS. In various embodiments, the treatments described herein reduce morbidity or mortality of an exposed population of human patients or accelerates recovery from symptoms of ARS. ARS often presents as a sequence of phased symptoms, which may vary with individual radiation sensitivity, type of radiation, and the radiation dose absorbed. Generally, without wishing to be bound by theory, the extent of symptoms will heighten and the duration of each phase will shorten with increasing radiation dose. ARS can be divided into three phases: prodromal phase (a.k.a. N-V-D stage), latent period and manifest illness. In various embodiments, the flagellin-related compositions (and/or additional agents), as described herein, may be administered to a human patient in any one of these three stages (i.e. the flagellin-related compositions (and/or additional agents) may be administered to a human patient in the prodromal phase, the flagellin-related compositions (and/or additional agents) may be administered to a human patient in latent period, or the flagellin-related compositions (and/or additional agents) may be administered to a human patient in manifest illness stage).

[0109] In the prodromal phase there is often a relatively rapid onset of nausea, vomiting, and malaise. Use of antiemetics, (e.g. oral prophylactic antiemetics) such as granisetron (KYTRIL), ondansetron (ZOFRAN), and 5-HT3 blockers with or without dexamethasone, may be indicated in situations where high-dose radiological exposure has occurred, is likely, or is unavoidable. Accordingly, in various embodiments, the flagellin-related compositions (and/or additional agents) may be administered to a human patient in receiving an anti-emetic agent or CBLB502 may be administered to a human patient in combination with an anti-emetic agent. For example, the flagellin-related compositions (and/or additional agents) may also be added to the following antiemetic regimens: Ondansetron: initially 0.15 mg/kg IV; a continuous IV dose option consists of 8 mg followed by 1 mg/h for the next 24 hours. Oral dose is 8 mg every 8 hours as needed or Granisetron (oral dosage form): dose is usually 1 mg initially, then repeated 12 hours after the first dose. Alternatively, 2 mg may be taken as one dose. IV dose is based on body weight; typically 10 .mu.g/kg (4.5 .mu.g/lb) of body weight.

[0110] In the latent period, a human patient may be relatively symptom free. The length of this phase varies with the dose. The latent phase is longest preceding the bone-marrow depression of the hematopoietic syndrome and may vary between about 2 and 6 weeks. The latent period is somewhat shorter prior to the gastrointestinal syndrome, lasting from a few days to a week. It is shortest of all preceding the neurovascular syndrome, lasting only a matter of hours. These times are variable and may be modified by the presence of other disease or injury. Manifest illness presents with the clinical symptoms associated with the major organ system injured (marrow, intestinal, neurovascular).

[0111] In some embodiments, the present invention relates to the mitigation of, or protection of cells from, the effects of exposure to radiation. In some embodiments, the present invention pertains to a method of mitigating and/or protecting a human patient from radiation comprising administering the flagellin-related compositions (and/or additional agents). In some embodiments, the radiation is ionizing radiation. In some embodiments, the ionizing radiation is sufficient to cause gastrointestinal syndrome or hematopoietic syndrome.

[0112] In some embodiments, the ARS comprises one of more of gastrointestinal syndrome; hematopoietic syndrome; neurovascular syndrome; apoptosis-mediated tissue damage, wherein the apoptosis is optionally attributable to cellular stress; and ionizing radiation induced apoptosis tissue damage.

[0113] Hematopoietic syndrome (a.k.a. bone marrow syndrome) is characterized by loss of hematopoietic cells and their progenitors making it impossible to regenerate blood and lymphoid system. This syndrome is often marked by a drop in the number of blood cells, i.e., aplastic anemia. This may result in infections (e.g. opportunistic infections) due to a low amount of white blood cells, bleeding due to a lack of platelets, and anemia due to few red blood cells in the circulation. These changes can be detected by blood tests after receiving a whole-body acute dose. Conventional trauma and burns resulting from a bomb blast are complicated by the poor wound healing caused by hematopoietic syndrome, increasing mortality. Death may occur as a consequence of infection (result of immunosuppression), hemorrhage and/or anemia. Hematopoietic syndrome usually prevails at the lower doses of radiation and leads to the more delayed death than GI syndrome.

[0114] Gastrointestinal syndrome is caused by massive cell death in the intestinal epithelium, predominantly in the small intestine, followed by disintegration of intestinal wall and death from bacteremia and sepsis. Symptoms of this form of radiation injury include nausea, vomiting, loss of appetite, loss of absorptive capacity, hemorrhage in denuded areas, and abdominal pain. Illustrative systemic effects of gastrointestinal syndrome include malnutrition, dehydration, renal failure, anemia, sepsis, etc. Without treatment (including, for example, bone marrow transplant), death is common (e.g. via infection from intestinal bacteria). In some embodiments, the flagellin-related compositions (and/or additional agents), may be used in combination with bone marrow transplant. In some embodiments, the flagellin-related compositions (and/or additional agents), may be used in combination with one or more inhibitors of GI syndrome and/or any of the additional agents described herein.

[0115] Neurovascular syndrome presents with neurological symptoms such as dizziness, headache, or decreased level of consciousness, occurring within minutes to a few hours, and with an absence of vomiting. Additional symptoms include extreme nervousness and confusion; severe nausea, vomiting, and watery diarrhea; loss of consciousness; and burning sensations of the skin. Neurovascular syndrome is commonly fatal.

[0116] In some embodiments, the present invention provides a method for reducing the risk of death following exposure to irradiation comprising administering an effective amount of the flagellin-related compositions (and/or additional agents) In some embodiments, the radiation is potentially lethal, and, optionally, occurs as the result of a radiation disaster. In various embodiments, the flagellin-related compositions (and/or additional agents) is administered within about 25 hours following radiation exposure. In some embodiments, the present invention provides a method for reducing the risk of death following exposure to potentially lethal irradiation occurring as the result of a radiation disaster, comprising administering the flagellin-related compositions (and/or additional agents) within about 25 hours following radiation exposure.

[0117] In various embodiments, the flagellin-related compositions (and/or additional agents) are administered to a patient who has been exposed to a high dose of radiation, namely a whole body dose. In various embodiments, the high dose of radiation may not be uniform. In various embodiments, the ARS is a result of a high dose of radiation. In various embodiments, the high dose of radiation is about 2.0 Gy, or about 2.5 Gy, or about 3.0 Gy, or about 3.5 Gy, or about 4.0 Gy, or about 4.5 Gy, or about 5 Gy, or about 10 Gy, or about 15 Gy, or about 20 Gy, or about 25 Gy, or about 30 Gy. In various embodiments, the high dose of radiation is about 5 to about 30 Gy, or about 10 to 25 Gy, or about 15 to 20 Gy. In some embodiments, the high dose of radiation is assessed by one or more of physical dosimetry and/or biological dosimetry (e.g. multiparameter dose assessments), cytogenics (e.g. chromosomal analysis for, for example, blood samples (including, by way of non-limiting example, dicentric analysis). In various embodiments, whole-body radiation doses can be divided into sublethal (<2 Gy), potentially lethal (2-10 Gy), and supralethal (>10 Gy).

[0118] Reperfusion Injuries

[0119] In some embodiments, the present invention pertains to a method of treating the effects of reperfusion on a subject's tissue comprising administering the flagellin-related compositions (and/or additional agents) described herein. The flagellin-related compositions (and/or additional agents) described herein may be administered in combination with an antioxidant, such as, for example, amifostine and vitamin E.

[0120] Reperfusion may be caused by an injury, which may be ischemia or hypoxia. The ischemia may result from a condition such as, for example, tachycardia, infarction, hypotension, embolism, thromboembolism (blood clot), sickle cell disease, localized pressure to extremities to the body, and tumors. The hypoxia may be selected from hypoxemic hypoxia (carbon monoxide poisoning; sleep apnea, chronic obstructive pulmonary disease, respiratory arrest; shunts), anemic hypoxia (O.sub.2 content low), hypoxemic hypoxia, and histotoxic hypoxia. The localized pressure may be due to a tourniquet.

[0121] The flagellin-related compositions (and/or additional agents) described herein may be administered prior to, together with, or after the influx of oxygen. The tissue may be for example, the GI tract, lung, kidney, liver, cardiovascular system, blood vessel endothelium, central nervous system, peripheral nervous system, muscle, bone, and hair follicle.

[0122] Reperfusion may damage a body component when blood supply returns to the body component after the injury. The effects of reperfusion may be more damaging to the body component than the injury itself. There are several mechanism and mediators of reperfusion including, for example, oxygen free radicals, intracellular calcium overload, and endothelial dysfunction. Excessive quantities of reactive oxygen species, when reintroduced into a previously injured body component, undergo a sequential reduction leading to the formation of oxygen free radicals. Potent oxidant radicals, such as superoxide anion, hydroxyl radical, and peroxynitrite may be produced within the first few minutes of reflow to the body component and may play a crucial role in the development of reperfusion injury. Oxygen free radicals also can be generated from sources other than reduction of molecular oxygen. These sources include enzymes, such as, for example, xanthine oxidase, cytochrome oxidase, and cyclooxygenase, and the oxidation of catecholamines.

[0123] Reperfusion is also a potent stimulus for neutrophil activation and accumulation, which in turn serve as potent stimuli for reactive oxygen species production. Specifically, the main products of the neutrophil respiratory burst are strong oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite. Neutrophils are the most abundant type of phagocyte, normally representing 50 to 60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of injured body component. Oxygen-derived free radicals produce damage by reacting with polyunsaturated fatty acids, resulting in the formation of lipid peroxides and hydroperoxides that damage the body component and impair the function of membrane-bound enzyme systems. Free radicals stimulate the endothelial release of platelet activating factor and chemokines such as neutrophil activator factor, chemokine (C-X-C motif) ligand 1, and chemokine (C-X-C motif) ligand 1 which attracts more neutrophils and amplifies the production of oxidant radicals and the degree of reperfusion injury. Reactive oxygen species also quench nitric oxide, exaggerating endothelial injury and tissue cell dysfunction. In addition to an increased production, there is also a relative deficiency in endogenous oxidant scavenging enzymes, which further exaggerates free radical-mediated cardiac dysfunction.

[0124] Reperfusion may further result in marked endothelial cell dysfunction. Endothelial dysfunction facilitates the expression of a prothrombotic phenotype characterized by platelet and neutrophil activation, important mediators of reperfusion. Once neutrophils make contact with the dysfunctional endothelium, they are activated, and in a series of well-defined steps (rolling, firm adherence, and transmigration) they migrate into areas of tissue injury through endothelial cell junctions as part of the innate immune response.

[0125] Changes in intracellular calcium homeostasis play an important role in the development of reperfusion. Reperfusion may be associated with an increase in intracellular calcium; this effect may be related to increased sarcolemmal calcium entry through L-type calcium channels or may be secondary to alterations in sarcoplasmic reticulum calcium cycling. In addition to intracellular calcium overload, alterations in myofilament sensitivity to calcium have been implicated in reperfusion. Activation of calcium-dependent proteases (calpain I) with resultant myofibril proteolysis has been suggested to underscore reperfusion injury, as has proteolysis of troponin.

[0126] Reperfusion of tissue cells subjected to an injury had an altered cellular metabolism, which in turn may contribute to delayed functional recovery. For example, an injury may induce anaerobic metabolism in the cell with a net production of lactate. Lactate release persists during reperfusion, suggesting a delayed recovery of normal aerobic metabolism. Likewise, the activity of mitochondrial pyruvate dehydrogenase (PDH) may be inhibited up to 40% after an injury and may remain depressed for up to 30 minutes after reperfusion.

[0127] Each of these events during reperfusion can lead to stress to the tissue cells and programmed cell death (apoptosis) and necrosis of the tissue cells. Apoptosis normally functions to "clean" tissues from wounded and genetically damaged cells, while cytokines serve to mobilize the defense system of the organism against the pathogen. However, under conditions of severe injury both stress response mechanisms can by themselves act as causes of death.

[0128] In various embodiments, the effects of reperfusion may be caused by an injury to the body. The injury may be due to ischemia, hypoxia, an infarction, or an embolism. Treatment of the injury may lead to reperfusion and further damage to the body component.

[0129] Ischemia may be an absolute or relative shortage of blood supply to a body component. Relative shortage may be a mismatch, however small, of blood supplied (oxygen delivery) to a body component versus blood required to a body component for the adequate oxygenation. Ischemia may also be an inadequate flow of blood to a part of the body due to a constriction or blockage of blood vessels supplying it and may affect any body component in the body. Insufficient blood supply causes body components to become hypoxic, or, if no oxygen is supplied at all, anoxic. This may cause necrosis. The mechanisms of ischemia may vary greatly. For example, ischemia to any body component may be due to tachycardia (abnormally rapid beating of the heart), atherosclerosis (lipid-laden plaque obstructing the lumen of arteries), hypotension (low blood pressure in septic shock, heart failure), thromboembolisms (blood clots), outside compression of blood vessels (tumor), embolisms (foreign bodies in the circulation, e.g., amniotic fluid embolism), sickle cell disease (abnormally shaped hemoglobin), infarctions, induced g-forces which restrict the blood flow and force the blood to extremities of the body, localized extreme cold due to frostbite, ice, improper cold compression therapy, and any other force that restricts blood flow to the extremities such as a tourniquet. Force to restrict blood flow to extremities may be required due to severe lacerations, incisions, puncture such as a knifing, crushing injuries due to blunt force trauma, and ballistic trauma due to gunshot or shrapnel wounds. Ischemia may be a feature of heart diseases, ischemic colitis, transient ischemia attacks, cerebrovascular accidents, acute renal injury, ruptured arteriovenous malformations, and peripheral artery occlusive disease.

[0130] Hypoxia may be a deprivation of adequate supply of oxygen. Hypoxia may be pathological condition in which the body as a whole (generalized hypoxia) or region of the body (tissue hypoxia) is deprived of adequate oxygen supply. A variation in levels of arterial oxygen may be due to a mismatch between supply and demand of oxygen by body components. A complete deprivation of oxygen supply is anoxia. Hypoxia may be hypoxemic hypoxia, anemic hypoxia, hypoxemic hypoxia, histotoxic hypoxia, histotoxic hypoxia, and ischemic hypoxia.

[0131] Hypoxemic hypoxia may be an inadequate supply of oxygen to the body as a whole caused by low partial pressure of oxygen in arterial blood. Hypoxemic hypoxia may be due to low partial pressure of atmospheric oxygen such as at high altitudes, replacement of oxygen in breathing mix of a modified atmosphere such as a sewer, replacement of oxygen intentionally as in recreational use of nitrous oxide, a decrease in oxygen saturation of the blood due to sleep apnea, or hypopnea, inadequate pulmonary ventilation such as chronic obstructive pulmonary disease or respiratory arrest, anatomical or mechanical shunts in the pulmonary circulation or a right to left shunt in the heart and lung. Shunts may cause collapsed alveoli that are still perfused or a block in ventilation to an area of the lung. Shunts may present blood meant for the pulmonary system to not be ventilated and prevent gas exchange because the blood vessels empty into the left ventricle and the bronchial circulation, which supplies the bronchi with oxygen.

[0132] Anemia hypoxia may be the total oxygen content is reduced but the arterial oxygen pressure is normal. Hypoxemic hypoxia may be when blood fails to deliver oxygen to target body components. Hypoxemic hypoxia may be caused by carbon monoxide poisoning which inhibits the ability of hemoglobin to release the oxygen bound to it, or methaemoglobinaemia, an abnormal hemoglobin that accumulates in the blood. Histotoxic hypoxia may be due to being unable to effectively use oxygen due to disabled oxidative phosphorylation enzymes.

[0133] Infarction is a type of pathological condition that can cause ischemia. Infarction may be a macroscopic area of necrotic tissue caused the loss of an adequate blood supply due to an occlusion. The infarction may be a white infarction composed of platelets and causes necrosis in organ tissues such as heart, spleen, and kidneys. The infarction may be a red infarction composed of red blood cells and fibrin strands in organ tissues of the lung. Disease associated with infarction may include myocardial infarction, pulmonary embolism, cerebrovascular accident (stroke), acute renal failure, peripheral artery occlusive disease (example being gangrene), antiphospholipid syndrome, sepsis, giant cell arthritis, hernia, and volvulus.

[0134] Embolism is a type of pathological condition that can cause ischemia. Embolism may be an object that migrates from one part of the body and causes an occlusion or blockage of a blood vessel in another part of the body. An embolism may be thromboembolism, fat embolism, air embolism, septic embolism, tissue embolism, foreign body embolism, amniotic fluid embolism. Thromboembolism may be a blood clot that is completely or partially detached from the site of thrombosis. Fat embolism may be endogenous fat tissues that escape into the blood circulation. The fracture of bones is one example of a leakage of fat tissue into the ruptured vessels and arteries. Air embolism may be a rupture of alveoli and inhaled air that leaks into the blood vessels. The puncture of the subclavian vein or intravenous therapy are examples of leakage of air into the blood vessels. A gas embolism may be gasses such as nitrogen and helium because insoluble and forming small bubbles in the blood.

Pharmaceutically Acceptable Salts and Excipients

[0135] The flagellin-related compositions (and/or additional agents) described herein can possess a sufficiently basic functional group, which can react with an inorganic or organic acid, or a carboxyl group, which can react with an inorganic or organic base, to form a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

[0136] Pharmaceutically acceptable salts include, by way of non-limiting example, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, .alpha.-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, glycollate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, xylenesulfonate, and tartarate salts.

[0137] The term "pharmaceutically acceptable salt" also refers to a salt of the compositions of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

[0138] In some embodiments, the compositions described herein are in the form of a pharmaceutically acceptable salt.

[0139] Further, any flagellin-related compositions (and/or additional agents) described herein can be administered to a subject as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.

[0140] Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.

Formulations, Administration, Dosing, and Treatment Regimens

[0141] The present invention includes the described flagellin-related compositions (and/or additional agents) in various formulations. Any flagellin-related composition (and/or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

[0142] Where necessary, the flagellin-related compositions (and/or additional agents) can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.

[0143] The formulations comprising the flagellin-related compositions (and/or additional agents) of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art)

[0144] In one embodiment, any flagellin-related composition (and/or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

[0145] Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. In some embodiments, the administering is effected orally or by parenteral injection. The mode of administration can be left to the discretion of the practitioner, and depends in-part upon the site of the medical condition. In most instances, administration results in the release of any agent described herein into the bloodstream.

[0146] Any flagellin-related composition (and/or additional agents) described herein can be administered orally. Such flagellin-related compositions (and/or additional agents) can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer.

[0147] In specific embodiments, it may be desirable to administer locally to the area in need of treatment.

[0148] In one embodiment, any flagellin-related composition (and/or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for oral administration to humans. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can comprise one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving any flagellin-related composition (and/or additional agents) described herein are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade. Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, etc., and mixtures thereof.

[0149] Dosage forms suitable for parenteral administration (e.g. intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.

[0150] The dosage of any flagellin-related composition (and/or additional agents) described herein as well as the dosing schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject's general health, and the administering physician's discretion. Any agent described herein, can be administered prior to (e.g., about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks before), concurrently with, or subsequent to (e.g., about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks after) the administration of an additional therapeutic agent, to a subject in need thereof. In various embodiments any agent described herein is administered about 1 minute apart, about 10 minutes apart, about 30 minutes apart, less than about 1 hour apart, about 1 hour apart, about 1 hour to about 2 hours apart, about 2 hours to about 3 hours apart, about 3 hours to about 4 hours apart, about 4 hours to about 5 hours apart, about 5 hours to about 6 hours apart, about 6 hours to about 7 hours apart, about 7 hours to about 8 hours apart, about 8 hours to about 9 hours apart, about 9 hours to about 10 hours apart, about 10 hours to about 11 hours apart, about 11 hours to about 12 hours apart, no more than about 24 hours apart or no more than 48 hours apart.

[0151] The amount of any flagellin-related composition (and/or additional agents) described herein that is admixed with the carrier materials to produce a single dosage can vary depending upon the subject being treated and the particular mode of administration. In vitro or in vivo assays can be employed to help identify optimal dosage ranges.

[0152] In general, the doses that are useful are known to those in the art. For example, doses may be determined with reference Physicians' Desk Reference, 66th Edition, PDR Network; 2012 Edition (Dec. 27, 2011), the contents of which are incorporated by reference in its entirety.

[0153] The dosage of any flagellin-related composition (and/or additional agents) described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.

[0154] Generally, when orally administered to a mammal, the dosage of any flagellin-related composition (and/or additional agents) described herein may be about 0.001 mg/kg/day to about 100 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day. When orally administered to a human, the dosage of any agent described herein is normally about 0.001 mg to about 1000 mg per day, about 1 mg to about 600 mg per day, or about 5 mg to about 30 mg per day.

[0155] For administration of any flagellin-related composition (and/or additional agents) described herein by parenteral injection, the dosage is normally about 0.1 mg to about 250 mg per day, about 1 mg to about 20 mg per day, or about 3 mg to about 5 mg per day. Injections may be given up to four times daily. Generally, when orally or parenterally administered, the dosage of any agent described herein is normally about 0.1 mg to about 1500 mg per day, or about 0.5 mg to about 10 mg per day, or about 0.5 mg to about 5 mg per day. A dosage of up to about 3000 mg per day can be administered.

[0156] In another embodiment, delivery can be in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

[0157] Any flagellin-related composition (and/or additional agents) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the agents described herein. The invention thus provides single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

[0158] Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0159] In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al, 1985, Science 228:190; During et al, 1989, Ann. Neurol. 25:351; Floward et al., 1989, J. Neurosurg. 71:105).

[0160] In another embodiment, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) may be used.

[0161] Administration of any flagellin-related composition (and/or additional agents) described herein can, independently, be one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years. Administration can be for the duration of about one day or about one month, about two months, about three months, about six months, about one year, about two years, about three years, and may even be for the life of the subject. Chronic, long-term administration will be indicated in many cases. The dosage may be administered as a single dose or divided into multiple doses. In general, the desired dosage should be administered at set intervals for a prolonged period, usually at least over several weeks or months, although longer periods of administration of several months or years or more may be needed.

[0162] The dosage regimen utilizing any flagellin-related composition (and/or additional agents) described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific compound of the invention employed. Any flagellin-related composition (and/or additional agents) described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, any flagellin-related composition (and/or additional agents) described herein can be administered continuously rather than intermittently throughout the dosage regimen.

Combination Therapies and Conjugation

[0163] In some embodiments, the invention provides for flagellin-related compositions and methods that further comprise administering an additional agent to a subject. In some embodiments, the invention pertains to co-administration and/or co-formulation. Any of the compositions described herein may be co-formulated and/or co-administered.

[0164] In some embodiments, any flagellin-related composition described herein acts synergistically when co-administered with another agent and is administered at doses that are lower than the doses commonly employed when such agents are used as monotherapy. In various embodiments, any agent referenced herein may be used in combination with any of the flagellin-related compositions described herein.

[0165] In some embodiments, the present invention pertains to chemotherapeutic agents as additional agents.

[0166] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as minoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; def of amine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE. vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); lapatinib (Tykerb); inhibitors of PKC-.alpha., Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation and pharmaceutically acceptable salts, acids or derivatives of any of the above. In addition, the methods of treatment can further include the use of radiation. In addition, the methods of treatment can further include the use of photodynamic therapy.

[0167] In some embodiments, the flagellin-related compositions (and/or additional agents) described herein, include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the composition such that covalent attachment does not prevent the activity of the composition. For example, but not by way of limitation, derivatives include composition that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of turicamycin, etc. Additionally, the derivative can contain one or more non-classical amino acids.

[0168] In still other embodiments, the flagellin-related compositions (and/or additional agents) described herein further comprise a cytotoxic agent, comprising, in exemplary embodiments, a toxin, a chemotherapeutic agent, a radioisotope, and an agent that causes apoptosis or cell death. Such agents may be conjugated to a composition described herein.

[0169] The flagellin-related compositions (and/or additional agents) described herein may thus be modified post-translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

[0170] Exemplary cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimytotic agents such as the vinca alkaloids, vincristine and vinblastine. Other cytotoxic agents include paditaxel (taxol), ricin, Pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), interferons, and mixtures of these cytotoxic agents.

[0171] Further cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine, bleomycin, VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcytabine, leucovorine, steroids, cyclophosphamide, melphalan, vinca alkaloids (e.g., vinblastine, vincristine, vindesine and vinorelbine), mustines, tyrosine kinase inhibitors, radiotherapy, sex hormone antagonists, selective androgen receptor modulators, selective estrogen receptor modulators, PDGF antagonists, TNF antagonists, IL-1 antagonists, interleukins (e.g. IL-12 or IL-2), IL-12R antagonists, Toxin conjugated monoclonal antibodies, tumor antigen specific monoclonal antibodies, Erbitux, Avastin, Pertuzumab, anti-CD20 antibodies, Rituxan, ocrelizumab, ofatumumab, DXL625, HERCEPTIN.RTM., or any combination thereof. Toxic enzymes from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin may be conjugated to the therapeutic agents (e.g. antibodies) to generate cell-type-specific-killing reagents (Youle, et al., Proc. Nat'l Acad. Sci. USA 77:5483 (1980); Gilliland, et al., Proc. Nat'l Acad. Sci. USA 77:4539 (1980); Krolick, et al., Proc. Nat'l Acad. Sci. USA 77:5419 (1980)).

[0172] Other cytotoxic agents include cytotoxic ribonucleases as described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the invention also relate to radioimmunoconjugates where a radionuclide that emits alpha or beta particles is stably coupled to the antibody, or binding fragments thereof, with or without the use of a complex-forming agent. Such radionuclides include beta-emitters such as Phosphorus-32, Scandium-47, Copper-67, Gallium-67, Yttrium-88, Yttrium-90, Iodine-125, Iodine-131, Samarium-153, Lutetium-177, Rhenium-186 or Rhenium-188, and alpha-emitters such as Astatine-211, Lead-212, Bismuth-212, Bismuth-213 or Actinium-225.

[0173] Exemplary detectable moieties further include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase and luciferase. Further exemplary fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin and dansyl chloride. Further exemplary chemiluminescent moieties include, but are not limited to, luminol. Further exemplary bioluminescent materials include, but are not limited to, luciferin and aequorin. Further exemplary radioactive materials include, but are not limited to, Iodine-125, Carbon-14, Sulfur-35, Tritium and Phosphorus-32.

[0174] In various embodiments, the additional agents of the present invention include one or more of blood products, colony stimulating factors, cytokines and/or growth factors, antibiotics, diluting and/or blocking agents, mobilizing or chelating agents, stem cell transplants, antioxidants or free radicals, and radioprotectants.

[0175] In some embodiments, the blood product is one or more of hematopoietic growth factors, such as filgrastim (e.g. NEUPOGEN), a granulocyte colony-stimulating factor (G-CSF), which may be optionally pegylated (e.g. NEULASTA); sargramostim (LEUKINE); and a granulocyte-macrophage colony-stimulating factor (GM-CSF) and a KSF.

[0176] In some embodiments, the additional agent is one or more cytokines and/or growth factors that may confer radioprotection by replenishing and/or protecting the radiosensitive stem cell populations. Radioprotection with minimal side effects may be achieved by the use of stem cell factor (SCF, c-kit ligand), Flt-3 ligand, and interleukin-1 fragment IL-1 b-rd. Protection may be achieved through induction of proliferation of stem cells (e.g. via all mentioned cytokines), and prevention of their apoptosis (e.g. via SCF). The treatment allows accumulation of leukocytes and their precursors prior to irradiation thus enabling quicker reconstitution of the immune system after irradiation. SCF efficiently rescues lethally irradiated mice with a dose modifying factor (DMF) in range 1.3-1.35 and is also effective against gastrointestinal syndrome. Flt-3 ligand also provides strong protection in mice and rabbits.

[0177] Several factors, while not cytokines by nature, stimulate the proliferation of the immunocytes and may be used in combination with the flagellin-related compositions at the doses and regimens described herein. For example, 5-AED (5-androstenediol) is a steroid that stimulates the expression of cytokines and increases resistance to bacterial and viral infections. Synthetic compounds, such as ammonium tri-chloro(dioxoethylene-O,O'-) tellurate (AS-101), may also be used to induce secretion of numerous cytokines and for combination with the flagellin-related compositions. Growth factors and cytokines may also be used to provide protection against the gastrointestinal syndrome. Keratinocyte growth factor (KGF) promotes proliferation and differentiation in the intestinal mucosa, and increases the post-irradiation cell survival in the intestinal crypts. Flematopoietic cytokine and radioprotectant SCF may also increase intestinal stem cell survival and associated short-term organism survival.

[0178] In certain embodiments, the flagellin-related compositions may be added to a regimen of cytokines (e.g. for FILGRASTIM (G-CSF) 2.5-5 .mu.g/kg/d QD s.c. (100-200 .mu.g/m.sup.2/d); for SARGRAMOSTIM (GM-CSF) 5-10 .mu.g/kg/d QD s.c. (200-400 .mu.g/m.sup.2/d); and/or for PEGFILGRASTIM (pegG-CSF) 6 mg once s.c).

[0179] In some embodiments, the antibiotic is one or more of an anti-bacterial (anti-gram positive and anti-gram negative agents), and/or anti-fungal, and/or anti-viral agent. By way of non-limiting example, in some embodiments, the antibiotic may be a quinolone, e.g. ciprofloxacin, levofloxacin, a third- or fourth-generation cephalosporin with pseudomonal coverage: e.g., cefepime, ceftazidime, or an aminoglycoside: e.g. gentamicin, amikacin, penicillin or amoxicillin, acyclovir, vanomycin. In various embodiments, the antibiotic targets Pseudomonas aeruginosa.

[0180] In some embodiments, the additional agent is a diluting and/or blocking agents. For example, stable iodide compounds may be used (e.g. liquid (ThyroShield) and the tablet (losat) KI (NUKEPILLS), Rad Block, I.A.A.A.M., No-Rad, Life Extension (LEF), KI4U, NukeProtect, ProKI)). A 130 mg dose of daily of oral potassium iodide (KI) may be used in conjunction with the flagellin-related compositions.

[0181] In some embodiments, the additional agent is a mobilizing or chelating agent. Illustrative mobilizing agents include propylthiouracil and methimazole, with may reduce the thyroid's retention of radioactive compounds. Further the flagellin-related compositions can be used alongside increasing oral fluids to a human patient to promote excretion. Illustrative chelating agents are water soluble and excreted in urine. Illustrative chelating agents include DTPA and EDTA. Dimercaprol forms stable chelates with mercury, lead, arsenic, gold, bismuth, chromium, and nickel and therefore may be considered for the treatment of internal contamination with the radioisotopes of these elements. Penicillamine chelates copper, iron, mercury, lead, gold, and possibly other heavy metals.

[0182] In some embodiments, the additional agent is a stem cell transplant (e.g. bone marrow transplant, PBSCT, MSCT). In some embodiments the stem cell transplant is Remestemcel-L (Osiris) of CLT-008 (Cellerant).

[0183] In some embodiments, the additional agent is an antioxidant or free radical. Antioxidants and free radical scavengers that may be used in the practice of the invention include, but are not limited to, thiols, such as cysteine, cysteamine, glutathione and bilirubin; amifostine (WR-2721); vitamin A; vitamin C; vitamin E; and flavonoids such as Indian holy basil (Ocimum sanctum), orientin and vicenin.

[0184] In some embodiments, the additional agent may be a radioprotectant e.g. an antioxidant (e.g. amifostine and vitamin E, gamma tocotrienol (a vitamin-E moiety), and genistein (a soy byproduct)), a cytokine (e.g. a stem cell factor), a growth factor (e.g. keratinocyte growth factor), a steroid (e.g. 5-androstenediol), ammonium triohloro(dioxoethylene-O,O')tellurate, thyroid protecting agents (e.g. Potassium iodide (KI) or potassium iodate (KIO.sub.3) (e.g. liquid (ThyroShield) and the tablet (losat) KI (NUKEPILLS), Rad Block, I.A.A.A.M., No-Rad, Life Extension (LEF), KI4U, NukeProtect, ProKI)), anti-nausea agents, anti-diarrhea agents, antiemetics ((e.g. oral prophylactic antiemetics) such as granisetron (KYTRIL), ondansetron (ZOFRAN), and 5-HT3 blockers with or without dexamethasone), analgesics, anxiolytics, sedatives, cytokine therapy, and antibiotics.

[0185] Gastric lavage and emetics, which can be used as additional agents, can be used to empty the stomach promptly and completely after the ingestion of poisonous materials. Purgatives, laxatives, and enemas, which also can be used as additional agents, can reduce the residence time of radioactive materials in the colon. Further additional agents include ion exchange resins which may limit gastrointestinal uptake of ingested or inhaled radionuclides, ferric ferrocyanide (Prussian blue) and alginates, which have been used in humans to accelerate fecal excretion of cesium-137.

[0186] In still other embodiments, the additional agent may be an agent used to treat radiation-related disorders, such as, for example, 5-AED (Humanetics), Ex-RAD (Onconova), Beclometasone Dipropionate (Soligenix), detoxified endotoxin, EA-230 (Exponential Biotherapies), ON-01210.Na (Onconova), Sothrombomodulin alfa (PAION), Remestemcel-L (Osiris), BIO-100, BIO-200, BIO-300, BIO-400, BIO-500 (Flumanetics), CLT-008 (Cellerant), EDL-2000 (RxBio), Homspera (ImmuneRegen), MnDTEIP (Aeolus Pharmaceuticals), RLIP-76 (Terapio), and RX-100 and RX 101 (RxBio).

[0187] Further, in some embodiments, the flagellin-related compositions (and/or additional agents) can be used in combination with shielding; reduction of radiation exposure time; and use of agents to reduce body exposure (e.g. uses of gloves, face mask, hood, protective clothing (e.g. anticontamination suits such as TYVEK ANTI-C SUITS or MOPP-4)).

Viral Vectors Encoding Therapeutic Agents and Cells Expressing Same

[0188] In various embodiments, the flagellin-related compositions (and/or additional agents) of the present invention is expressed by viral vectors and transformed cells. For example, the viral vectors and transformed human cells described herein may express the present compositions. In an embodiment, the viral vector or human cells expressing the therapeutic agent are capable of expressing the agent proximal to a tumor. The cells can be modified in vivo, or alternatively cells modified ex vivo can be administered to a patient by a variety of methods, such as by injection.

[0189] In one embodiment, the cell is a tumor cell. For ex vivo transformation, such tumor cells can be irradiated to eliminate the ability of the cell to replicate, as known in the art, while maintaining the transient expression of the therapeutic agent after administration. For in vivo transformation, non-integrative expression vectors may be preferred.

[0190] In certain embodiments, the tumor cell is autologous or endogenous. In the former instance, the tumor cell is taken from a patient, transfected or transduced with a construct encoding the therapeutic agent and re-introduced to the patient, for example after irradiation. In the latter instance, the tumor cell is transformed in vivo by local administration of an appropriate construct as described herein.

[0191] In an alternative embodiment, the modified tumor cell is allogeneic. The allogeneic tumor cell thus can be maintained in a cell line. In this instance, the tumor cell can be selected from the cell line, irradiated, and introduced to the patent.

[0192] Modified human cells capable of producing the flagellin-related compositions (and/or additional agents) can be made by transfecting or transducing the cells with an expression vector encoding the therapeutic agent. Expression vectors for the expression of the flagellin-related compositions (and/or additional agents), or a combination of therapeutic agents can be made by methods well known in the art.

[0193] In various embodiments, the flagellin-related compositions (and/or additional agents) can be administered to a patient in the form of one or more nucleic acid construct.

[0194] In one embodiment, the construct comprises a retroviral vector. Retroviral vectors are capable of permanently integrating DNA encoding flagellin-related compositions (and/or additional agents) into the cell genome. Thus, in the case of ex vivo manipulation of autologous or allogeneic cells, stable cell lines that constitutively produce the flagellin-related compositions (and/or additional agents) can be prepared. In an embodiment, the cells are irradiated prior to administration to a patient. The irradiated cells produce the flagellin-related compositions (and/or additional agents) for a limited period of time.

[0195] In one embodiment, the expression construct comprises an SFV vector, which demonstrates high levels of transient expression in mammalian cells. The SFV vector is described, for example, in Lundstrom, Expert Opin. Biol. Ther. 3:771-777 (2003), incorporated herein by reference in its entirety. Thus, in the case of in vivo manipulation of endogenous cells in a patient, transient expression of high levels of the flagellin-related compositions (and/or additional agents) can be accomplished.

[0196] Systems capable of expressing recombinant protein in vivo are known in the art. By way of example, the system can use the 2A mediated antibody expression system disclosed in Fang et al., Nature Biotech. 23(5): 584-590 (2005) and U.S. Patent Publication No. 2005/0003506, the disclosures of which are expressly incorporated by reference herein in their entirety. Other systems known in the art are contemplated, and can also be adapted to produce the flagellin-related compositions (and/or additional agents) in vivo as described herein.

[0197] In various embodiments, administration of the flagellin-related composition (and/or additional agents) expressing cells disclosed herein or the agents of the invention disclosed herein can be combined with administration of cytokines that stimulate antigen-presenting cells such as granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interleukin 3 (IL-3), interleukin 12 (IL-12), interferon, etc., or cellular vaccines capable of expressing such cytokines. In some embodiments, the flagellin-related composition (and/or additional agents) expressing cells are further modified to express such cytokines. Additional proteins and/or cytokines known to enhance T cell proliferation and secretion, such as IL-1, IL-2, B7, anti-CD3 and anti-CD28 can be employed simultaneously or sequentially with the flagellin-related compositions (and/or additional agents) of the invention to augment the immune response, and/or stimulate co-stimulatory pathways and/or induce activation/proliferation of effector T cells.

Vectors and Methods of Transformation

[0198] Expression vectors encoding the flagellin-related compositions (and/or additional agents) may be viral or non-viral. Viral vectors are preferred for use in vivo. Expression vectors of the invention comprise a nucleic acid encoding the flagellin-related compositions (and/or additional agents), or a complement thereof, operably linked to an expression control region, or complement thereof, that is functional in a mammalian cell. The expression control region is capable of driving expression of the operably linked blocking and/or stimulating agent encoding nucleic acid such that the blocking and/or stimulating agent is produced in a human cell transformed with the expression vector.

[0199] Expression control regions are regulatory polynucleotides (sometimes referred to herein as elements), such as promoters and enhancers, that influence expression of an operably linked nucleic acid.

[0200] An expression control region of an expression vector of the invention is capable of expressing operably linked encoding nucleic acid in a human cell. In an embodiment, the cell is a tumor cell. In another embodiment, the cell is a non-tumor cell.

[0201] In an embodiment, the expression control region confers regulatable expression to an operably linked nucleic acid. A signal (sometimes referred to as a stimulus) can increase or decrease expression of a nucleic acid operably linked to such an expression control region. Such expression control regions that increase expression in response to a signal are often referred to as inducible. Such expression control regions that decrease expression in response to a signal are often referred to as repressible. Typically, the amount of increase or decrease conferred by such elements is proportional to the amount of signal present; the greater the amount of signal, the greater the increase or decrease in expression.

[0202] In an embodiment, the present invention contemplates the use of inducible promoters capable of effecting high level of expression transiently in response to a cue. When in the proximity of a tumor cell, a cell transformed with an expression vector for the flagellin-related compositions (and/or additional agents) comprising such an expression control sequence is induced to transiently produce a high level of the agent by exposing the transformed cell to an appropriate cue. Exemplary inducible expression control regions include those comprising an inducible promoter that is stimulated with a cue such as a small molecule chemical compound. Particular examples can be found, for example, in U.S. Pat. Nos. 5,989,910, 5,935,934, 6,015,709, and 6,004,941, each of which is incorporated herein by reference in its entirety.

[0203] Expression control regions include full-length promoter sequences, such as native promoter and enhancer elements, as well as subsequences or polynucleotide variants which retain all or part of full-length or non-variant function. As used herein, the term "functional" and grammatical variants thereof, when used in reference to a nucleic acid sequence, subsequence or fragment, means that the sequence has one or more functions of native nucleic acid sequence (e.g., non-variant or unmodified sequence).

[0204] As used herein, "operable linkage" refers to a physical juxtaposition of the components so described as to permit them to function in their intended manner. In the example of an expression control element in operable linkage with a nucleic acid, the relationship is such that the control element modulates expression of the nucleic acid. Typically, an expression control region that modulates transcription is juxtaposed near the 5' end of the transcribed nucleic acid (i.e., "upstream"). Expression control regions can also be located at the 3' end of the transcribed sequence (i.e., "downstream") or within the transcript (e.g., in an intron). Expression control elements can be located at a distance away from the transcribed sequence (e.g., 100 to 500, 500 to 1000, 2000 to 5000, or more nucleotides from the nucleic acid). A specific example of an expression control element is a promoter, which is usually located 5' of the transcribed sequence. Another example of an expression control element is an enhancer, which can be located 5' or 3' of the transcribed sequence, or within the transcribed sequence.

[0205] Expression systems functional in human cells are well known in the art, and include viral systems. Generally, a promoter functional in a human cell is any DNA sequence capable of binding mammalian RNA polymerase and initiating the downstream (3') transcription of a B7-H4 ligand coding sequence into mRNA. A promoter will have a transcription initiating region, which is usually placed proximal to the 5' end of the coding sequence, and typically a TATA box located 25-30 base pairs upstream of the transcription initiation site. The TATA box is thought to direct RNA polymerase II to begin RNA synthesis at the correct site. A promoter will also typically contain an upstream promoter element (enhancer element), typically located within 100 to 200 base pairs upstream of the TATA box. An upstream promoter element determines the rate at which transcription is initiated and can act in either orientation. Of particular use as promoters are the promoters from mammalian viral genes, since the viral genes are often highly expressed and have a broad host range. Examples include the SV40 early promoter, mouse mammary tumor virus LTR promoter, adenovirus major late promoter, herpes simplex virus promoter, and the CMV promoter.

[0206] Typically, transcription termination and polyadenylation sequences recognized by mammalian cells are regulatory regions located 3' to the translation stop codon and thus, together with the promoter elements, flank the coding sequence. The 3' terminus of the mature mRNA is formed by site-specific post-translational cleavage and polyadenylation. Examples of transcription terminator and polyadenylation signals include those derived from SV40. Introns may also be included in expression constructs.

[0207] There are a variety of techniques available for introducing nucleic acids into viable cells. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, polymer-based systems, DEAE-dextran, viral transduction, the calcium phosphate precipitation method, etc. For in vivo gene transfer, a number of techniques and reagents may also be used, including liposomes; natural polymer-based delivery vehicles, such as chitosan and gelatin; viral vectors are also preferred for in vivo transduction. In some situations it is desirable to provide a targeting agent, such as an antibody or ligand specific for a tumor cell surface membrane protein. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g., capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al, Proc. Natl. Acad. Sci. USA 87, 3410-3414 (1990).

[0208] Where appropriate, gene delivery agents such as, e.g., integration sequences can also be employed. Numerous integration sequences are known in the art (see, e.g., Nunes-Duby et al., Nucleic Acids Res. 26:391-406, 1998; Sadwoski, J. Bacteriol., 165:341-357, 1986; Bestor, Cell, 122(3):322-325, 2005; Plasterk et al., TIG 15:326-332, 1999; Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). These include recombinases and transposases. Examples include Cre (Sternberg and Hamilton, J. Mol. Biol., 150:467-486, 1981), lambda (Nash, Nature, 247, 543-545, 1974), Flp (Broach, et al., Cell, 29:227-234, 1982), R (Matsuzaki, et al., J. Bacteriology, 172:610-618, 1990), cpC31 (see, e.g., Groth et al., J. Mol. Biol. 335:667-678, 2004), sleeping beauty, transposases of the mariner family (Plasterk et al., supra), and components for integrating viruses such as AAV, retroviruses, and antiviruses having components that provide for virus integration such as the LTR sequences of retroviruses or lentivirus and the ITR sequences of AAV (Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003).

Viral Vectors

[0209] In one aspect, the invention provides expression vectors for the expression of the flagellin-related compositions (and/or additional agents) that are viral vectors. Many viral vectors useful for gene therapy are known (see, e.g., Lundstrom, Trends Biotechnol., 21: 1 17, 122, 2003.

[0210] Exemplary viral vectors include those selected from Antiviruses (LV), retroviruses (RV), adenoviruses (AV), adeno-associated viruses (AAV), and a viruses, though other viral vectors may also be used. For in vivo uses, viral vectors that do not integrate into the host genome are preferred, such as a viruses and adenoviruses, with a viruses being especially preferred. Exemplary types of a viruses include Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV), with SFV being especially preferred. For in vitro uses, viral vectors that integrate into the host genome are preferred, such as retroviruses, AAV, and Antiviruses.

[0211] In an embodiment, the viral vector provides for transient high level expression in a transduced human cell.

[0212] In one embodiment, the viral vector does not provide for integration of the flagellin-related composition (and/or additional agents) encoding nucleic acid into the genome of a transduced human cell.

[0213] In another embodiment, the viral vector provides for integration of the flagellin-related compositions (and/or additional agents) encoding nucleic acid into the genome of a transduced human cell.

[0214] In one embodiment, the invention provides methods of transducing a human cell in vivo, comprising contacting a solid tumor in vivo with a viral vector of the invention.

[0215] In another embodiment, the invention provides methods of transducing a human cell ex vivo, comprising contacting a human cell ex vivo with the viral vector of the invention. In one embodiment, the human cell is a tumor cell. In one embodiment, the human cell is allogeneic. In one embodiment, the tumor cell is derived from the patient. In one embodiment, the human cell is a non-tumor cell, such as, e.g., an antigen presenting cell (APC), or a T cell.

[0216] Virus particle coats may be modified to alter specificity and improve cell/tissue targeting, as is well known in the art. Viral vectors may also be delivered in other vehicles, for example, liposomes. Liposomes may also have targeting moieties attached to their surface to improve cell/tissue targeting.

[0217] In some embodiments, the present invention provides human cells expressing the therapeutic agent of the invention. In various embodiments, the human cells express the agent proximal to a tumor cell of, for example, a patient.

Diagnostic and Predictive Methods

[0218] In some aspects, the invention provides a method for identifying a subject who may respond to treatment with a TLR5 agonist. In some embodiments, the present invention provides a method of determining if a patient's tumor expresses TLR5.

[0219] TLR5 expression may be a predictive marker for determining the grade and/or progression of a patient's tumor or dysplasia. In some embodiments, the flagellin-related compositions (and/or additional agents) described herein are useful in determining a tumor grade and/or stage of a particular cancer.

[0220] Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade may vary with each type of cancer and are known in the art.

[0221] Histologic grade, also called differentiation, refers to how much the tumor cells resemble normal cells of the same tissue type. Nuclear grade refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing.

[0222] Based on the microscopic appearance of cancer cells, pathologists commonly describe tumor grade by four degrees of severity: Grades 1, 2, 3, and 4. The cells of Grade 1 tumors resemble normal cells, and tend to grow and multiply slowly. Grade 1 tumors are generally considered the least aggressive in behavior. Conversely, the cells of Grade 3 or Grade 4 tumors do not look like normal cells of the same type. Grade 3 and 4 tumors tend to grow rapidly and spread faster than tumors with a lower grade. The American Joint Committee on Cancer recommends the following guidelines for grading tumors: GX-grade cannot be assessed (Undetermined grade); G1-well-differentiated (Low grade); G2-moderately differentiated (Intermediate grade); G3-poorly differentiated (High grade); and G4-undifferentiated (High grade).

[0223] Grading systems are different for each type of cancer. For example, pathologists use the Gleason system to describe the degree of differentiation of prostate cancer cells. The Gleason system uses scores ranging from Grade 2 to Grade 10. Lower Gleason scores describe well-differentiated, less aggressive tumors. Higher scores describe poorly differentiated, more aggressive tumors. Other grading systems include, for example, the Bloom-Richardson system for breast cancer and the Fuhrman system for kidney cancer.

[0224] Cancer survival rates or survival statistics may refer to the percentage of people who survive a certain type of cancer for a specific amount of time. Cancer statistics often use an overall five-year survival rate. For example the overall five-year survival rate for bladder cancer is 80 percent, i.e. 80 of every 100 of people diagnosed with bladder cancer were living five years after diagnosis and 20 out of every 100 died within five years of a bladder cancer diagnosis. Other types of survival rates may be used, for example: disease-free survival rate (number of people with cancer who achieve remission) and progression-free survival rate, (number of people who still have cancer, but their disease is not progressing).

[0225] In some embodiments, the flagellin-related compositions (and/or additional agents) described herein are useful in establishing a tumor grade for the purposes of diagnosis or prognosis of a particular cancer, including prognosing the survival rate, disease-free survival rate and/or progression-free survival rate prior to, during and/or after administration of a flagellin-related composition (and/or additional agents) disclosed herein and/or prior to, during and/or after administration of an anti-cancer agent or therapy.

[0226] In some embodiments, the flagellin-related compositions (and/or additional agents) described herein are used as part of a method of scoring tumor grades to assist in the selection and/or predict the outcome of treatment. For example, the flagellin-related compositions (and/or additional agents) described herein may be used to diagnose or identify the cancer from a patient as stage I (e.g. not locally advanced) predicting the need for less aggressive treatment. Alternatively, the therapeutic agent described herein may be used to diagnose or identify the cancer from a patient as stage II or III, (e.g. the cancer may be locally advanced) predicting the need for more aggressive treatment. Similarly, the flagellin-related compositions (and/or additional agents) described herein may be used to diagnose or identify the cancer from a patient as stage IV, or is metastatic, predicting the need for very aggressive treatment.

[0227] In some embodiments, the cancer is non-resectable. A non-resectable cancer is a malignancy which cannot be surgically removed, due either to the number of metastatic foci, or because it is in a surgical danger zone. In some embodiments, the therapeutic agent described herein is used as part of a method of treating tumors to assist in selecting the nature and/or timing/administration of treatment including, for example, administering anti-cancer agents which reduce tumor volume, prior to chemotherapeutic and/or radiation treatment, and/or increase or decrease the dose of chemotherapy or radiation administered to a patient.

[0228] In some embodiments, the cancer is multidrug resistant. For example, the patient may have undergone one or more cycles of chemotherapy, without substantial response. Alternatively or in addition, the tumor has one or more markers of multidrug resistance. Thus, as used herein, the term multidrug resistant means a cancer exhibiting non-responsiveness to at least one cycle of combination chemotherapy, or alternatively, has scored (diagnostically) as resistant to at least two of (including comparable agent to) docetaxel, paclitaxel, doxorubicin, epirubicin, carboplatin, cisplatin, vinblastine, vincristine, oxaliplatin, carmustine, fluorouracil, gemcitabine, cyclophosphamide, ifosfamide, topotecan, erlotinib, etoposide, and mitomycin. In some embodiments, the therapeutic agents described herein are useful in establishing whether the tumor is responsive to one or more chemotherapeutics, radiation therapy and/or other anti-cancer therapy.

[0229] In other embodiments, the cancer is a recurrence following conventional chemotherapy of an initial cancer. Often, recurrent cancer has developed drug resistance, and thus is particularly difficult to treat and often comes with a poor prognosis for survival.

[0230] In some embodiments, the flagellin-related compositions (and/or additional agents) described herein are used as part of a method of tumor evaluation which takes the place of a performance status. Performance status can be quantified using any system and methods for scoring a patient's performance status which are known in the art. The measure is often used to determine whether a patient can receive chemotherapy, dose adjustment, and/or to determine intensity of palliative care. There are various scoring systems, including the Karnofsky score and the Zubrod score. Parallel scoring systems include the Global Assessment of Functioning (GAF) score, which has been incorporated as the fifth axis of the Diagnostic and Statistical Manual (DSM) of psychiatry.

[0231] Higher performance status (e.g., at least about 80%, or at least about 70% using the Karnofsky scoring system) may indicate treatment to prevent progression of the disease state, and enhance the patient's ability to accept chemotherapy and/or radiation treatment. For example, when the therapeutic agent described herein indicates higher performance status, the patient is ambulatory and capable of self care. In other embodiments, when the therapeutic agent described herein indicates a low performance status (e.g., less than about 50%, less than about 30%, or less than about 20% using the Karnofsky scoring system), the patient is largely confined to bed or chair and is disabled even for self-care.

[0232] The Karnofsky score runs from 100 to 0, where 100 is "perfect" health and 0 is death. The score may be employed at intervals of 10, where: about 100% is normal, no complaints, no signs of disease; about 90% is capable of normal activity, few symptoms or signs of disease, about 80% is normal activity with some difficulty, some symptoms or signs; about 70% is caring for self, not capable of normal activity or work; about 60% is requiring some help, can take care of most personal requirements; about 50% requires help often, requires frequent medical care; about 40% is disabled, requires special care and help; about 30% is severely disabled, hospital admission indicated but no risk of death; about 20% is very ill, urgently requiring admission, requires supportive measures or treatment; and about 10% is moribund, rapidly progressive fatal disease processes.

[0233] The Zubrod scoring system for performance status includes: 0, fully active, able to carry on all pre-disease performance without restriction; 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2, ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than about 50% of waking hours; 3, capable of only limited self-care, confined to bed or chair more than about 50% of waking hours; 4, completely disabled, cannot carry on any self-care, totally confined to bed or chair; 5, dead.

[0234] In some embodiments, histological samples of tumors are graded using the therapeutic agent described herein according to Elston & Ellis, Histopathology, 1991, 19:403-10, which is hereby incorporated by reference in its entirety. In some embodiments, the therapeutic agent described herein is useful in establishing a tumor grade for the purposes of diagnosis or prognosis of a particular cancer.

[0235] In some embodiments, the flagellin-related compositions (and/or additional agents) described herein are useful for evaluating a subject and/or a specimen from a subject (e.g. a cancer patient). In some embodiments, evaluation is one or more of diagnosis, prognosis, and/or response to treatment.

[0236] Diagnosis refers to the process of attempting to determine or identify a possible disease or disorder, such as, for example, cancer. Prognosis refers to the predicting of a likely outcome of a disease or disorder, such as, for example, cancer. A complete prognosis often includes the expected duration, the function, and a description of the course of the disease, such as progressive decline, intermittent crisis, or sudden, unpredictable crisis. Response to treatment is a prediction of a patient's medical outcome when receiving a treatment. Responses to treatment can be, by way of non-limiting example, pathological complete response, survival, and probability of recurrence.

[0237] In various embodiments, the diagnostic and predictive methods described herein comprise evaluating a presence, absence, or level of a protein. In another embodiment, the methods described herein comprise evaluating a presence, absence, or level of expression of a nucleic acid. The compositions described herein may be used for these measurements. For example, in some embodiments, the methods described herein comprise contacting a specimen of the tumor or cells cultured from the tumor with a therapeutic agent as described herein.

[0238] In some embodiments, the present invention includes the measurement of a tumor specimen, including biopsy or surgical specimen samples. In some embodiments, the biopsy is a human biopsy. In various embodiments, the biopsy is any one of a frozen tumor tissue specimen, cultured cells, circulating tumor cells, and a formalin-fixed paraffin-embedded tumor tissue specimen. In some embodiments, the tumor specimen may be a biopsy sample, such as a frozen tumor tissue (cryosection) specimen. As is known in the art, a cryosection may employ a cryostat, which comprises a microtome inside a freezer. The surgical specimen is placed on a metal tissue disc which is then secured in a chuck and frozen rapidly to about -20.degree. C. to about -30.degree. C. The specimen is embedded in a gel like medium consisting of, for example, poly ethylene glycol and polyvinyl alcohol. The frozen tissue is cut frozen with the microtome portion of the cryostat, and the section is optionally picked up on a glass slide and stained. In some embodiments, the tumor specimen may be a biopsy sample, such as cultured cells. These cells may be processed using the usual cell culture techniques that are known in the art. These cells may be circulating tumor cells. In some embodiments, the tumor specimen may be a biopsy sample, such as a formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen. As is known in the art, a biopsy specimen may be placed in a container with formalin (a mixture of water and formaldehyde) or some other fluid to preserve it. The tissue sample may be placed into a mold with hot paraffin wax. The wax cools to form a solid block that protects the tissue. This paraffin wax block with the embedded tissue is placed on a microtome, which cuts very thin slices of the tissue. In certain embodiments, the tumor specimen contains less than about 100 mg of tissue, or in certain embodiments, contains about 50 mg of tissue or less. The tumor specimen (or biopsy) may contain from about 20 mg to about 50 mgs of tissue, such as about 35 mg of tissue. The tissue may be obtained, for example, as one or more (e.g., 1, 2, 3, 4, or 5) needle biopsies (e.g., using a 14-gauge needle or other suitable size). In some embodiments, the biopsy is a fine-needle aspiration in which a long, thin needle is inserted into a suspicious area and a syringe is used to draw out fluid and cells for analysis. In some embodiments, the biopsy is a core needle biopsy in which a large needle with a cutting tip is used during core needle biopsy to draw a column of tissue out of a suspicious area. In some embodiments, the biopsy is a vacuum-assisted biopsy in which a suction device increases the amount of fluid and cells that is extracted through the needle. In some embodiments, the biopsy is an image-guided biopsy in which a needle biopsy is combined with an imaging procedure, such as, for example, X ray, computerized tomography (CT), magnetic resonance imaging (MRI) or ultrasound. In other embodiments, the sample may be obtained via a device such as the MAMMOTOME.RTM. biopsy system, which is a laser guided, vacuum-assisted biopsy system for breast biopsy.

[0239] In some embodiments, the diagnostic and predictive methods and/or evaluation may direct treatment (including treatment with the therapeutic agents described herein). In one embodiment, the evaluation may direct the use or withholding of adjuvant therapy after resection. Adjuvant therapy, also called adjuvant care, is treatment that is given in addition to the primary, main or initial treatment. By way of non-limiting example, adjuvant therapy may be an additional treatment usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to occult disease. In some embodiments, the therapeutic agents described herein are used as an adjuvant therapy in the treatment of a cancer. In some embodiments, the therapeutic agents described herein are used as the sole adjuvant therapy in the treatment of a cancer. In some embodiments, the therapeutic agents described herein are withheld as an adjuvant therapy in the treatment of a cancer. For example, if a patient is unlikely to respond to a therapeutic agent described herein or will have a minimal response, treatment may not be administered in the interest of quality of life and to avoid unnecessary toxicity from ineffective chemotherapies. In such cases, palliative care may be used.

[0240] In some embodiments the therapeutic agents described herein are administered as a neoadjuvant therapy prior to resection. In certain embodiments, neoadjuvant therapy refers to therapy to shrink and/or downgrade the tumor prior to any surgery. In some embodiments, neoadjuvant therapy means chemotherapy administered to cancer patients prior to surgery. In some embodiments, neoadjuvant therapy means a therapeutic agent described herein is administered to cancer patients prior to surgery. Types of cancers for which neoadjuvant chemotherapy is commonly considered include, for example, breast, colorectal, ovarian, cervical, bladder, and lung. In some embodiments, the therapeutic agents described herein are used as a neoadjuvant therapy in the treatment of a cancer. In some embodiments, the use is prior to resection. In some embodiments, the therapeutic agents described herein are withheld as a neoadjuvant therapy in the treatment of a cancer. For example, if a patient is unlikely to respond to a therapeutic agent described herein or will have a minimal response, treatment may not be administered in the interest of quality of life and to avoid unnecessary toxicity from ineffective chemotherapies. In such cases, palliative care may be used.

Subjects and/or Animals

[0241] In some embodiments, the subject and/or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In other embodiments, the subject and/or animal is a non-mammal, such, for example, a zebrafish. In some embodiments, the subject and/or animal may comprise fluorescently-tagged cells (with e.g. GFP). In some embodiments, the subject and/or animal is a transgenic animal comprising a fluorescent cell.

[0242] In some embodiments, the subject and/or animal is a human. In some embodiments, the human is a pediatric human. In other embodiments, the human is an adult human. In other embodiments, the human is a geriatric human. In other embodiments, the human may be referred to as a patient.

[0243] In certain embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old.

[0244] In other embodiments, the subject is a non-human animal, and therefore the invention pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal.

Kits

[0245] The invention provides kits that can simplify the administration of any agent described herein. An exemplary kit of the invention comprises any composition described herein in unit dosage form. In one embodiment, the unit dosage form is a container, such as a pre-filled syringe, which can be sterile, containing any agent described herein and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. The kit can further comprise a label or printed instructions instructing the use of any agent described herein. The kit may also include a lid speculum, topical anesthetic, and a cleaning agent for the administration location. The kit can also further comprise one or more additional agent described herein. In one embodiment, the kit comprises a container containing an effective amount of a composition of the invention and an effective amount of another composition, such those described herein.

Definitions

[0246] The following definitions are used in connection with the invention disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this invention belongs.

[0247] As used herein, "a," "an," or "the" can mean one or more than one.

[0248] Further, the term "about" when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language "about 50" covers the range of 45 to 55.

[0249] An "effective amount," when used in connection with medical uses is an amount that is effective for providing a measurable treatment, prevention, or reduction in the rate of pathogenesis of a disease of interest.

[0250] As used herein, something is "decreased" if a read-out of activity and/or effect is reduced by a significant amount, such as by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or more, up to and including at least about 100%, in the presence of an agent or stimulus relative to the absence of such modulation. As will be understood by one of ordinary skill in the art, in some embodiments, activity is decreased and some downstream read-outs will decrease but others can increase.

[0251] Conversely, activity is "increased" if a read-out of activity and/or effect is increased by a significant amount, for example by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or more, up to and including at least about 100% or more, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 50-fold, at least about 100-fold, in the presence of an agent or stimulus, relative to the absence of such agent or stimulus.

[0252] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word "include," and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms "can" and "may" and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[0253] Although the open-ended term "comprising," as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as "consisting of" or "consisting essentially of."

[0254] As used herein, the words "preferred" and "preferably" refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.

[0255] The amount of compositions described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. flagellin-related compositions (and/or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a patient suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.

[0256] Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to about 50% of the population) and the ED50 (the dose therapeutically effective in about 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. In some embodiments, compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from in vitro assays, including, for example, cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model. Levels of the described compositions in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0257] In certain embodiments, the effect will result in a quantifiable change of at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 70%, or at least about 90%. In some embodiments, the effect will result in a quantifiable change of about 10%, about 20%, about 30%, about 50%, about 70%, or even about 90% or more. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.

[0258] In certain embodiments, a pharmacologically effective amount that will treat cancer will modulate the symptoms typically by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%. In exemplary embodiments, such modulations will result in, for example, statistically significant and quantifiable changes in the numbers of cancerous cells.

[0259] This invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1: Engineering of Flagellin-Related Compositions with Improved Efficacy Relative to CBLB502

[0260] a. Structure-Activity Relationship Analysis (SAR):

[0261] The results of analysis, which included a combination of site-directed mutagenesis and deletions are illustrated in FIG. 2. Resulting variants of CBLB502 were expressed in E. coli, purified and characterized by: (i) relative binding affinity in cell-free system by competition-based fluorescent polarization (FP) assay with recombinant purified fragment of TLR5 ectodomain of fish origin and (ii) relative signaling efficiency by cell-based luciferase reporter assay using wild-type CBLB502 as a reference (as described in Yoon et al. (2012)). This analysis confirmed the role of amino acid segments and certain residues of domain D1 in the formation of primary and secondary interfaces predicted from 3D structure (FIG. 3). It also revealed the importance of domain D0 for signaling (but not primary binding) although the actual role of this domain remained unknown. This analysis also revealed that only the C-terminal segment of D0 (C_D0) is essential, while the N-terminal segment can be eliminated without loss of signaling activity (as in, for example, the deletion variant S33 (SEQ ID NO: 17)).

[0262] In vivo testing of the signaling activity of the mutants in primary and secondary interface as well as the delta-D0 deletion variant of CBLB502 revealed a correlation with the in vitro signaling data. This was established by injection of varying doses of respective mutants (recombinant purified and detoxed proteins) into NF-kB-luciferase reporter mice and measurement of luciferase activity in various organs (See FIG. 4, panels A-E).

[0263] Briefly, NF-kB luciferase reporter mice were injected s.c with CBLB502 mutants (three mice per group) as indicated. The relative amounts of injection used were based on their signaling efficacy in cell based NF-kB reporter assays. Organs were collected 3 hours post injection and snap frozen in dry ice. Tissue homogenates were prepared by pulverization of organs followed by lysis using RIPA buffer supplemented with protease inhibitors. For luciferase assays, 20 ul of each lysate was mixed with 30 ul of luciferin reagent (Bright-Glo luciferase assay system, Promega Inc.) and luciferase activity was quantified using a luminometer. Luciferase activity was normalized based on protein concentration measured using Bradford assay. The results demonstrate that while the response in the liver observed for the S33 mutant was moderately increased about 3-fold, this mutant showed a much stronger enhancement (>10-fold at the same dose of 0.3 .mu.g) was observed in the bladder and large intestine.

[0264] During additional systematic SAR, a large number of truncated variants were generated and characterized primarily for signaling activity (using luciferase-based or a standard CBLB502 bioactivity assay using LacZ reporter system). These deletions (partially illustrated by diagrams in FIG. 5) allowed us to refine the boundaries of the minimal essential core and address a potential relevance of the length (from 33 aa to 12 aa) and position of the tag (N-terminal vs. C-terminal) as well as test the possibility to minimize a linker region (as in the construct "33ML" (SEQ ID NO: 35)).

[0265] A list of CBLB502 variants comprising an extensive SAR analysis is provided in Table 2. Among the most important observations, without wishing to be bound by theory, is the principle possibility to eliminate at least one half of the indigenous C_D0 segment, leaving only its N-terminal half (470-485) capped by the C-terminal His-tag (the presence of the cap is essential for activity as the variant 33-485 loses about 90% of signaling activity, see Table 2). These observations taken together suggest, without wishing to be bound by theory, that the D0 domain has only minor (if any) contribution to direct interactions with TLR5, and its role may be limited to maintaining structural integrity of D1 domain. On the other hand, the residual C_D0 segment (470-485) cannot be removed or replaced by the C-terminal half of C_D0 (485-504) or other sequences (e.g. fragment of GFP as in CGD1 or the N-D0 segment as in a new construct MF233 (SEQ ID NO: 123), see below Table 2). At the same time, some of the polar residues could be replaced by alanine in this segment without appreciable loss of activity (see Table 2).

TABLE-US-00002 TABLE 2 CBLB502 deletion/fusion variants Relative EC50 vs 502 CBLB502 Length Binding Signaling Signaling variant ID Brief description (aa) Modular composition (design) Objectives Conclusions (FP) (Luc) (LacZ) 502 Starting point- 329 6xH-EK-Tag(33a~"N-Tag-HEK")-ND0_ND1 (1-175)-Linker16-CD1_CD0 (401-504) 1.0 1.0 1.0 original construct ['aa 32-44: N-terminal spoke region (NS); aa 464-469: C-terminal spoke region (CS)] SY3 Delta D0: described 262 6xH-Thrombin-Tag (37aa; "N-Tag-HT")-ND1 (Start@aa 33)-Linker16-CD1 (Term@ aa465) 2.9 185 309 before 1 445 Delta CD0: 272 N-Tag-HT-ND0_ND1-Linker16-CD1 (Term@ aa 443) Importance of C-terminal fragment Deletion of CD0 fragment alone 0.4 141000 694 Truncated CD1 of D0 domain (CD0) and 26 C- has significant effect- 2 451 Delta CD0: 289 N-Tag-HT-ND0-ND1-Linker16-CD1 (Term@ aa 460) terminal aa of D1 fragment (CD1) approximately 50-100 times ND 97 105 Truncated CD1 in signaling? lower activity. Additional 3 467 Delta CD0 295 N-Tag-HT-ND0-ND1-Linker16-CD1 (Term@ aa 466) truncation of 26 C-terminal aa of 1.0 71 57 4 470CT Delta CD0: Minimal 274 ND0-ND1-Linker16-CD1 (Term@ aa 469)-Thrombin- CD1 fragmentieads to nearly loss ND 44 3 C-Tag 6xH-Tag (13 aa: C-Tag) of activity (at least 700 times) 5 S33 Delta ND0: N- 300 N-Tag-HT-ND1 (Start@ aa 33)-Linker16-CD1-CD0 [Variant CBLB502-S33 was [Vriant S33 showed improved 0.8 1.4 ND terminal tag characterized in vivo] PK and higher in vivo activity 6 33CT Delta ND0: C- 275 ND1 (Start@ aa 33)-Linker16-CD1-CD0-C-Tag Contribution of N-terminal fragment by PD, Luc-mice and in ND 2.3 ND terminal tag of D0 domain (ND0) and N-terminal radioprotection.] 7 37CT Delta ND0 273 ND1 (Start@ aa 37)-Linker16-CD1-CD0-C-Tag spoke region (NS; aa 32-44) to Deletion of ND0 fragment and ND 3.2 ND signaling? truncation of NS has little effect 8 N45 Delta ND0 288 N-Tag-HT-ND1 (Start@ aa45)-Linker16-CD1-CD0 on activity (1.5-3.5 times ND 3.6 ND 9 45CT Delta ND0 285 ND1 (Start@ aa 45)-Linker16-CD1-CD0-"Long" C- decrease), regardless of position ND 3.5 ND Tag (34 aa) of the tag. 10 33-485 Delta ND0: 281 N-Tag-HT-ND1 (Start@ aa 33)-Linker16-CD1-CD0 Minimal essential fragment of Truncation of 20 C-termianl aa of ND 11 ND Truncated CD0 (Term@ aa485) CD0? CD0 leads to 11x-lower activity 11 33ML Delta ND0: 250 ND1 (Start@ aa 33)-Linker3-CD1 (Start@aa413)- Test structure-based hypothesis-minimize the linker and have start of ND 1.5 1.3 Minimized Linker, CD0-C-Tag CD1 at aa 413 (401 in CBLB502). Confirmed Truncated CD1 12 MF227C 33ML based: 227 ND1 (Start@ aa 33)-Linker3-CD1-CD0 (deleted aa Continue testing further The N-terminal part of CD0 is ND ND 5.5 Deletion within CD0 470-492)-C-Tag minimization in 33ML background. essential (5x loss) 13 MF227N 33ML based: 227 ND1 (aa 33-152)-Linker3-CD1-CD0-C-Tag Hypothesis: C-terminal capping of C-terminal part of ND1 (aa 153- ND ND 159 Truncated ND1 D1 domain with C-tag may yield 175, connector) is indispensable. 14 485CT 33ML based: 233 ND1-Linker3-CD1-CD0 (Term@aa485)-C-Tag the shortest active variant. Partial CD0 (aa 470-485) + C- ND ND 1.2 Truncated CD0 terminal cap (Thrombin'6xHis Tag) retaine full activity (in contrust with 11x loss in 33-485 with N-tag 15 485D 485CT baseed: 229 ND1-Linker3-CD1-CD0 (Term@aa485)-C-Tag; Detrimental (44x loss) - defines ND ND 44 Q439::F442 deletion Q439::F442 deletion boundaries 16 SY3CT Delta D0: minimal 217 ND1-Linker3-CD1-C-Tag Only partially true: This variant is ND ND 16 linker: C-terminal tag >20x more active then N-terminal tag version (SV3) Still it is worse than 502 by 18x. 17 NGD1 Fusion: N-terminal 380 GPF (aa 1-157)-Linker7-ND1-Linker3-CD1-C-Tag Hypothesis: (1) capping (N-terminal (1) N-terminal GFP-cap is not ND ND 58 GFP fragment (1- and C-terminal separate. or together) helpful: C-terminal brings activity to 157)-D1 of D1 domain alone can stabilize it 1/ of 502, (2) GFP fusion was 18 CGD1 Fusion: D1-C- 303 ND1-Linker3-CD1-Linker7'-GFP (aa 158-238)-C- and make active. We used N-terminal fluorescent but not active ND ND 8 terminal GFP Tag and C-terminal fragments of GFP for fragment (158-238) capping. (2) Fusion of N- and C- 19 GD1G Fusion: N-GFP (1- 466 GFP (aa 1-157)-Linker7-ND1-Linker3-CD1-Linker7'- terminal fragments of GFP to D1 ND ND 259 157)-D1-C-GFP GFP (aa158-238)-C-Tag domain instead of D0 (GD1G Mutant) (158-238) may stabilize D1 doamin and allow us to monitor its stabilized conformation through reconstitution of GFP fluorescence* 20 CPM194 Circular Permutant: 194 CD1-Linker3-ND1 (Term@aa152)-C-Tag Exploring alternative approach in So, far unsuccessful. One protein ND ND N/A CD1 (413-469) // stabilizing D1 using circular not folded. The other is folded but ND1 (33-152) permutation technique. inactive 21 CPM217 Circular Permutant: 217 CD1-Linker3-ND1 (Term@aa175)-C-Tag ND ND 1112 CD1 (413-469) // ND1 (33-175) Ghosh, I., Hamilton, A. D. & Regan L. Antiparallel leucine zipper-directed protein reassembly: application to the green fluorescent protein. J. Am. Chem. Soc. 122, 5658-5659 (2000). Jeong, J. et al. Monitoring of conformational change in maltose binding protein using split green fluorescent protein. Biochem. Biophys. Res. Commun. 339, 647-651. (2006). Latz E, Verma A, Visintin A, Gong M, Sirois CM, et al. (2007) Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nature. Immunology 8:772-779. indicates data missing or illegible when filed

[0266] In summary, the variant CBLB502-485CT ("CBLB533" (SEQ ID NO: 71)) represents the result of ultimate minimization of CBLB502 without loss of signaling activity (at least in vitro). This variant (233 aa long) is 30% shorter than CBLB502 (329 aa). (See FIG. 5).

[0267] In vivo characterization was accomplished for the key intermediate in minimization--CBLB502-S33 (SEQ ID NO: 17) with deleted N_D0 segment and the original 33aa N-terminal tag (FIG. 5). The respective recombinant purified protein displayed nearly full signaling activity in vitro (Table 2). Remarkably, the first results of in vivo testing in NF-kB-Luc-reporter mice performed side-by-side with CBLB502 revealed a substantially higher potency of CBLB502-S33 in vivo (FIG. 6) based on Xenogen imaging. A more quantitative analysis of luciferase activity in individual organs showed that while the response in the liver was moderately increased, about 3-fold, a much stronger enhancement (>10-fold, at the same dose 0.3 .mu.g) was observed in bladder and large intestine (FIG. 7).

[0268] Importantly, the enhanced response was also observed at the level of radioprotection potency (FIG. 8).

[0269] This observation suggests, without wishing to be bound by theory, that a minimized variant of CBLB502 can be efficiently used for anti-acute radiation syndrome (ARS) indications at lower doses. This enhanced potency may also be manifested in radiomitigation mode (post-exposure administration). This expectation is substantiated by the observed stronger cytokine response (FIG. 9) including the key cytokines (G-CSF and IL-6) selected as CBLB502 PD-biomarkers and proven to be mechanistically essential for its radiomitigation activity (Burdelya et al. 2008).

[0270] An apparent rationale for the correlated enhancement of CBLB502-S33 in vivo activity at the level of NF-kB signaling, radioprotection and cytokine production (PD) is a substantially improved PK (FIG. 10). The enhanced persistence of CBLB502-S33 in plasma might reflect higher stability to proteolysis or, more likely, less efficient "trapping" in certain organs/tissues (e.g. in the liver) and slower clearance from circulation thus increasing exposure of other tissues. The latter interpretation provides additional evidence of the contribution of such tissues (e.g. peripheral blood cells) to the MOA of the drug.

[0271] By way of non-limiting summary, characterization of CBLB502-S33 showed that the SAR analysis and iterative minimization deliver biologically active protein variants with improved pharmacological properties. This information was used to design, engineer and characterize the ultimate design for CBLB533

[0272] The SAR results suggest the ultimate design of CBLB533 based on the variant CBLB502-485CT (with or without additional mutations). This protein can be produced in sufficient amount and characterized in vivo similar to the analysis performed for the intermediate lead candidate CBLB502-S33 additionally expanded by testing of radiomitigation properties. Importantly, they provided an optimal scaffold for designing the de-immunized Nextgen drug candidate CBLB543.

Example 2: Engineering of Flagellin-Related Compositions with Reduced Antigenicity Relative to CBLB502

[0273] Anti-CBLB502 antibodies (preexisting or/and boosted by CBLB502 treatment) showing neutralizing activity in vitro should also neutralize its NF-kB signaling (and therefore therapeutic) activity. This was confirmed by the direct experiment in mice (FIG. 11). Indeed, the injection of CBLB502 neutralizing human sera or monoclonal antibodies in NF-kB luciferase mice completely abrogates the luciferase activity in organ (live) lysates.

[0274] In this experiment, five groups of NF-kB reporter mice (3 per group) were injected intravenously with (1) PBS (2) non neutralizing serum, (3) neutralizing serum (day 15 bleed) (4) mAb 7C (5) mAb 11D and animals were bled after 45 minutes. The monoclonal antibodies were used at the dose of 100 .mu.g per mouse. CBLB502 (1 .mu.g) was injected subcutaneously to all mice one hour after the initial injection of antibodies. Animals were imaged three hours after CBLB502 injection and liver was collected for preparation of lysates. The results from this study are shown in Table 3.

[0275] The specific activity of luciferase was measured per the following protocol. A Bio-pulverizer was used to crush the liver samples on the dry ice. 750 .mu.l of 1.times. Reporter Lysis Buffer (Promega cat #E397A)+1.times. protease inhibitor cocktail (PIC, sigma P8340) was added and the homogenized mixture was centrifuged at 13,000 rpm at 4.degree. C. for 30 minutes. The supernatant was collected into a clean eppendorf tube and the protein concentration of the supernatant was measured. 20 .mu.l of supernatant and 20 .mu.l of luciferase buffer (Promega E2620) were added. Everything was normalized to the lowest protein sample and added accordingly, and the volume of the supernatant was adjusted using the Lysis buffer with PIC. The luciferase activity was measured on a luminoplate reader.

TABLE-US-00003 TABLE 3 In vivo neutralization of CBLB502 by injection of antisera and antibodies (neutralizing and not neutralizing) in reporter mice. Anti-CBLB502 antibody assay results Anti- Sample NAb % CBLB502 Sample # ID Study group inhibition titer 1 #1-1 PBS -1.08 0 2 #1-2 PBS -4.68 0 3 #1-3 PBS 0.51 0 4 #2-1 Non-neutralizing 1.77 0 human serum 5 #2-2 Non-neutralizing -5.38 0 human serum 6 #2-3 Non-neutralizing 0.15 0 human serum 7 #3-1 Neutralizing 77.37 19462 human serum 8 #3-2 Neutralizing 86.04 20879 human serum 9 #3-3 Neutralizing 83.52 17000 human serum 10 #4-1 Non-neutralizing 5.18 791 MAb 7C 11 #4-2 Non-neutralizing 1.21 487 MAb 7C 12 #4-3 Non-neutralizing 2.63 858 MAb 7C 13 #5-1 Neutralizing 44.81 114496 MAb 11D 14 #5-2 Neutralizing 49.41 87249 MAb 11D 15 #5-3 Neutralizing 54.48 109475 MAb 11D *Human sera were diluted 10-fold with PBS for injections **Both MAbs, 7C and 11D, were at 2 mg/ml in PBS for injections ***Mouse serum samples were collected 1 hr after Ab injections

[0276] A brief summary of is provided below (and shown in Tables 4, and 5 and FIG. 12).

TABLE-US-00004 TABLE 4 CBLB502 epitope mapping and de-immunization Signaling EC50 Nor- malized Scaf- Length by Neutralization by antibodies (IC50 improvement vs. 502) Protein fold Mutations (aa) CB1B502 mAB4D11 mAb11D04 NSP79 NSP85 NSP99 NSP61 NSP103 P12 P14 Note MIM1 502 N455A; 329 0.9 No improvement in neutralization with 1 based N457A any of the antibodies MIM2 502 N455A; 329 1.2 based N457A; R460A MIM3 502 N448A; 329 4.6 based N451A; N455A, N457A; R460A MIM4 502 Q439:: 329 37 based F442 deletion; N448A; N451A; N455A, N457A; R460A MIM5 502 Q439A; 329 54 based N440K; R441A; N448A; N451A; N455A, N457A; R460A 33MIMX S33 N68A; 300 1.3 ~10x 4-5X No 2x 1x ~3x ~2x 2 based F131A; improvement Q142A; E153A; T154A; N440A; D443A; S444A; T447A MIXN 33ML N68A; 250 1.5 ~10x ~10x 4-5X 4-5X 3 based F131A; Q142A; E153A; T154A MIXC 33ML N440A; 250 1.5 ~10x ~10x worse based D443A; S444A; T447A ME42 33ML D42A; 250 1.3 4x 5x 2x 2x 1x 1x 4 based A45G ME100 33ML N100A; 250 0.6 >5x >10x 3x 2x 1x 2x based T102A ME104 33ML S104A; 250 1.0 >5x >10x >5x >5x 1x 2x based S106A; D107A ME110 33ML S110A; 250 0.7 >5x >10x 3x 2x 1x 2x based D113A ME117 33ML Q117A; 250 0.8 >5x >10x 2x 2x 1x 1x based E120A ME124P 33ML R124A 250 * based ME124 33ML R124A; 250 0.9 3x 6x 2x 1x 3x 1x based N127A; Q128A ME132 33ML N132A; 250 0.94 >5x >10x 4x >5x 2x 3x based G133A ME142 33ML Q142A; 250 0.3 >5x >10x 3x >5x 2x 2x based K144A ME150 33ML N150S; 250 0.5 >5x >10x 3x 2x 1x 2x based D151A; G152A ME468 33ML Y468A; 250 0.7 >5x >10x 2x 2x 4x 1x based A469G; T470A; S473A ME100/ 33ML N100A; 250 * 110 based T102A; S110A; D113A ME104N 33ML N100A; 250 0.9 1x 2x 2x 2x 1x 1x based T102A; S104A; S106A; D107A; S110A; D113A 33GPS 33ML Deletion 240 * based N100:: D113. Replaced with linker "GPSG" 33MX 33ML N68A; 250 1.3 >4x >4x >2x >2x 6x 7x 5 based F131A; Q142A; E153; T154A; S104A; S106A; D107A; S110A; D113A; N132A; G133A; K144A; N127Q; N474Q

TABLE-US-00005 TABLE 5 Antigenicity of CBLB502 deletion variants by antibody titration (ELISA) with multiple human antisera Titers Plate Plate Plate Plate 1 Plate 2 Plate 3 Plate 4 Plate 5 Plate 6 Plate 7 8 9 Mab 10 Plate 11 Plate 12 Pt. serum Pt. serum Pt. serum Pt. serum Pt. serum Pt. serum Pt. serum MAb 11D Mab Goat Rabbit #004 #006 #009 #010 #012 #008 #013 7C Neu- 12D PAb PAb Day 15, Day 15, Day 15, Day 15, Day 15, No No No tral- No CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 effect izing effect assays assays Deletion 429687 319746 117275 261211 543635 3331 7023 1392 39297 11433 33248 41555 SY3 414991 319843 160498 276131 626631 2413 8462 1619 39722 10233 35372 40853 Deletion 429436 322443 199057 264892 649834 9846 9490 1596 42485 11725 38755 39092 467 67857 152052 21824 57521 150700 978 914 1470 8609 1577 40988 19077 Deletion 519509 357298 296948 337398 761754 12082 23459 1547 52663 15364 59596 46738 S33 Deletion 445 CBLB502 Ref, Std Titer % of CBLB502 reference standard Plate Plate Plate Plate 1 Plate 2 Plate 3 Plate 4 Plate 5 Plate 6 Plate 7 8 9 Mab 10 Plate 11 Plate 12 Pt. serum Pt. serum Pt. serum Pt. serum Pt. serum Pt. serum Pt. serum MAb 11D Mab Goat Rabbit #004 #006 #009 #010 #012 #008 #013 7C Neu- 12D PAb PAb Day 15, Day 15, Day 15, Day 15, Day 15, No No No tral- No CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 CBLB502 effect izing effect assays assays Deletion 83 89 39 77 71 28 30 90 75 74 56 89 SY3 80 90 54 82 82 20 36 105 75 67 59 87 Deletion 83 90 67 85 85 81 40 103 81 76 65 84 467 13 43 7 20 20 8 4 95 16 10 69 41 Deletion 100 100 100 100 100 100 100 100 100 100 100 100 S33 Deletion 445 CBLB502 Ref, Std

[0277] The initial studies were based on the computational prediction of linear epitopes, a comparative analysis of antigenicity (assessed by ELISA with a series of human serum samples) for a series of truncated variants, and the observation that the deletion variant 445 (see Table 2 for composition) significantly lost antigenicity pointing to the existence of the major epitope within a rather short amino acid segment (440-470). However the analysis of antigenicity in a number of mutants generated based on this premise did not confirm these predictions (see FIG. 12).

[0278] Based on these observations, in the following work, the approach was adjusted to the use of predicted structural (potentially noncontiguous) epitopes (FIG. 13), testing intermediate mutants for "neutralizing antigenicity" assessed by the extent of inhibition by neutralizing Abs in signaling assay. We progressed from using a full-size CBLB502 scaffold to the first truncated lead CBLB502-S33 (see Table 2 for composition), and its further modification S33MX (SEQ ID NO: 150).

[0279] In the first series of designed mutants, substantial progress was attained in decreasing sensitivity to neutralizing monoclonal antibodies and neutralizing antisera raised against CBLB502. An improvement was observed on a series of human normal sera containing an appreciable un-induced titer of neutralizing antibodies.

[0280] To address this problem, an additional series of mutant were designed and characterized.

[0281] As a result of such iterations, the majority of neutralizing epitopes were mapped and eliminated without loss of signaling activity (see Table 4).

[0282] To engineer the first generation of fully active "deimmunized" CBLB502 lead candidate (CBLB543), the following was undertaken.

[0283] Epitope mapping data obtained as described above (See Table 5) provided foundation for the ultimate design of the de-immunized CBLB543 lead candidate (CBLB502-S33MX (SEQ ID NO: 150)). This protein was engineered and characterized by signaling activity (unchanged) and neutralizing antigenicity. As illustrated in FIG. 14 (for individual data, see Table 4), in this protein the neutralizing antigenicity was substantially reduced compared to CBLB502. The additional comparison with CBLB502-S33ML (SEQ ID NO: 35), a truncated scaffold used for lead engineering shows this effect is due to a combination of mutations, and not reduced size.

Example 3: Potency and Pharmacological Properties of De-Immunized Variants (CBLB502-33MX and CBLB502-S331

[0284] Studies were undertaken to evaluate the PK/PD properties of selected flagellin-related compositions Specifically, the PK/PD properties of the partially deimmunized protein CBLB502-33MX were compared with those of CBLB502. Accordingly, this study established the functional and pharmacological characteristics of the engineered new variant CBLB502-33MX with substantially reduced "neutralizing antigenicity" and thus resistant to neutralization by human neutralizing antibodies in the in vitro signaling assay.

[0285] In-life phase of PK/PD study: 320 C57Bl6 mice were used for the experiment in groups of 10 mice. CBLB502 (1 and 2 .mu.g/kg) and 33MX (1 and 2 .mu.g/kg) were injected intravenously. The animals were sacrificed after 5 min, 15 min, 30 min, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after treatment, and plasma samples were collected.

[0286] PK measurements: the concentration of CBLB502 and 33MX in the plasma samples was measured according to the standard ELISA-based protocol using CBLB502 and 33MX calibration curves.

[0287] The results of PK measurements are illustrated in FIG. 15. FIG. 15, panels A and B show quantification of CBLB502 and 33MX in mouse plasma samples. (BLQ--below the limit of quantification). Therefore, CBLB502-33MX has very similar PK properties to that of parental CBLB502, i.e. it clears from circulation at approximately the same rate. Accordingly, PK features of CBLB502 are not abrogated by the mutations that were engineered to de-immunize the construct (e.g. in the context of CBLB502-33MX).

[0288] The same 320 plasma samples were used for cytokine profiling for the analysis of PD properties of 33MX as compared to CBLB502. The data (FIG. 16) shows that CBLB502-33MX has a very similar PD profile to the parental CBLB502. Accordingly, PD features of CBLB502 also are not abrogated by the mutations that were engineered to de-immunize the construct (e.g. in the context of CBLB502-33MX).

[0289] In vivo signaling of the parental CBLB502 was compared to an intermediate variant CBLB502-S33 (minimized, prior to deimmunization) and CBLB502-33MX, the final product of Stage I deimmunization. A NF-kB-luciferase reporter assay in mice was used and mice were injected with the one of the following proteins: CBLB502 (at doses of 0.1 .mu.g, 0.3 .mu.g, 1 .mu.g and 3 .mu.g); CBLB502-S33 (at doses of 0.1 .mu.g, 0.3 .mu.g, 1 .mu.g and 3 .mu.g); and CBLB502-33MX (at doses of 0.1 .mu.g, 0.3 .mu.g, 1 .mu.g and 3 .mu.g). 3 hours after treatment the mice were sacrificed and the following organs were harvested and frozen at -80.degree. C.: liver, bladder, small and large intestine, heart, spleen, lungs, brain and kidney. Luciferase activity in organ lysates was measured using Bright-Glo Luciferase Assay solution (Promega) and presented as specific luciferase activity (RLU/mg of protein+/-SEM).

[0290] The results of experiment shown in FIG. 17 demonstrate that NF-.kappa.B activating ability of de-immunized candidate 33MX is similar to S33 and CBLB502 and in some organs (for example, large intestine and lungs) even exceeds activity of these proteins in some organs

[0291] Therefore, among others, this Example shows that that de-immunized variant CBLB502-33MX fully retained or exceeded in some parameters the biological activity and pharmacological characteristics of the original CBLB502.

Example 4: In Vivo Efficacy of 33MX in a Murine Model of Local Head-And-Neck Irradiation

[0292] The in vivo effects of 33MX in the context of irradiation were evaluated at a variety of doses as compared to CBLB502. Treatment was injected 1 h after each irradiation preventing damage and accelerating tissue recovery following fractionated H&N irradiation.

[0293] Six groups by 8 mice were evaluated and are listed in the order that the data is presented in FIG. 18 (in series for 8 tissue types, the bars identified from left to right for each tissue type): Group 1 (vehicle): 6 Gy.times.5 times with 24 h interval (30 Gy total), inject PBS-Tween 1 h after each IR, Group 6 (33MX, 0.03 .mu.g): 6 Gy.times.5 times with 24 h interval (30 Gy total), inject 0.03 .mu.g 33MX 1 h after each IR, Group 5 (33MX, 0.1 .mu.g): 6 Gy.times.5 times with 24 h interval (30 Gy total), inject 0.1 .mu.g 33MX 1 h after each IR, Group 4 (33MX, 0.3 .mu.g): 6 Gy.times.5 times with 24 h interval (30 Gy total), inject 0.3 .mu.g 33MX 1 h after each IR, Group 3 (33MX, 1 .mu.g): 6 Gy.times.5 times with 24 h interval (30 Gy total), inject 1 .mu.g 33MX 1 h after each IR, and Group 2 (CBLB502, 0.1 .mu.g): 6 Gy.times.5 times with 24 h interval (30 Gy total), to inject 0.1 .mu.g CBLB502 1 h after each IR (this dose was determined to be particularly efficacious in a separate study),

[0294] All mice were taken for histopathological analysis of mouse epithelia, tongue, upper esophagus, salivary glands and skin on day 10 after the first IR (day 0).

[0295] The results of the study are presented in FIG. 18. Injury scores are based on histological evaluation of the tissue sections. The scores values scale: 0 for no injury and 4 for the highest injury.

EQUIVALENTS

[0296] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

[0297] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

[0298] All patents and publications referenced herein are hereby incorporated by reference in their entireties.

[0299] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0300] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

REFERENCES

[0301] 1. Yoon S I, Kurnasov O, Natarajan V, Hong M, Gudkov A V, Osterman A L, Wilson I A., 2012. Structural Basis of TLR5-Flagellin Recognition and Signaling. Science 335:859-864 (PMID: 22344444)

[0302] 2. Smith K D, Andersen-Nissen E, Hayashi F, Strobe K, Bergman M A, Barrett S L, Cookson B T, Aderem A. 2003. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol. 4:1247-53 (PMID: 14625549)

[0303] 3. Mizel, S. B., A. P. West, R. R. Hantgan. 2003. Identification of a sequence in human Toll-like receptor 5 required for the binding of Gram-negative flagellin. J. Biol. Chem. 278:23624-23629 (PMID: 12711596)

[0304] 4. Murthy, K. G., Deb, A., Goonesekera, S., Szabo, C. & Salzman, A. L. (2004) J. Biol. Chem. 279:5667-5675 (PMID: 14634022)

[0305] 5. Andersen-Nissen E., Smith K. D., Strobe K. L., Barrett S. L., Cookson B. T., Logan S. M., Aderem A. (2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc. Natl. Acad. Sci. U.S.A. 102: 9247-9252 (PMID: 15956202)

[0306] 6. Andersen-Nissen E, Smith K D, Bonneau R, Strong R K, Aderem A. 2007. A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med. 204:393-403 (PMID: 17283206)

[0307] 7. Burdelya L G, Krivokrysenko V I, Tallant T C, Strom E, Gleiberman A S, Gupta D, Kurnasov O V, Fort F L, Osterman A L, Didonato J A, Feinstein E, Gudkov A V., 2008. An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320:226-230 (PMID: 18403709).

[0308] 8. Huleatt J W, Nakaar V, Desai P, Huang Y, Hewitt D, Jacobs A, Tang J, McDonald W, Song L, Evans R K et al. 2008. Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TRL5 ligand flagellin. Vaccine. 26:201-214.

Sequence CWU 1

1

2941505PRTSalmonella dublin 1Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu145 150 155 160Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175Gly Pro Lys Glu Ala Thr Val Gly Asp Leu Lys Ser Ser Phe Lys Asn 180 185 190Val Thr Gly Tyr Asp Thr Tyr Ala Ala Gly Ala Asp Lys Tyr Arg Val 195 200 205Asp Ile Asn Ser Gly Ala Val Val Thr Asp Ala Ala Ala Pro Asp Lys 210 215 220Val Tyr Val Asn Ala Ala Asn Gly Gln Leu Thr Thr Asp Asp Ala Glu225 230 235 240Asn Asn Thr Ala Val Asp Leu Phe Lys Thr Thr Lys Ser Thr Ala Gly 245 250 255Thr Ala Glu Ala Lys Ala Ile Ala Gly Ala Ile Lys Gly Gly Lys Glu 260 265 270Gly Asp Thr Phe Asp Tyr Lys Gly Val Thr Phe Thr Ile Asp Thr Lys 275 280 285Thr Gly Asp Asp Gly Asn Gly Lys Val Ser Thr Thr Ile Asn Gly Glu 290 295 300Lys Val Thr Leu Thr Val Ala Asp Ile Ala Thr Gly Ala Ala Asp Val305 310 315 320Asn Ala Ala Thr Leu Gln Ser Ser Lys Asn Val Tyr Thr Ser Val Val 325 330 335Asn Gly Gln Phe Thr Phe Asp Asp Lys Thr Lys Asn Glu Ser Ala Lys 340 345 350Leu Ser Asp Leu Glu Ala Asn Asn Ala Val Lys Gly Glu Ser Lys Ile 355 360 365Thr Val Asn Gly Ala Glu Tyr Thr Ala Asn Ala Thr Gly Asp Lys Ile 370 375 380Thr Leu Ala Gly Lys Thr Met Phe Ile Asp Lys Thr Ala Ser Gly Val385 390 395 400Ser Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala 405 410 415Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 420 425 430Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 435 440 445Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile 450 455 460Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln465 470 475 480Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val 485 490 495Pro Gln Asn Val Leu Ser Leu Leu Arg 500 5052329PRTArtificial SequenceSynthetic sequence 2Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp 20 25 30Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln 35 40 45Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg 50 55 60Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly65 70 75 80Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln 85 90 95Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu 100 105 110Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu 115 120 125Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser 130 135 140Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser145 150 155 160Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln 165 170 175Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp 180 185 190Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val 195 200 205Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met 210 215 220Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala225 230 235 240Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 245 250 255Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 260 265 270Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile 275 280 285Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln 290 295 300Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val305 310 315 320Pro Gln Asn Val Leu Ser Leu Leu Arg 325321DNAArtificial SequenceSynthetic sequence 3taatacgact cactataggg g 21420DNAArtificial SequenceSynthetic sequence 4attgcgcaga ccactgaagg 2056PRTArtificial SequenceSynthetic sequence 5Leu Val Pro Arg Gly Ser1 565PRTArtificial SequenceSynthetic sequence 6Asp Asp Asp Asp Lys1 5713PRTArtificial SequenceSynthetic sequence 7Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala1 5 1086PRTArtificial SequenceSynthetic sequence 8Glu Asp Ala Asp Tyr Ala1 5914PRTArtificial SequenceSynthetic sequence 9Ala Ala Ser Ala Gly Ala Gly Gln Gly Gly Gly Gly Ser Gly1 5 101014PRTArtificial SequenceSynthetic sequence 10Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr1 5 101122PRTArtificial SequenceSynthetic sequence 11Gly Gly Gly Arg Thr Ser Ser Ser Ala Ala Ser Ala Gly Ala Gly Gln1 5 10 15Gly Gly Gly Gly Ser Gly 20124PRTArtificial SequenceSynthetic sequence 12Gly Pro Ser Gly11312PRTArtificial SequenceSynthetic sequence 13Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe1 5 10144PRTArtificial SequenceSynthetic sequence 14Gly Ser Pro Gly11518PRTArtificial SequenceSynthetic sequence 15Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser1 5 10 15Leu Asp1616PRTArtificial SequenceSynthetic sequence 16Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly1 5 10 1517300PRTArtificial SequenceSynthetic sequence 17Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln65 70 75 80Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 130 135 140Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile145 150 155 160Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser225 230 235 240Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala 275 280 285Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 290 295 3001848DNAArtificial SequenceSynthetic sequence 18gcagattctg cagcaggctg gttgataatc tggcgcaggc taaccagg 481960DNAArtificial SequenceSynthetic sequence 19tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 602048DNAArtificial SequenceSynthetic sequence 20cctggttagc ctgcgccaga ttatcaacca gcctgctgca gaatctgc 4821936DNAArtificial SequenceSynthetic sequence 21taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgtc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt tgataa 93622281PRTArtificial SequenceSynthetic sequence 22Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln65 70 75 80Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 130 135 140Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile145 150 155 160Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser225 230 235 240Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270Lys Ala Gln Ile Leu Gln Gln Ala Gly 275 28023329PRTArtificial SequenceSynthetic sequence 23Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu145 150 155 160Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 180 185 190Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 195 200 205Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 210 215 220Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn225 230 235 240Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 245 250 255Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 260 265 270Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 275 280 285Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 290 295 300His His Gly Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Asp305 310 315 320Leu Tyr Asp Asp Asp Asp Lys Asp Pro 325241005DNAArtificial SequenceSynthetic sequence 24atggcacaag tcattaatac aaacagcctg tcgctgttga cccagaataa cctgaacaaa 60tctcagtcct cactgagttc cgctattgag cgtctgtcct ctggtctgcg tatcaacagc 120gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 180ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 240gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 300aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 360gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 420gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 480caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaatt 540tccggtggtg gtggtggaat tctagactcc atgggtacat taatcaatga agacgctgcc 600gcagccaaga aaagtaccgc taacccactg gcttcaattg attctgcatt gtcaaaagtg 660gacgcagttc gttcttctct gggggcaatt caaaaccgtt ttgattcagc cattaccaac 720cttggcaata cggtaaccaa tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat 780gcaacggaag tttctaatat gtctaaagcg cagattctgc agcaggctgg tacttccgtt 840ctggcgcagg ctaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 900catcatcatc atcatcatgg tatggctagc atgactggtg gacagcaaat gggtcgggat 960ctgtacgacg atgacgataa ggatccgtaa gtcgacaagc ttgcg 10052531DNAArtificial SequenceSynthetic sequence 25cgaaagacca tatggcaggc caggcgattg c 312633DNAArtificial SequenceSynthetic sequence 26cgcaagcttg tcgacttacg gatccttatc gtc 3327952DNAArtificial SequenceSynthetic sequence 27taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat ggcaggccag gcgattgcta accgcttcac 120ttctaatatc aaaggtctga ctcaggcttc ccgtaacgct aacgacggca tttctattgc 180gcagaccact gaaggtgcgc

tgaatgaaat caacaacaac ctgcagcgtg tgcgtgagtt 240gtctgttcag gccactaacg ggactaactc tgattccgat ctgaaatcta tccaggatga 300aattcagcaa cgtctggaag aaatcgatcg cgtttctaat cagactcaat ttaacggtgt 360taaagtcctg tctcaggaca accagatgaa aatccaggtt ggtgctaacg atggtgaaac 420cattaccatc gatctgcaaa aaattgatgt gaaaagcctt ggccttgatg ggttcaatgt 480taattccccg ggaatttccg gtggtggtgg tggaattcta gactccatgg gtacattaat 540caatgaagac gctgccgcag ccaagaaaag taccgctaac ccactggctt caattgattc 600tgcattgtca aaagtggacg cagttcgttc ttctctgggg gcaattcaaa accgctttga 660ttcagccatt accaaccttg gcaatacggt aaccaatctg aactccgcgc gtagccgtat 720cgaagatgct gactatgcaa cggaagtttc taatatgtct aaagcgcaga ttctgcagca 780ggctggtact tccgttctgg cgcaggctaa ccaggttccg caaaacgtcc tctctttact 840ggttccgcgg ggttctcatc atcatcatca tcatggtatg gctagcatga ctggtggaca 900gcaaatgggt cgggatctgt acgacgatga cgataaggat ccgtaagtcg ac 95228285PRTArtificial SequenceSynthetic sequence 28Met Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly1 5 10 15Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln 20 25 30Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 35 40 45Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 50 55 60Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp65 70 75 80Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 85 90 95Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile 100 105 110Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 115 120 125Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 130 135 140Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys145 150 155 160Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 165 170 175Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser 180 185 190Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 195 200 205Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 210 215 220Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala225 230 235 240Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser 245 250 255His His His His His His Gly Met Ala Ser Met Thr Gly Gly Gln Gln 260 265 270Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp Pro 275 280 28529765DNAArtificial SequenceSynthetic sequence 29atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240ggaccatcag gtcaggatga aattcagcaa cgtctggaag aaatcgatcg cgtttctaat 300cagactcaat ttaacggtgt taaagtcctg tctcaggaca accagatgaa aatccaggtt 360ggtgctaacg atggtgaaac cattaccatc gatctgcaaa aaattgatgt gaaaagcctt 420ggccttgatg ggttcaatgt taattccccg ggaagtaccg ctaacccact ggcttcaatt 480gattctgcat tgtcaaaagt ggacgcagtt cgttcttctc tgggggcaat tcaaaaccgc 540tttgattcag ccattaccaa ccttggcaat acggtaacca atctgaactc cgcgcgtagc 600cgtatcgaag atgctgacta tgcaacggaa gtttctaata tgtctaaagc gcagattctg 660cagcaggctg gtacttccgt tctggcgcag gctaaccagg ttccgcaaaa cgtcctctct 720ttactggttc cgcggggttc tcatcatcat catcatcatg gttaa 76530254PRTArtificial SequenceSynthetic sequence 30Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gly Pro Ser Gly Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 85 90 95Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 100 105 110Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile 115 120 125Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 130 135 140Phe Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile145 150 155 160Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala 165 170 175Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val 180 185 190Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala 195 200 205Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly 210 215 220Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser225 230 235 240Leu Leu Val Pro Arg Gly Ser His His His His His His Gly 245 2503132DNAArtificial SequenceSynthetic sequence 31gatatacata tgagcgggtt acggatcaac ag 323229DNAArtificial SequenceSynthetic sequence 32agatctcccg gggaattaac attgaaccc 2933816DNAArtificial SequenceSynthetic sequence 33taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tggaccatca 300ggtgaaattc agcaacgtct ggaagaaatc gatcgcgttt ctaatcagac tcaatttaac 360ggtgttaaag tcctgtctca ggacaaccag atgaaaatcc aggttggtgc taacgatggt 420gaaaccatta ccatcgatct gcaaaaaatt gatgtgaaaa gccttggcct tgatgggttc 480aatgttaatt ccccgggaag taccgctaac ccactggctt caattgattc tgcattgtca 540aaagtggacg cagttcgttc ttctctgggg gcaattcaaa accgctttga ttcagccatt 600accaaccttg gcaatacggt aaccaatctg aactccgcgc gtagccgtat cgaagatgct 660gactatgcaa cggaagtttc taatatgtct aaagcgcaga ttctgcagca ggctggtact 720tccgttctgg cgcaggctaa ccaggttccg caaaacgtcc tctctttact ggttccgcgg 780ggttctcatc atcatcatca tcatggttaa gtcgac 81634240PRTArtificial SequenceSynthetic sequence 34Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Gly Pro Ser Gly Glu Ile Gln Gln Arg Leu Glu Glu65 70 75 80Ile Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu 85 90 95Ser Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu 100 105 110Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu 115 120 125Asp Gly Phe Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala 130 135 140Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu145 150 155 160Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn 165 170 175Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp 180 185 190Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln 195 200 205Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val 210 215 220Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His His His Gly225 230 235 24035275PRTArtificial SequenceSynthetic sequence 35Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly145 150 155 160Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 165 170 175Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 180 185 190Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 195 200 205Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 210 215 220Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile225 230 235 240Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 245 250 255Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 260 265 270His His Gly 27536828DNAArtificial SequenceSynthetic sequence 36atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aatttccggt ggtggtggtg gaattctaga ctccatgggt 480acattaatca atgaagacgc tgccgcagcc aagaaaagta ccgctaaccc actggcttca 540attgattctg cattgtcaaa agtggacgca gttcgttctt ctctgggggc aattcaaaac 600cgctttgatt cagccattac caaccttggc aatacggtaa ccaatctgaa ctccgcgcgt 660agccgtatcg aagatgctga ctatgcaacg gaagtttcta atatgtctaa agcgcagatt 720ctgcagcagg ctggtacttc cgttctggcg caggctaacc aggttccgca aaacgtcctc 780tctttactgg ttccgcgggg ttctcatcat catcatcatc atggttaa 8283741DNAArtificial SequenceSynthetic sequence 37tctagacccg ggaagtaccg ctaacccact ggcttcaatt g 413840DNAArtificial SequenceSynthetic sequence 38ccagtcatgt cgacttaacc atgatgatga tgatgatgag 403955DNAArtificial SequenceSynthetic sequence 39ctcatcatca tcatcatcat ggttaagtcg acaagcttgc ggccgcagag ctcgc 5540846DNAArtificial SequenceSynthetic sequence 40taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 84641753DNAArtificial SequenceSynthetic sequence 41atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 75342250PRTArtificial SequenceSynthetic sequence 42Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 250431005DNAArtificial SequenceSynthetic sequence 43atggcacaag tcattaatac aaacagcctg tcgctgttga cccagaataa cctgaacaaa 60tctcagtcct cactgagttc cgctattgag cgtctgtcct ctggtctgcg tatcaacggc 120gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 180ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 240gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 300aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 360gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 420gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 480caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaatt 540tccggtggtg gtggtggaat tctagactcc atgggtacat taatcaatga agacgctgcc 600gcagccaaga aaagtaccgc taacccactg gcttcaattg attctgcatt gtcaaaagtg 660gacgcagttc gttcttctct gggggcaatt caaaaccgct ttgattcagc cattaccaac 720cttggcaata cggtaaccaa tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat 780gcaacggaag tttctaatat gtctaaagcg cagattctgc agcaggctgg tacttccgtt 840ctggcgcagg ctaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 900catcatcatc atcatcatgg tatggctagc atgactggtg gacagcaaat gggtcgggat 960ctgtacgacg atgacgataa ggatccgtaa gtcgacaagc ttgcg 100544329PRTArtificial SequenceSynthetic sequence 44Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Gly Ala Lys Asp Asp Ala

Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu145 150 155 160Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 180 185 190Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 195 200 205Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 210 215 220Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn225 230 235 240Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 245 250 255Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 260 265 270Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 275 280 285Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 290 295 300His His Gly Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Asp305 310 315 320Leu Tyr Asp Asp Asp Asp Lys Asp Pro 3254536DNAArtificial SequenceSynthetic sequence 45ctctggtcat atgatcaaca gcgcgaaaga cgatgc 364646DNAArtificial SequenceSynthetic sequence 46tctagagtcg actattaagc cataccatga tgatgatgat gatgag 4647918DNAArtificial SequenceSynthetic sequence 47taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat gatcaacagc gcgaaagacg atgcggcagg 120ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt ctgactcagg cttcccgtaa 180cgctaacgac ggcatttcta ttgcgcagac cactgaaggt gcgctgaatg aaatcaacaa 240caacctgcag cgtgtgcgtg agttgtctgt tcaggccact aacgggacta actctgattc 300cgatctgaaa tctatccagg atgaaattca gcaacgtctg gaagaaatcg atcgcgtttc 360taatcagact caatttaacg gtgttaaagt cctgtctcag gacaaccaga tgaaaatcca 420ggttggtgct aacgatggtg aaaccattac catcgatctg caaaaaattg atgtgaaaag 480ccttggcctt gatgggttca atgttaattc cccgggaatt tccggtggtg gtggtggaat 540tctagactcc atgggtacat taatcaatga agacgctgcc gcagccaaga aaagtaccgc 600taacccactg gcttcaattg attctgcatt gtcaaaagtg gacgcagttc gttcttctct 660gggggcaatt caaaaccgct ttgattcagc cattaccaac cttggcaata cggtaaccaa 720tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat gcaacggaag tttctaatat 780gtctaaagcg cagattctgc agcaggctgg tacttccgtt ctggcgcagg ctaaccaggt 840tccgcaaaac gtcctctctt tactggttcc gcggggttct catcatcatc atcatcatgg 900tatggcttaa tagtcgac 91848273PRTArtificial SequenceSynthetic sequence 48Met Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala Ile Ala Asn1 5 10 15Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala 20 25 30Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu 35 40 45Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr 50 55 60Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile65 70 75 80Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe 85 90 95Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val 100 105 110Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp 115 120 125Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn Ser Pro Gly Ile 130 135 140Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly Thr Leu Ile Asn145 150 155 160Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn Pro Leu Ala Ser 165 170 175Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly 180 185 190Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr 195 200 205Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr 210 215 220Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala225 230 235 240Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu 245 250 255Ser Leu Leu Val Pro Arg Gly Ser His His His His His His Gly Met 260 265 270Ala49333PRTArtificial SequenceSynthetic sequence 49Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp65 70 75 80Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile145 150 155 160Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys225 230 235 240Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 270Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 275 280 285Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met 290 295 300Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln305 310 315 320Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 325 330501002DNAArtificial SequenceSynthetic sequence 50atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cctggttccg cgcggtagcg cgaaggatcc gatggcacaa 120gtcattaata caaacagcct gtcgctgttg acccagaata acctgaacaa atctcagtcc 180tcactgagtt ccgctattga gcgtctgtcc tctggtctgc gtatcaacag cgcgaaagac 240gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 300gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 360gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 420aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 480gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 540atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 600gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaat ttccggtggt 660ggtggtggaa ttctagactc catgggtaca ttaatcaatg aagacgctgc cgcagccaag 720aaaagtaccg ctaacccact ggcttcaatt gattctgcat tgtcaaaagt ggacgcagtt 780cgttcttctc tgggggcaat tcaaaaccgt tttgattcag ccattaccaa ccttggcaat 840acggtaacca atctgaactc cgcgcgtagc cgtatcgaag atgctgacta tgcaacggaa 900gtttctaata tgtctaaagc gcagattctg cagcaggctg gtacttccgt tctggcgcag 960gctaaccagg ttccgcaaaa cgtcctctct ttactgcgtt aa 10025142DNAArtificial SequenceSynthetic sequence 51ggcaattcaa aaccgttttg attaagccat taccaacctt gg 425242DNAArtificial SequenceSynthetic sequence 52ccaaggttgg taatggctta atcaaaacgg ttttgaattg cc 4253906DNAArtificial SequenceSynthetic sequence 53taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgat ggcacaagtc attaatacaa acagcctgtc gctgttgacc 240cagaataacc tgaacaaatc tcagtcctca ctgagttccg ctattgagcg tctgtcctct 300ggtctgcgta tcaacagcgc gaaagacgat gcggcaggcc aggcgattgc taaccgcttc 360acttctaata tcaaaggtct gactcaggct tcccgtaacg ctaacgacgg catttctatt 420gcgcagacca ctgaaggtgc gctgaatgaa atcaacaaca acctgcagcg tgtgcgtgag 480ttgtctgttc aggccactaa cgggactaac tctgattccg atctgaaatc tatccaggat 540gaaattcagc aacgtctgga agaaatcgat cgcgtttcta atcagactca atttaacggt 600gttaaagtcc tgtctcagga caaccagatg aaaatccagg ttggtgctaa cgatggtgaa 660accattacca tcgatctgca aaaaattgat gtgaaaagcc ttggccttga tgggttcaat 720gttaattccc cgggaatttc cggtggtggt ggtggaattc tagactccat gggtacatta 780atcaatgaag acgctgccgc agccaagaaa agtaccgcta acccactggc ttcaattgat 840tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgtttt 900gattaa 90654272PRTArtificial SequenceSynthetic sequence 54Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp65 70 75 80Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile145 150 155 160Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys225 230 235 240Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 2705545DNAArtificial SequenceSynthetic sequence 55caatctgaac tccgcgcgtt gacgtatcta agatgctgac tatgc 455645DNAArtificial SequenceSynthetic sequence 56gcatagtcag catcttagat acgtcaacgc gcggagttca gattg 4557966DNAArtificial SequenceSynthetic sequence 57taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgat ggcacaagtc attaatacaa acagcctgtc gctgttgacc 240cagaataacc tgaacaaatc tcagtcctca ctgagttccg ctattgagcg tctgtcctct 300ggtctgcgta tcaacagcgc gaaagacgat gcggcaggcc aggcgattgc taaccgcttc 360acttctaata tcaaaggtct gactcaggct tcccgtaacg ctaacgacgg catttctatt 420gcgcagacca ctgaaggtgc gctgaatgaa atcaacaaca acctgcagcg tgtgcgtgag 480ttgtctgttc aggccactaa cgggactaac tctgattccg atctgaaatc tatccaggat 540gaaattcagc aacgtctgga agaaatcgat cgcgtttcta atcagactca atttaacggt 600gttaaagtcc tgtctcagga caaccagatg aaaatccagg ttggtgctaa cgatggtgaa 660accattacca tcgatctgca aaaaattgat gtgaaaagcc ttggccttga tgggttcaat 720gttaattccc cgggaatttc cggtggtggt ggtggaattc tagactccat gggtacatta 780atcaatgaag acgctgccgc agccaagaaa agtaccgcta acccactggc ttcaattgat 840tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgtttt 900gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgttgacgt 960atctaa 96658289PRTArtificial SequenceSynthetic sequence 58Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp65 70 75 80Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile145 150 155 160Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys225 230 235 240Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 270Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 275 280 285Arg5948DNAArtificial SequenceSynthetic sequence 59cgtagccgta tcgaagatgc ttaataggca acggaagttt ctaatatg 486048DNAArtificial SequenceSynthetic sequence 60catattagaa acttccgttg cctattaagc atcttcgata cggctacg 4861978DNAArtificial SequenceSynthetic sequence 61taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgat ggcacaagtc attaatacaa acagcctgtc gctgttgacc 240cagaataacc tgaacaaatc tcagtcctca ctgagttccg ctattgagcg tctgtcctct 300ggtctgcgta tcaacagcgc gaaagacgat gcggcaggcc aggcgattgc taaccgcttc 360acttctaata tcaaaggtct gactcaggct tcccgtaacg ctaacgacgg catttctatt 420gcgcagacca ctgaaggtgc gctgaatgaa atcaacaaca acctgcagcg tgtgcgtgag 480ttgtctgttc aggccactaa cgggactaac tctgattccg atctgaaatc tatccaggat 540gaaattcagc aacgtctgga agaaatcgat cgcgtttcta atcagactca atttaacggt 600gttaaagtcc tgtctcagga caaccagatg aaaatccagg ttggtgctaa cgatggtgaa 660accattacca tcgatctgca aaaaattgat gtgaaaagcc ttggccttga tgggttcaat 720gttaattccc cgggaatttc cggtggtggt ggtggaattc tagactccat gggtacatta 780atcaatgaag acgctgccgc agccaagaaa agtaccgcta acccactggc ttcaattgat 840tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgtttt 900gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 960atcgaagatg cttaatag 97862295PRTArtificial SequenceSynthetic sequence 62Met Arg Gly Ser His His His His His His Gly

Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp65 70 75 80Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile145 150 155 160Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys225 230 235 240Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 270Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 275 280 285Arg Ser Arg Ile Glu Asp Ala 290 29563990DNAArtificial SequenceSynthetic sequence 63atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cgatgacgat aaggatccga tggcacaagt cattaataca 120aacagcctgt cgctgttgac ccagaataac ctgaacaaat ctcagtcctc actgagttcc 180gctattgagc gtctgtcctc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa 9906433DNAArtificial SequenceSynthetic sequence 64cgataaggat catatggcac aagtcattaa tac 336578DNAArtificial SequenceSynthetic sequence 65agatctgtcg acttaaccat gatgatgatg atgatgagaa ccccgcggaa ccagtgcata 60gtcagcatct tcgatacg 7866918DNAArtificial SequenceSynthetic sequence 66taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg gcacaagtca ttaatacaaa cagcctgtcg 120ctgttgaccc agaataacct gaacaaatct cagtcctcac tgagttccgc tattgagcgt 180ctgtcctctg gtctgcgtat caacagcgcg aaagacgatg cggcaggcca ggcgattgct 240aaccgcttca cttctaatat caaaggtctg actcaggctt cccgtaacgc taacgacggc 300atttctattg cgcagaccac tgaaggtgcg ctgaatgaaa tcaacaacaa cctgcagcgt 360gtgcgtgagt tgtctgttca ggccactaac gggactaact ctgattccga tctgaaatct 420atccaggatg aaattcagca acgtctggaa gaaatcgatc gcgtttctaa tcagactcaa 480tttaacggtg ttaaagtcct gtctcaggac aaccagatga aaatccaggt tggtgctaac 540gatggtgaaa ccattaccat cgatctgcaa aaaattgatg tgaaaagcct tggccttgat 600gggttcaatg ttaattcccc gggaatttcc ggtggtggtg gtggaattct agactccatg 660ggtacattaa tcaatgaaga cgctgccgca gccaagaaaa gtaccgctaa cccactggct 720tcaattgatt ctgcattgtc aaaagtggac gcagttcgtt cttctctggg ggcaattcaa 780aaccgttttg attcagccat taccaacctt ggcaatacgg taaccaatct gaactccgcg 840cgtagccgta tcgaagatgc tgactatgca ctggttccgc ggggttctca tcatcatcat 900catcatggtt aagtcgac 91867274PRTArtificial SequenceSynthetic sequence 67Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu145 150 155 160Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 180 185 190Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 195 200 205Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 210 215 220Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn225 230 235 240Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 245 250 255Asp Ala Asp Tyr Ala Leu Val Pro Arg Gly Ser His His His His His 260 265 270His Gly6840DNAArtificial SequenceSynthetic sequence 68agatctccgc ggaaccagac cagcctgctg cagaatctgc 4069795DNAArtificial SequenceSynthetic sequence 69taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 79570702DNAArtificial SequenceSynthetic sequence 70atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 70271233PRTArtificial SequenceSynthetic sequence 71Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg 210 215 220Gly Ser His His His His His His Gly225 23072120DNAArtificial SequenceSynthetic sequence 72aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattc aaaaccgttt tgattcagcc attaccgccc ttggcaatac ggtaaccaat 1207340PRTArtificial SequenceSynthetic sequence 73Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val1 5 10 15Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 20 25 30Ala Leu Gly Asn Thr Val Thr Asn 35 407446DNAArtificial SequenceSynthetic sequence 74gttcgttctt ctctgggggc aattgattca gccattaccg cccttg 467546DNAArtificial SequenceSynthetic sequence 75caagggcggt aatggctgaa tcaattgccc ccagagaaga acgaac 4676783DNAArtificial SequenceSynthetic sequence 76taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattgatt cagccattac cgcccttggc aatacggtaa ccaatctgaa ctccgcgcgt 660agccgtatcg aagatgctga ctatgcaacg gaagtttcta atatgtctaa agcgcagatt 720ctgcagcagg ctggtctggt tccgcggggt tctcatcatc atcatcatca tggttaagtc 780gac 78377229PRTArtificial SequenceSynthetic sequence 77Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Asp Ser Ala 165 170 175Ile Thr Ala Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser 180 185 190Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys 195 200 205Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg Gly Ser His His 210 215 220His His His His Gly22578654DNAArtificial SequenceSynthetic sequence 78atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cactggttcc gcggggttct catcatcatc atcatcatgg ttaa 65479217PRTArtificial SequenceSynthetic sequence 79Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu Val Pro Arg 195 200 205Gly Ser His His His His His His Gly 210 21580714DNAArtificial SequenceSynthetic sequence 80atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca tatgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa 420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aaagaatgga 480atcaaagcta acttcaaaat tcgccacaac attgaagatg gatccgttca actagcagac 540cattatcaac aaaatactcc aattggcgat ggccctgtcc ttttaccaga caaccattac 600ctgtcgacac aatctgccct tttgaaagat cccaacgaaa agcgtgacca catggtcctt 660cttgagtttg taactgctgc tgggattaca catggcatgg atgaactata caaa 71481238PRTArtificial SequenceSynthetic sequence 81Met Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val1 5 10 15Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu 20 25 30Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys 35 40

45Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu 50 55 60Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Arg65 70 75 80His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg 85 90 95Thr Ile Ser Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val 100 105 110Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile 115 120 125Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn 130 135 140Tyr Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Lys Asn Gly145 150 155 160Ile Lys Ala Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser Val 165 170 175Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro 180 185 190Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu Leu 195 200 205Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val 210 215 220Thr Ala Ala Gly Ile Thr His Gly Met Asp Glu Leu Tyr Lys225 230 23582717DNAArtificial SequenceSynthetic sequence 82atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca catgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa 420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aaagaatgga 480atcaaagcta acttcaaaat tcgccacaac attgaagatg gatccgttca actagcagac 540cattatcaac aaaatactcc aattggcgat ggccctgtcc ttttaccaga caaccattac 600ctgtcgacac aatctgccct tttgaaagat cccaacgaaa agcgtgacca catggtcctt 660cttgagtttg taactgctgc tgggattaca catggcatgg atgaactata caaataa 7178354DNAArtificial SequenceSynthetic sequence 83tctagacggc cgatctcagg taagaatgga atcaaagcta acttcaaaat tcgc 548420PRTArtificial SequenceSynthetic sequence 84Asn Val Tyr Ile Pro Ile Ser Gly Lys Asn Gly Ile Lys Ala Asn Phe1 5 10 15Lys Ile Arg His 208545DNAArtificial SequenceSynthetic sequence 85agatctccgc ggtttgtata gttcatccat gccatgtgta atccc 45861005DNAArtificial SequenceSynthetic sequence 86taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcac tggttccgcc gatctcaggt 720aagaatggaa tcaaagctaa cttcaaaatt cgccacaaca ttgaagatgg atccgttcaa 780ctagcagacc attatcaaca aaatactcca attggcgatg gccctgtcct tttaccagac 840aaccattacc tgtcgacaca atctgccctt ttgaaagatc ccaacgaaaa gcgtgaccac 900atggtccttc ttgagtttgt aactgctgct gggattacac atggcatgga tgaactatac 960aaaccgcggg gttctcatca tcatcatcat catggttaag tcgac 100587912DNAArtificial SequenceSynthetic sequence 87atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cactggttcc gccgatctca ggtaagaatg gaatcaaagc taacttcaaa 660attcgccaca acattgaaga tggatccgtt caactagcag accattatca acaaaatact 720ccaattggcg atggccctgt ccttttacca gacaaccatt acctgtcgac acaatctgcc 780cttttgaaag atcccaacga aaagcgtgac cacatggtcc ttcttgagtt tgtaactgct 840gctgggatta cacatggcat ggatgaacta tacaaaccgc ggggttctca tcatcatcat 900catcatggtt aa 91288303PRTArtificial SequenceSynthetic sequence 88Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu Val Pro Pro 195 200 205Ile Ser Gly Lys Asn Gly Ile Lys Ala Asn Phe Lys Ile Arg His Asn 210 215 220Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr225 230 235 240Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser 245 250 255Thr Gln Ser Ala Leu Leu Lys Asp Pro Asn Glu Lys Arg Asp His Met 260 265 270Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr His Gly Met Asp 275 280 285Glu Leu Tyr Lys Pro Arg Gly Ser His His His His His His Gly 290 295 30089585DNAArtificial SequenceSynthetic sequence 89atgagtaccg ctaacccact ggcttcaatt gattctgcat tgtcaaaagt ggacgcagtt 60cgttcttctc tgggggcaat tcaaaaccgc tttgattcag ccattaccaa ccttggcaat 120acggtaacca atctgaactc cgcgcgtagc cgtatcgaag atgctgacta tgcatccccg 180ggaagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 240cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 300tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 360cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 420caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 480aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 540ggtctggttc cgcggggttc tcatcatcat catcatcatg gttaa 58590194PRTArtificial SequenceSynthetic sequence 90Met Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys1 5 10 15Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 20 25 30Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 35 40 45Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Ser Pro Gly Ser Gly Leu 50 55 60Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala Ile Ala Asn65 70 75 80Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala 85 90 95Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu 100 105 110Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr 115 120 125Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile 130 135 140Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe145 150 155 160Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val 165 170 175Gly Ala Asn Asp Gly Leu Val Pro Arg Gly Ser His His His His His 180 185 190His Gly91678DNAArtificial SequenceSynthetic sequence 91taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaccgcta acccactggc ttcaattgat 120tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt 180gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 240atcgaagatg ctgactatgc atccccggga agcgggttac ggatcaacag cgcgaaagac 300gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 360gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 420gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 480aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 540gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 600atgaaaatcc aggttggtgc taacgatggt ctggttccgc ggggttctca tcatcatcat 660catcatggtt aagtcgac 6789240DNAArtificial SequenceSynthetic sequence 92tctagacata tgagtaccgc taacccactg gcttcaattg 409338DNAArtificial SequenceSynthetic sequence 93gcttcccggg gatgcatagt cagcatcttc gatacggc 389434DNAArtificial SequenceSynthetic sequence 94gcatccccgg gaagcgggtt acggatcaac agcg 349550DNAArtificial SequenceSynthetic sequence 95agatctccgc ggaaccagac catcgttagc accaacctgg attttcatct 5096654DNAArtificial SequenceSynthetic sequence 96atgagtaccg ctaacccact ggcttcaatt gattctgcat tgtcaaaagt ggacgcagtt 60cgttcttctc tgggggcaat tcaaaaccgc tttgattcag ccattaccaa ccttggcaat 120acggtaacca atctgaactc cgcgcgtagc cgtatcgaag atgctgacta tgcatccccg 180ggaagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 240cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 300tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 360cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 420caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 480aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 540ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 600ttcaatgtta atctggttcc gcggggttct catcatcatc atcatcatgg ttaa 65497217PRTArtificial SequenceSynthetic sequence 97Met Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys1 5 10 15Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 20 25 30Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 35 40 45Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Ser Pro Gly Ser Gly Leu 50 55 60Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala Ile Ala Asn65 70 75 80Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala 85 90 95Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu 100 105 110Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr 115 120 125Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile 130 135 140Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe145 150 155 160Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val 165 170 175Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp 180 185 190Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn Leu Val Pro Arg 195 200 205Gly Ser His His His His His His Gly 210 21598747DNAArtificial SequenceSynthetic sequence 98taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaccgcta acccactggc ttcaattgat 120tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt 180gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 240atcgaagatg ctgactatgc atccccggga agcgggttac ggatcaacag cgcgaaagac 300gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 360gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 420gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 480aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 540gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 600atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 660gatgtgaaaa gccttggcct tgatgggttc aatgttaatc tggttccgcg gggttctcat 720catcatcatc atcatggtta agtcgac 7479945DNAArtificial SequenceSynthetic sequence 99agatctccgc ggaaccagat taacattgaa cccatcaagg ccaag 4510038DNAArtificial SequenceSynthetic sequence 100cccgttatcc ggatcacatg aaacggcatg actttttc 3810138DNAArtificial SequenceSynthetic sequence 101gaaaaagtca tgccgtttca tgtgatccgg ataacggg 3810221DNAArtificial SequenceSynthetic sequence 102ctgttccatg gccaacactt g 2110346DNAArtificial SequenceSynthetic sequence 103tctagacata tgagtaaagg agaagaactt ttcactggag ttgtcc 4610463DNAArtificial SequenceSynthetic sequence 104ggcctatgcg gccgcagtaa aggagaagaa cttttcactg gagttgtccc aattcttgtt 60gaa 6310557DNAArtificial SequenceSynthetic sequence 105agatctatta atgcggcctg ataggccttg tttgtctgcc gtgatgtata cattgtg 5710618PRTArtificial SequenceSynthetic sequence 106Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Gly Leu Ser Gly Arg1 5 10 15Asn Met1071494DNAArtificial SequenceSynthetic sequence 107taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaaaggag aagaactttt cactggagtt 120gtcccaattc ttgttgaatt agatggtgat gttaatgggc acaaattttc tgtcagtgga 180gagggtgaag gtgatgcaac atacggaaaa cttaccctta aatttatttg cactactgga 240aaactacctg ttccatggcc aacacttgtc actactctga cgtatggtgt tcaatgcttt 300tcccgttatc cggatcacat gaaacggcat gactttttca agagtgccat gcccgaaggt 360tatgtacagg aacgcactat atctttcaaa gatgacggga actacaagac gcgtgctgaa 420gtcaagtttg aaggtgatac ccttgttaat cgtatcgagt taaaaggtat tgattttaaa 480gaagatggaa acattctcgg acacaaactc gagtacaact ataactcaca caatgtatac 540atcacggcag acaaacaagg cctatcaggc cgcattatga gcgggttacg gatcaacagc 600gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 660ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 720gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 780aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 840gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 900gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 960caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaagt 1020accgctaacc cactggcttc aattgattct gcattgtcaa aagtggacgc agttcgttct 1080tctctggggg caattcaaaa ccgctttgat tcagccatta ccaaccttgg caatacggta 1140accaatctga actccgcgcg tagccgtatc gaagatgctg actatgcact ggttccgccg 1200atctcaggta agaatggaat caaagctaac ttcaaaattc gccacaacat tgaagatgga 1260tccgttcaac tagcagacca ttatcaacaa aatactccaa ttggcgatgg ccctgtcctt 1320ttaccagaca accattacct gtcgacacaa tctgcccttt tgaaagatcc caacgaaaag 1380cgtgaccaca tggtccttct tgagtttgta actgctgctg ggattacaca tggcatggat 1440gaactataca aaccgcgggg ttctcatcat catcatcatc atggttaagt cgac 14941081401DNAArtificial SequenceSynthetic sequence 108atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca catgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa

420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aggcctatca 480ggccgcatta tgagcgggtt acggatcaac agcgcgaaag acgatgcggc aggccaggcg 540attgctaacc gcttcacttc taatatcaaa ggtctgactc aggcttcccg taacgctaac 600gacggcattt ctattgcgca gaccactgaa ggtgcgctga atgaaatcaa caacaacctg 660cagcgtgtgc gtgagttgtc tgttcaggcc actaacggga ctaactctga ttccgatctg 720aaatctatcc aggatgaaat tcagcaacgt ctggaagaaa tcgatcgcgt ttctaatcag 780actcaattta acggtgttaa agtcctgtct caggacaacc agatgaaaat ccaggttggt 840gctaacgatg gtgaaaccat taccatcgat ctgcaaaaaa ttgatgtgaa aagccttggc 900cttgatgggt tcaatgttaa ttccccggga agtaccgcta acccactggc ttcaattgat 960tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt 1020gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 1080atcgaagatg ctgactatgc actggttccg ccgatctcag gtaagaatgg aatcaaagct 1140aacttcaaaa ttcgccacaa cattgaagat ggatccgttc aactagcaga ccattatcaa 1200caaaatactc caattggcga tggccctgtc cttttaccag acaaccatta cctgtcgaca 1260caatctgccc ttttgaaaga tcccaacgaa aagcgtgacc acatggtcct tcttgagttt 1320gtaactgctg ctgggattac acatggcatg gatgaactat acaaaccgcg gggttctcat 1380catcatcatc atcatggtta a 1401109466PRTArtificial SequenceSynthetic sequence 109Met Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val1 5 10 15Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu 20 25 30Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys 35 40 45Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu 50 55 60Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Arg65 70 75 80His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg 85 90 95Thr Ile Ser Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val 100 105 110Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile 115 120 125Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn 130 135 140Tyr Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Gly Leu Ser145 150 155 160Gly Arg Ile Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala 165 170 175Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu 180 185 190Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr 195 200 205Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg 210 215 220Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu225 230 235 240Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg 245 250 255Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp 260 265 270Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr 275 280 285Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe 290 295 300Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp305 310 315 320Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile 325 330 335Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr 340 345 350Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu 355 360 365Val Pro Pro Ile Ser Gly Lys Asn Gly Ile Lys Ala Asn Phe Lys Ile 370 375 380Arg His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln385 390 395 400Gln Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His 405 410 415Tyr Leu Ser Thr Gln Ser Ala Leu Leu Lys Asp Pro Asn Glu Lys Arg 420 425 430Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr His 435 440 445Gly Met Asp Glu Leu Tyr Lys Pro Arg Gly Ser His His His His His 450 455 460His Gly465110124DNAArtificial SequenceSynthetic sequence 110cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 60acattaatca atgaagacgc tgccgcagcc aagaaaagta ccgctaaccc actggcttca 120attg 12411141PRTArtificial SequenceSynthetic sequence 111Leu Gly Leu Asp Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly1 5 10 15Gly Gly Gly Ile Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 20 25 30Ser Thr Ala Asn Pro Leu Ala Ser Ile 35 4011272DNAArtificial SequenceSynthetic sequence 112agatctccgc ggaaccagta aagagaggac gttttgcgga acctggtttg catagtcagc 60atcttcgata cg 72113777DNAArtificial SequenceSynthetic sequence 113taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgttttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa accaggttcc gcaaaacgtc 720ctctctttac tggttccgcg gggttctcat catcatcatc atcatggtta agtcgac 777114684DNAArtificial SequenceSynthetic sequence 114atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgttt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 660catcatcatc atcatcatgg ttaa 684115227PRTArtificial SequenceSynthetic sequence 115Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Asn Gln Val Pro 195 200 205Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 210 215 220His His Gly22511642DNAArtificial SequenceSynthetic sequence 116agatctcccg gggaaccatc gttagcacca acctggattt tc 42117777DNAArtificial SequenceSynthetic sequence 117taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt tccccgggaa gtaccgctaa cccactggct 480tcaattgatt ctgcattgtc aaaagtggac gcagttcgtt cttctctggg ggcaattcaa 540aaccgctttg attcagccat taccaacctt ggcaatacgg taaccaatct gaactccgcg 600cgtagccgta tcgaagatgc tgactatgca acggaagttt ctaatatgtc taaagcgcag 660attctgcagc aggctggtac ttccgttctg gcgcaggcta accaggttcc gcaaaacgtc 720ctctctttac tggttccgcg gggttctcat catcatcatc atcatggtta agtcgac 777118684DNAArtificial SequenceSynthetic sequence 118atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggttccccgg gaagtaccgc taacccactg gcttcaattg attctgcatt gtcaaaagtg 420gacgcagttc gttcttctct gggggcaatt caaaaccgct ttgattcagc cattaccaac 480cttggcaata cggtaaccaa tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat 540gcaacggaag tttctaatat gtctaaagcg cagattctgc agcaggctgg tacttccgtt 600ctggcgcagg ctaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 660catcatcatc atcatcatgg ttaa 684119227PRTArtificial SequenceSynthetic sequence 119Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Ser Pro Gly Ser Thr Ala Asn 115 120 125Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 130 135 140Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn145 150 155 160Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 165 170 175Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 180 185 190Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 195 200 205Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 210 215 220His His Gly22512090DNAArtificial SequenceSynthetic sequence 120agatctccgc ggaaccagca ggttattctg ggtcaacagc gacaggctgt ttgtattaat 60gacttgtgca tagtcagcat cttcgatacg 90121795DNAArtificial SequenceSynthetic sequence 121taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcac aagtcattaa tacaaacagc 720ctgtcgctgt tgacccagaa taacctgctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795122702DNAArtificial SequenceSynthetic sequence 122atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cacaagtcat taatacaaac agcctgtcgc tgttgaccca gaataacctg 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 702123233PRTArtificial SequenceSynthetic sequence 123Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Gln Val Ile Asn 195 200 205Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn Asn Leu Leu Val Pro Arg 210 215 220Gly Ser His His His His His His Gly225 23012449DNAArtificial SequenceSynthetic sequence 124gctgactatg caacggcagt ttctgctatg tctgcagcgc agattctgc 4912549DNAArtificial SequenceSynthetic sequence 125gcagaatctg cgctgcagac atagcagaaa ctgccgttgc atagtcagc 49126795DNAArtificial SequenceSynthetic sequence 126taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggcagtttc tgctatgtct 720gcagcgcaga ttctgcagca ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795127702DNAArtificial SequenceSynthetic sequence

127atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggcagt ttctgctatg tctgcagcgc agattctgca gcaggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 702128233PRTArtificial SequenceSynthetic sequence 128Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Ala Val Ser 195 200 205Ala Met Ser Ala Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg 210 215 220Gly Ser His His His His His His Gly225 23012954DNAArtificial SequenceSynthetic sequence 129gtttctaata tgtctaaagc ggcgattctg ggagcggctg gtctggttcc gcgg 5413054DNAArtificial SequenceSynthetic sequence 130ccgcggaacc agaccagccg ctcccagaat cgccgcttta gacatattag aaac 54131795DNAArtificial SequenceSynthetic sequence 131taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcggcga ttctgggagc ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795132702DNAArtificial SequenceSynthetic sequence 132atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgg cgattctggg agcggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 702133233PRTArtificial SequenceSynthetic sequence 133Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Ala Ile Leu Gly Ala Ala Gly Leu Val Pro Arg 210 215 220Gly Ser His His His His His His Gly225 23013425DNAArtificial SequenceSynthetic sequence 134tctagaggat ccggcaggcc aggcg 2513522DNAArtificial SequenceSynthetic sequence 135cgcaagcttg tcgacttaac gc 22136970DNAArtificial SequenceSynthetic sequence 136taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccggc aggccaggcg attgctaacc gcttcacttc taatatcaaa 240ggtctgactc aggcttcccg taacgctaac gacggcattt ctattgcgca gaccactgaa 300ggtgcgctga atgaaatcaa caacaacctg cagcgtgtgc gtgagttgtc tgttcaggcc 360actaacggga ctaactctga ttccgatctg aaatctatcc aggatgaaat tcagcaacgt 420ctggaagaaa tcgatcgcgt ttctaatcag actcaattta acggtgttaa agtcctgtct 480caggacaacc agatgaaaat ccaggttggt gctaacgatg gtgaaaccat taccatcgat 540ctgcaaaaaa ttgatgtgaa aagccttggc cttgatgggt tcaatgttaa ttccccggga 600atttccggtg gtggtggtgg aattctagac tccatgggta cattaatcaa tgaagacgct 660gccgcagcca agaaaagtac cgctaaccca ctggcttcaa ttgattctgc attgtcaaaa 720gtggacgcag ttcgttcttc tctgggggca attcaaaacc gttttgattc agccattacc 780aaccttggca atacggtaac caatctgaac tccgcgcgta gccgtatcga agatgctgac 840tatgcaacgg aagtttctaa tatgtctaaa gcgcagattc tgcagcaggc tggtacttcc 900gttctggcgc aggctaacca ggttccgcaa aacgtcctct ctttactgcg ttaagtcgac 960aagcttgcgg 970137288PRTArtificial SequenceSynthetic sequence 137Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser 35 40 45Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile 50 55 60Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn65 70 75 80Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn 85 90 95Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu 100 105 110Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys 115 120 125Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp 130 135 140Gly Glu Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu145 150 155 160Gly Leu Asp Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly 165 170 175Gly Gly Ile Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala 180 185 190Ala Ala Lys Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala 195 200 205Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn 210 215 220Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu225 230 235 240Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val 245 250 255Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val 260 265 270Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 275 280 2851381236DNAArtificial SequenceSynthetic sequence 138taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaaaggag aagaactttt cactggagtt 120gtcccaattc ttgttgaatt agatggtgat gttaatgggc acaaattttc tgtcagtgga 180gagggtgaag gtgatgcaac atacggaaaa cttaccctta aatttatttg cactactgga 240aaactacctg ttccatggcc aacacttgtc actactctga cgtatggtgt tcaatgcttt 300tcccgttatc cggatcacat gaaacggcat gactttttca agagtgccat gcccgaaggt 360tatgtacagg aacgcactat atctttcaaa gatgacggga actacaagac gcgtgctgaa 420gtcaagtttg aaggtgatac ccttgttaat cgtatcgagt taaaaggtat tgattttaaa 480gaagatggaa acattctcgg acacaaactc gagtacaact ataactcaca caatgtatac 540atcacggcag acaaacaagg cctatcaggc cgcattatga gcgggttacg gatcaacagc 600gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 660ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 720gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 780aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 840gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 900gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 960caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaagt 1020accgctaacc cactggcttc aattgattct gcattgtcaa aagtggacgc agttcgttct 1080tctctggggg caattcaaaa ccgctttgat tcagccatta ccaaccttgg caatacggta 1140accaatctga actccgcgcg tagccgtatc gaagatgctg actatgcact ggttccgcgg 1200ggttctcatc atcatcatca tcatggttaa gtcgac 12361391143DNAArtificial SequenceSynthetic sequence 139atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca catgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa 420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aggcctatca 480ggccgcatta tgagcgggtt acggatcaac agcgcgaaag acgatgcggc aggccaggcg 540attgctaacc gcttcacttc taatatcaaa ggtctgactc aggcttcccg taacgctaac 600gacggcattt ctattgcgca gaccactgaa ggtgcgctga atgaaatcaa caacaacctg 660cagcgtgtgc gtgagttgtc tgttcaggcc actaacggga ctaactctga ttccgatctg 720aaatctatcc aggatgaaat tcagcaacgt ctggaagaaa tcgatcgcgt ttctaatcag 780actcaattta acggtgttaa agtcctgtct caggacaacc agatgaaaat ccaggttggt 840gctaacgatg gtgaaaccat taccatcgat ctgcaaaaaa ttgatgtgaa aagccttggc 900cttgatgggt tcaatgttaa ttccccggga agtaccgcta acccactggc ttcaattgat 960tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt 1020gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 1080atcgaagatg ctgactatgc actggttccg cggggttctc atcatcatca tcatcatggt 1140taa 1143140380PRTArtificial SequenceSynthetic sequence 140Met Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val1 5 10 15Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu 20 25 30Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys 35 40 45Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu 50 55 60Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Arg65 70 75 80His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg 85 90 95Thr Ile Ser Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val 100 105 110Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile 115 120 125Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn 130 135 140Tyr Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Gly Leu Ser145 150 155 160Gly Arg Ile Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala 165 170 175Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu 180 185 190Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr 195 200 205Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg 210 215 220Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu225 230 235 240Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg 245 250 255Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp 260 265 270Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr 275 280 285Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe 290 295 300Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp305 310 315 320Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile 325 330 335Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr 340 345 350Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu 355 360 365Val Pro Arg Gly Ser His His His His His His Gly 370 375 38014136DNAArtificial SequenceSynthetic sequence 141tctagaggat ccgtctggtc tgcgtatcaa cagcgc 36142996DNAArtificial SequenceSynthetic sequence 142taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgtc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa gtcgac 996143903DNAArtificial SequenceSynthetic sequence 143atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cctggttccg cgcggtagcg cgaaggatcc gtctggtctg 120cgtatcaaca gcgcgaaaga cgatgcggca ggccaggcga ttgctaaccg cttcacttct 180aatatcaaag gtctgactca ggcttcccgt aacgctaacg acggcatttc tattgcgcag 240accactgaag gtgcgctgaa tgaaatcaac aacaacctgc agcgtgtgcg tgagttgtct 300gttcaggcca ctaacgggac taactctgat tccgatctga aatctatcca ggatgaaatt 360cagcaacgtc tggaagaaat cgatcgcgtt tctaatcaga

ctcaatttaa cggtgttaaa 420gtcctgtctc aggacaacca gatgaaaatc caggttggtg ctaacgatgg tgaaaccatt 480accatcgatc tgcaaaaaat tgatgtgaaa agccttggcc ttgatgggtt caatgttaat 540tccccgggaa tttccggtgg tggtggtgga attctagact ccatgggtac attaatcaat 600gaagacgctg ccgcagccaa gaaaagtacc gctaacccac tggcttcaat tgattctgca 660ttgtcaaaag tggacgcagt tcgttcttct ctgggggcaa ttcaaaaccg ttttgattca 720gccattacca accttggcaa tacggtaacc aatctgaact ccgcgcgtag ccgtatcgaa 780gatgctgact atgcaacgga agtttctaat atgtctaaag cgcagattct gcagcaggct 840ggtacttccg ttctggcgca ggctaaccag gttccgcaaa acgtcctctc tttactgcgt 900taa 903144300PRTArtificial SequenceSynthetic sequence 144Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln65 70 75 80Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 130 135 140Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile145 150 155 160Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser225 230 235 240Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala 275 280 285Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 290 295 30014544DNAArtificial SequenceSynthetic sequence 145agatctccgc ggaaccagtg catagtcagc atcttcgata cggc 44146747DNAArtificial SequenceSynthetic sequence 146taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcac tggttccgcg gggttctcat 720catcatcatc atcatggtta agtcgac 747147654DNAArtificial SequenceSynthetic sequence 147atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cactggttcc gcggggttct catcatcatc atcatcatgg ttaa 654148217PRTArtificial SequenceSynthetic sequence 148Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu Val Pro Arg 195 200 205Gly Ser His His His His His His Gly 210 215149753DNAArtificial SequenceSynthetic sequence 149atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctgc agacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactgccggg gctaacgctg atgccgctct gaaagctatc 240caggctgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctcagca gactcaagct 300gccgctgtta aagtcctgtc tcaggacaac gcaatggcaa tccaggttgg tgctaacgat 360ggtgccgcta ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctcaaatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 753150250PRTArtificial SequenceSynthetic sequence 150Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Ala Gly Ala Asn Ala Asp Ala Ala Leu Lys Ala Ile65 70 75 80Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Gln 85 90 95Gln Thr Gln Ala Ala Ala Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110Ala Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Gln Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 250151846DNAArtificial SequenceSynthetic sequence 151taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctgcaga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aacgctgatg ccgctctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctcagcagac tcaagctgcc gctgttaaag tcctgtctca ggacaacgca 420atggcaatcc aggttggtgc taacgatggt gccgctatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc tcaaatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846152795DNAArtificial SequenceSynthetic sequence 152taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctgcaga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aacgctgatg ccgctctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctcagcagac tcaagctgcc gctgttaaag tcctgtctca ggacaacgca 420atggcaatcc aggttggtgc taacgatggt gccgctatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc tcaaatgtct 720aaagcgcaga ttctgcagca ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795153702DNAArtificial SequenceSynthetic sequence 153atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctgc agacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactgccggg gctaacgctg atgccgctct gaaagctatc 240caggctgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctcagca gactcaagct 300gccgctgtta aagtcctgtc tcaggacaac gcaatggcaa tccaggttgg tgctaacgat 360ggtgccgcta ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctcaaatg tctaaagcgc agattctgca gcaggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 702154233PRTArtificial SequenceSynthetic sequence 154Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Ala Gly Ala Asn Ala Asp Ala Ala Leu Lys Ala Ile65 70 75 80Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Gln 85 90 95Gln Thr Gln Ala Ala Ala Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110Ala Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Gln Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg 210 215 220Gly Ser His His His His His His Gly225 230155990DNAArtificial SequenceSynthetic sequence 155atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cgatgacgat aaggatccga tggcacaagt cattaataca 120aacagcctgt cgctgttgac ccagaataac ctgcagaaat ctcagtcctc actgagttcc 180gctattgagc gtctgtcctc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccactc aagggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480cagcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctcaaatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa 990156180DNAArtificial SequenceSynthetic sequence 156aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattc aaaaccgttt tgattcagcc attaccgccc ttggcgctac ggtaaccgct 120ctggcctccg cgcgtagcgc tatcgaagat gctgactatg caacggaagt ttctcaaatg 18015760PRTArtificial SequenceSynthetic sequence 157Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val1 5 10 15Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 20 25 30Ala Leu Gly Ala Thr Val Thr Ala Leu Ala Ser Ala Arg Ser Ala Ile 35 40 45Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met 50 55 6015850DNAArtificial SequenceSynthetic sequence 158gcagttcgtt cttctctggg ggcaattgat tcagccatta ccgcccttgg 5015950DNAArtificial SequenceSynthetic sequence 159ccaagggcgg taatggctga atcaattgcc cccagagaag aacgaactgc 501601066DNAArtificial SequenceSynthetic sequence 160taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat gcggggttct catcatcatc atcatcatgg 120tatggctagc atgactggtg gacagcaaat gggtcgggat ctgtacgacg atgacgataa 180ggatccgatg gcacaagtca ttaatacaaa cagcctgtcg ctgttgaccc agaataacct 240gaacaaatct cagtcctcac tgagttccgc tattgagcgt ctgtcctctg gtctgcgtat 300caacagcgcg aaagacgatg cggcaggcca ggcgattgct aaccgcttca cttctaatat 360caaaggtctg actcaggctt cccgtaacgc taacgacggc atttctattg cgcagaccac 420tgaaggtgcg ctgaatgaaa tcaacaacaa cctgcagcgt gtgcgtgagt tgtctgttca 480ggccactaac gggactaact ctgattccga tctgaaatct atccaggatg aaattcagca 540acgtctggaa gaaatcgatc gcgtttctaa tcagactcaa tttaacggtg ttaaagtcct 600gtctcaggac aaccagatga aaatccaggt tggtgctaac gatggtgaaa ccattaccat 660cgatctgcaa aaaattgatg tgaaaagcct tggccttgat gggttcaatg ttaattcccc 720gggaatttcc ggtggtggtg gtggaattct agactccatg ggtacattaa tcaatgaaga 780cgctgccgca gccaagaaaa gtaccgctaa cccactggct tcaattgatt ctgcattgtc 840aaaagtggac gcagttcgtt cttctctggg ggcaattgat tcagccatta ccgcccttgg 900cgctacggta accgctctgg cctccgcggc tagccgtatc gaagatgctg actatgcaac 960ggaagtttct aatatgtcta aagcgcagat tctgcagcag gctggtactt ccgttctggc 1020gcaggctaac caggttccgc aaaacgtcct ctctttactg cgttaa 1066161325PRTArtificial SequenceSynthetic sequence 161Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5

10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp 20 25 30Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln 35 40 45Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg 50 55 60Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly65 70 75 80Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln 85 90 95Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu 100 105 110Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu 115 120 125Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser 130 135 140Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser145 150 155 160Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln 165 170 175Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp 180 185 190Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val 195 200 205Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met 210 215 220Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala225 230 235 240Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 245 250 255Arg Ser Ser Leu Gly Ala Ile Asp Ser Ala Ile Thr Ala Leu Gly Ala 260 265 270Thr Val Thr Ala Leu Ala Ser Ala Ala Ser Arg Ile Glu Asp Ala Asp 275 280 285Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln 290 295 300Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val305 310 315 320Leu Ser Leu Leu Arg 325162180DNAArtificial SequenceSynthetic sequence 162aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattg caaaggcttt tgattcagcc attaccgccc ttggcgctac ggtaaccgct 120ctggcctccg cgcgtagcgc tatcgaagat gctgactatg caacggaagt ttctcaaatg 18016360PRTArtificial SequenceSynthetic sequence 163Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val1 5 10 15Arg Ser Ser Leu Gly Ala Ile Ala Lys Ala Phe Asp Ser Ala Ile Thr 20 25 30Ala Leu Gly Ala Thr Val Thr Ala Leu Ala Ser Ala Arg Ser Ala Ile 35 40 45Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met 50 55 6016450DNAArtificial SequenceSynthetic sequence 164cgttcttctc tgggggcaat tgcaaaggct tttgattcag ccattaccgc 5016550DNAArtificial SequenceSynthetic sequence 165gcggtaatgg ctgaatcaaa agcctttgca attgccccca gagaagaacg 501661078DNAArtificial SequenceSynthetic sequence 166taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat gcggggttct catcatcatc atcatcatgg 120tatggctagc atgactggtg gacagcaaat gggtcgggat ctgtacgacg atgacgataa 180ggatccgatg gcacaagtca ttaatacaaa cagcctgtcg ctgttgaccc agaataacct 240gaacaaatct cagtcctcac tgagttccgc tattgagcgt ctgtcctctg gtctgcgtat 300caacagcgcg aaagacgatg cggcaggcca ggcgattgct aaccgcttca cttctaatat 360caaaggtctg actcaggctt cccgtaacgc taacgacggc atttctattg cgcagaccac 420tgaaggtgcg ctgaatgaaa tcaacaacaa cctgcagcgt gtgcgtgagt tgtctgttca 480ggccactaac gggactaact ctgattccga tctgaaatct atccaggatg aaattcagca 540acgtctggaa gaaatcgatc gcgtttctaa tcagactcaa tttaacggtg ttaaagtcct 600gtctcaggac aaccagatga aaatccaggt tggtgctaac gatggtgaaa ccattaccat 660cgatctgcaa aaaattgatg tgaaaagcct tggccttgat gggttcaatg ttaattcccc 720gggaatttcc ggtggtggtg gtggaattct agactccatg ggtacattaa tcaatgaaga 780cgctgccgca gccaagaaaa gtaccgctaa cccactggct tcaattgatt ctgcattgtc 840aaaagtggac gcagttcgtt cttctctggg ggcaattgca aaggcttttg attcagccat 900taccgccctt ggcgctacgg taaccgctct ggcctccgcg gctagccgta tcgaagatgc 960tgactatgca acggaagttt ctaatatgtc taaagcgcag attctgcagc aggctggtac 1020ttccgttctg gcgcaggcta accaggttcc gcaaaacgtc ctctctttac tgcgttaa 1078167329PRTArtificial SequenceSynthetic sequence 167Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp 20 25 30Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln 35 40 45Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg 50 55 60Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly65 70 75 80Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln 85 90 95Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu 100 105 110Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu 115 120 125Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser 130 135 140Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser145 150 155 160Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln 165 170 175Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp 180 185 190Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val 195 200 205Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met 210 215 220Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala225 230 235 240Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 245 250 255Arg Ser Ser Leu Gly Ala Ile Ala Lys Ala Phe Asp Ser Ala Ile Thr 260 265 270Ala Leu Gly Ala Thr Val Thr Ala Leu Ala Ser Ala Ala Ser Arg Ile 275 280 285Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln 290 295 300Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val305 310 315 320Pro Gln Asn Val Leu Ser Leu Leu Arg 325168903DNAArtificial SequenceSynthetic sequence 168atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cctggttccg cgcggtagcg cgaaggatcc gtctggtctg 120cgtatcaaca gcgcgaaaga cgatgcggca ggccaggcga ttgctaaccg cttcacttct 180aatatcaaag gtctgactca ggcttcccgt aacgctgcag acggcatttc tattgcgcag 240accactgaag gtgcgctgaa tgaaatcaac aacaacctgc agcgtgtgcg tgagttgtct 300gttcaggcca ctaacgggac taactctgat tccgatctga aatctatcca ggatgaaatt 360cagcaacgtc tggaagaaat cgatcgcgtt tctaatcaga ctcaagctaa cggtgttaaa 420gtcctgtctc aggacaacgc aatgaaaatc caggttggtg ctaacgatgg tgccgctatt 480accatcgatc tgcaaaaaat tgatgtgaaa agccttggcc ttgatgggtt caatgttaat 540tccccgggaa tttccggtgg tggtggtgga attctagact ccatgggtac attaatcaat 600gaagacgctg ccgcagccaa gaaaagtacc gctaacccac tggcttcaat tgattctgca 660ttgtcaaaag tggacgcagt tcgttcttct ctgggggcaa ttcaagctcg ttttgccgcg 720gccattgcta accttggcaa tacggtaacc aatctgaact ccgcgcgtag ccgtatcgaa 780gatgctgact atgcaacgga agtttctaat atgtctaaag cgcagattct gcagcaggct 840ggtacttccg ttctggcgca ggctaaccag gttccgcaaa acgtcctctc tttactgcgt 900taa 903169300PRTArtificial SequenceSynthetic sequence 169Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr1 5 10 15Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60Leu Thr Gln Ala Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln65 70 75 80Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125Arg Val Ser Asn Gln Thr Gln Ala Asn Gly Val Lys Val Leu Ser Gln 130 135 140Asp Asn Ala Met Lys Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile145 150 155 160Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Ala Arg Phe Ala Ala225 230 235 240Ala Ile Ala Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala 275 280 285Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 290 295 300170996DNAArtificial SequenceSynthetic sequence 170taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgtc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctgcagacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aagctaacgg tgttaaagtc ctgtctcagg acaacgcaat gaaaatccag 540gttggtgcta acgatggtgc cgctattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aagctcgttt tgccgcggcc attgctaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa gtcgac 99617179DNAArtificial SequenceSynthetic sequence 171agatctgtcg acttaaccat gatgatgatg atgatgagaa ccccgcggaa ccagtaaaga 60gaggacgttt tgcggaacc 79172846DNAArtificial SequenceSynthetic sequence 172taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaag ctcgttttgc cgcggccatt gctaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846173250PRTArtificial SequenceSynthetic sequence 173Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Ala Arg 165 170 175Phe Ala Ala Ala Ile Ala Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25017447DNAArtificial SequenceSynthetic sequence 174agatctcata tgagcgggtt acggatcaac agcgcgaaag acgatgc 47175846DNAArtificial SequenceSynthetic sequence 175taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctgcaga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaagctaac ggtgttaaag tcctgtctca ggacaacgca 420atgaaaatcc aggttggtgc taacgatggt gccgctatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846176250PRTArtificial SequenceSynthetic sequence 176Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Ala Asn Gly Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His

His His Gly 245 250177270DNAArtificial SequenceSynthetic sequence 177aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 120ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctcaaatg 180tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 240ccgcaaaacg tcctctcttt actgcgttaa 27017860DNAArtificial SequenceSynthetic sequence 178attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 6017920PRTArtificial SequenceSynthetic sequence 179Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser1 5 10 15Arg Ile Glu Asp 2018046DNAArtificial SequenceSynthetic sequence 180ccttggcaat acggtaaccg ctctggcctc cgcgcgtagc cgtatc 4618146DNAArtificial SequenceSynthetic sequence 181gatacggcta cgcgcggagg ccagagcggt taccgtattg ccaagg 4618260DNAArtificial SequenceSynthetic sequence 182acggtaaccg ctctggcctc cgcgcgtagc cgtatcgaag atgctgacta tgcaacggaa 6018320PRTArtificial SequenceSynthetic sequence 183Thr Val Thr Ala Leu Ala Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp1 5 10 15Tyr Ala Thr Glu 2018434DNAArtificial SequenceSynthetic sequence 184gctctggcct ccgcggctag ccgtatcgaa gatg 3418534DNAArtificial SequenceSynthetic sequence 185catcttcgat acggctagcc gcggaggcca gagc 3418660DNAArtificial SequenceSynthetic sequence 186caaaaccgtt ttgattcagc cattaccaac cttggcaata cggtaaccgc tctggcctcc 6018720PRTArtificial SequenceSynthetic sequence 187Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr1 5 10 15Ala Leu Ala Ser 2018848DNAArtificial SequenceSynthetic sequence 188gttttgattc agccattacc gcccttggcg ctacggtaac cgctctgg 4818948DNAArtificial SequenceSynthetic sequence 189ccagagcggt taccgtagcg ccaagggcgg taatggctga atcaaaac 4819039DNAArtificial SequenceSynthetic sequence 190caacagcgcg aaagccgatg cgggaggcca ggcgattgc 3919139DNAArtificial SequenceSynthetic sequence 191gcaatcgcct ggcctcccgc atcggctttc gcgctgttg 39192846DNAArtificial SequenceSynthetic sequence 192taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagcc 120gatgcgggag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846193250PRTArtificial SequenceSynthetic sequence 193Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Ala Asp Ala Gly Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25019443DNAArtificial SequenceSynthetic sequence 194gtctgttcag gccactgccg gggctaactc tgattccgat ctg 4319543DNAArtificial SequenceSynthetic sequence 195cagatcggaa tcagagttag ccccggcagt ggcctgaaca gac 43196846DNAArtificial SequenceSynthetic sequence 196taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846197250PRTArtificial SequenceSynthetic sequence 197Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Ala Gly Ala Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25019845DNAArtificial SequenceSynthetic sequence 198ctgattccga tctgaaagct atccaggctg aaattcagca acgtc 4519945DNAArtificial SequenceSynthetic sequence 199gacgttgctg aatttcagcc tggatagctt tcagatcgga atcag 45200846DNAArtificial SequenceSynthetic sequence 200taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aactctgatt ccgatctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846201753DNAArtificial SequenceSynthetic sequence 201atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactgccggg gctaactctg attccgatct gaaagctatc 240caggctgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 753202250PRTArtificial SequenceSynthetic sequence 202Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Ala Gly Ala Asn Ser Asp Ser Asp Leu Lys Ala Ile65 70 75 80Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25020345DNAArtificial SequenceSynthetic sequence 203gccactaacg ggactaacgc tgatgccgct ctgaaatcta tccag 4520445DNAArtificial SequenceSynthetic sequence 204ctggatagat ttcagagcgg catcagcgtt agtcccgtta gtggc 45205846DNAArtificial SequenceSynthetic sequence 205taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aacgctgatg ccgctctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846206250PRTArtificial SequenceSynthetic sequence 206Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ala Asp Ala Ala Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25020745DNAArtificial SequenceSynthetic sequence 207gccactgccg gggctaacgc tgatgccgct ctgaaagcta tccag 4520845DNAArtificial SequenceSynthetic sequence 208ctggatagct ttcagagcgg catcagcgtt agccccggca gtggc 45209846DNAArtificial SequenceSynthetic sequence 209taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aacgctgatg ccgctctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846210250PRTArtificial SequenceSynthetic sequence 210Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Ala Gly Ala Asn Ala Asp Ala Ala

Leu Lys Ala Ile65 70 75 80Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 250211846DNAArtificial SequenceSynthetic sequence 211taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846212250PRTArtificial SequenceSynthetic sequence 212Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ala Ile65 70 75 80Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25021345DNAArtificial SequenceSynthetic sequence 213ctatccagga tgaaattcag gcacgtctgg cagaaatcga tcgcg 4521445DNAArtificial SequenceSynthetic sequence 214cgcgatcgat ttctgccaga cgtgcctgaa tttcatcctg gatag 45215846DNAArtificial SequenceSynthetic sequence 215taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc aggcacgtct ggcagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846216250PRTArtificial SequenceSynthetic sequence 216Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Ala Arg Leu Ala Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25021759DNAArtificial SequenceSynthetic sequence 217ggaagaaatc gatgccgttt ctgctgcgac tcaatttaac ggtgttaaag tcctgtctc 5921859DNAArtificial SequenceSynthetic sequence 218gagacaggac tttaacaccg ttaaattgag tcgcagcaga aacggcatcg atttcttcc 59219846DNAArtificial SequenceSynthetic sequence 219taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatgccgttt ctgctgcgac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846220250PRTArtificial SequenceSynthetic sequence 220Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Ala Val Ser Ala 85 90 95Ala Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25022153DNAArtificial SequenceSynthetic sequence 221cagcaacgtc tggaagaaat cgatgccgtt tctaatcaga ctcaatttaa cgg 5322253DNAArtificial SequenceSynthetic sequence 222ccgttaaatt gagtctgatt agaaacggca tcgatttctt ccagacgttg ctg 53223753DNAArtificial SequenceSynthetic sequence 223atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatgccg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 753224846DNAArtificial SequenceSynthetic sequence 224taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatgccgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846225250PRTArtificial SequenceSynthetic sequence 225Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Ala Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25022653DNAArtificial SequenceSynthetic sequence 226cgtttctaat cagactcaat ttgccgctgt taaagtcctg tctcaggaca acc 5322753DNAArtificial SequenceSynthetic sequence 227ggttgtcctg agacaggact ttaacagcgg caaattgagt ctgattagaa acg 53228846DNAArtificial SequenceSynthetic sequence 228taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttgcc gctgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846229250PRTArtificial SequenceSynthetic sequence 229Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Ala Ala Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210

215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25023052DNAArtificial SequenceSynthetic sequence 230gttaaagtcc tgtctcagga caacgcgatg gcaatccagg ttggtgctaa cg 5223152DNAArtificial SequenceSynthetic sequence 231cgttagcacc aacctggatt gccatcgcgt tgtcctgaga caggacttta ac 52232846DNAArtificial SequenceSynthetic sequence 232taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaacgcg 420atggcaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846233250PRTArtificial SequenceSynthetic sequence 233Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110Ala Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25023453DNAArtificial SequenceSynthetic sequence 234gatgaaaatc caggttggtg ctagcgctgc tgaaaccatt accatcgatc tgc 5323553DNAArtificial SequenceSynthetic sequence 235gcagatcgat ggtaatggtt tcagcagcgc tagcaccaac ctggattttc atc 53236846DNAArtificial SequenceSynthetic sequence 236taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc tagcgctgct gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846237250PRTArtificial SequenceSynthetic sequence 237Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Ser Ala Ala Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 25023856DNAArtificial SequenceSynthetic sequence 238gccgtatcga agatgctgac gctggagcgg aagttgctaa tatgtctaaa gcgcag 5623956DNAArtificial SequenceSynthetic sequence 239ctgcgcttta gacatattag caacttccgc tccagcgtca gcatcttcga tacggc 56240846DNAArtificial SequenceSynthetic sequence 240taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gacgctggag cggaagttgc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846241250PRTArtificial SequenceSynthetic sequence 241Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln1 5 10 15Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile65 70 75 80Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu145 150 155 160Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Ala Gly Ala Glu Val Ala 195 200 205Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro225 230 235 240Arg Gly Ser His His His His His His Gly 245 2502423PRTArtificial SequenceSynthetic sequence 242Ser Pro Gly1243293PRTArtificial SequenceSynthetic sequence 243Met Gly His His His His His His Ser Gly Met Glu Glu Phe Asn Met1 5 10 15Arg Ile Asn Thr Asn Val Ala Ala Met Asn Thr Tyr Ser Arg Leu Thr 20 25 30Ala Ala Asn Thr Ala Lys Ser Asn Ser Leu Ala Lys Leu Ser Ser Gly 35 40 45Leu Arg Ile Asn Lys Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile Ser 50 55 60Glu Lys Met Lys Ser Gln Ile Gly Gly Leu Thr Gln Ala Lys Arg Asn65 70 75 80Ala Gln Asp Gly Ile Ser Leu Val Gln Thr Ala Glu Gly Ala Leu Asn 85 90 95Glu Thr His Ser Ile Leu Glu Arg Met Arg Asp Leu Ala Val Gln Gly 100 105 110Ser Asn Gly Thr Leu Thr Ser Ser Asp Arg Gly Ser Ile Asn Lys Glu 115 120 125Leu Lys Ala Leu His Gln Glu Leu Thr Arg Ile Ser Asn Thr Thr Glu 130 135 140Phe Asn Thr Gln Lys Leu Phe Ser Gln Thr Lys Gln Lys Ser Val Thr145 150 155 160Phe Thr Phe Gln Ile Gly Ala Asn Ala Gly Gln Thr Leu Ser Val Ala 165 170 175Ile Thr Ala Met Ser Gly Glu Ala Leu Leu Val Ser Thr Asp Ala Lys 180 185 190Phe Ser Leu Asn Ala Ala Gly Thr Asn Ala Gly Ala Met Ile Lys Ser 195 200 205Ile Asp Ala Ala Ile Ala Lys Val Ser Asp Gln Arg Ala Asp Leu Gly 210 215 220Ala Val Gln Asn Arg Leu Glu His Thr Ile Asn Asn Leu Thr Ala Thr225 230 235 240Asn Glu Asn Leu Ser Asp Ala Asn Ser Arg Ile Arg Asp Val Asp Met 245 250 255Ala Glu Glu Met Met Thr Phe Thr Lys Ser Asn Ile Leu Ser Gln Ala 260 265 270Ala Thr Ser Met Leu Ala Gln Ala Asn Ala Met Pro Asn Ser Val Leu 275 280 285Asn Leu Leu Gln Gly 290244280PRTArtificial SequenceSynthetic sequence 244Met Gly His His His His His His Ser Gly Met Arg Ile Asn His Asn1 5 10 15Ile Ser Ala Leu Asn Ala Trp Arg Asn Ile Asp Gln Thr Gln Tyr Ser 20 25 30Met Ser Lys Thr Leu Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Arg 35 40 45Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile Ser Glu Lys Met Arg Gly 50 55 60Gln Ile Lys Gly Leu Asn Met Ala Ile Lys Asn Ala Gln Asp Ala Ile65 70 75 80Ser Leu Ile Gln Thr Ala Glu Gly Ala Leu Thr Glu Val His Ser Ile 85 90 95Leu Gln Arg Met Arg Glu Leu Ala Val Gln Ala Ala Ser Asp Thr Asn 100 105 110Thr Asn Val Asp Arg Glu Gln Ile Gln Lys Glu Ile Asp Gln Leu Arg 115 120 125Glu Glu Ile Asp Arg Ile Ala Arg Thr Thr Glu Phe Asn Thr Lys Lys 130 135 140Leu Leu Asp Gly Lys Leu Glu Gly Phe Arg Ser Gln Val Asp Ala Lys145 150 155 160Val Val Thr Gly Gly Asn Ile Asn Val Gln Leu Gly Thr Val Ser Ser 165 170 175Lys Ala Val Glu Gly Thr Tyr Val Ile Glu Val Gly Ala Ala Glu Arg 180 185 190Ala Ile Met Val Val Asp Ala Ala Ile His Arg Val Ser Thr Ala Arg 195 200 205Ala Ala Leu Gly Ala Ile Gln Asn Arg Leu Glu His Thr Ile Ser Asn 210 215 220Leu Gly Val Ala Ala Glu Asn Leu Thr Ala Ala Glu Ser Arg Ile Arg225 230 235 240Asp Ala Asp Met Ala Lys Glu Met Met Glu Phe Thr Lys Gln Gln Ile 245 250 255Leu Leu Gln Ser Ser Met Ala Met Leu Ala Gln Ser Asn Thr Leu Pro 260 265 270Gln Asn Val Leu Gln Leu Met Arg 275 280245168PRTArtificial SequenceSynthetic sequence 245Met Gly His His His His His His Ser Gly Leu Asn Met Ala Ile Lys1 5 10 15Asn Ala Gln Asp Ala Ile Ser Leu Ile Gln Thr Ala Glu Gly Ala Leu 20 25 30Thr Glu Val His Ser Ile Leu Gln Arg Met Arg Glu Leu Ala Val Gln 35 40 45Ala Ala Ser Asp Thr Asn Thr Asn Val Asp Arg Glu Gln Ile Gln Lys 50 55 60Glu Ile Asp Gln Leu Arg Glu Glu Ile Asp Arg Ile Ala Arg Thr Thr65 70 75 80Glu Phe Asn Thr Lys Lys Leu Leu Asp Gly Lys Leu Glu Gly Phe Arg 85 90 95Ser Gln Val Asp Ala Lys Val Val Thr Gly Gly Asn Ile Asn Val Gln 100 105 110Leu Gly Thr Val Ser Ser Lys Ala Val Glu Gly Thr Tyr Val Ile Glu 115 120 125Val Gly Ala Ala Glu Arg Ala Ile Met Val Val Asp Ala Ala Ile His 130 135 140Arg Val Ser Thr Ala Arg Ala Ala Leu Gly Ala Ile Gln Asn Arg Leu145 150 155 160Glu His Thr Ile Ser Asn Leu Gly 165246285PRTArtificial SequenceSynthetic sequence 246Met Gly His His His His His His Ser Gly Met Ser Leu Arg Ile Asn1 5 10 15Asn Asn Ile Glu Ala Leu Asn Ala Trp Arg Ala Leu Asn Ser Thr Ser 20 25 30Asn Ala Leu Gln Lys Ser Met Glu Lys Leu Ser Ser Gly Leu Arg Ile 35 40 45Asn Arg Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile Ser Glu Lys Leu 50 55 60Arg Ala Gln Ile Arg Gly Leu Asn Gln Ala Ile Arg Asn Ala Gln Asp65 70 75 80Gly Ile Ser Leu Ile Gln Thr Ala Glu Gly Gly Leu Ser Glu Ile Gln 85 90 95Asn Ile Leu Gln Arg Met Arg Glu Leu Gly Val Gln Ala Ala Asn Gly 100 105 110Thr Leu Asn Asn Gln Asp Ile Ser Ala Ile Thr Thr Glu Leu Asn Gln 115 120 125Leu Phe Asn Glu Ile Asp Arg Ile Ala Gly Ala Thr Glu Phe Asn Thr 130 135 140Lys Asn Leu Leu Ala Val Ser Thr Gly Leu Val Val Thr Leu Gln Val145 150 155 160Gly Ala Asn Ala Gly Gln Val Ile Ala Phe Thr Ile Asp Asn Ala Gly 165 170 175Thr Ala Ser Leu Gly Leu Ser Ser Ala Asp Leu Ala Ile Asn Asp Asn 180 185 190Ala Ser Ala Ser Ala Phe Ile Ser Lys Val Asp Ser Ala Leu Gln Lys 195 200 205Val Ser Thr Tyr Arg Ala Asn Leu Gly Ser Ile Gln Asn Arg Leu Glu 210 215 220His Thr Ile Ala Asn Leu Gly Ile Ala Ser Glu Asn Leu Ser Ala Ser225 230 235 240Glu Ser Arg Ile Arg Asp Val Asp Met Ala Ala Glu Met Met Asn Phe 245 250 255Thr Lys Asn Gln Ile Leu Gln Gln Ala Gly Val Ala Ile Leu Ala Gln 260 265 270Ala Asn Gln Ala Pro Gln Ala Val Leu Gln Leu Leu Arg 275 280 285247171PRTArtificial SequenceSynthetic sequence 247Met Gly His His His His His His Ser Gly Leu Asn Gln Ala Ile Arg1 5 10 15Asn Ala Gln Asp Gly Ile Ser Leu Ile Gln Thr Ala Glu Gly Gly Leu 20 25 30Ser Glu Ile Gln Asn Ile Leu Gln Arg Met Arg Glu Leu Gly Val Gln 35 40

45Ala Ala Asn Gly Thr Leu Asn Asn Gln Asp Ile Ser Ala Ile Thr Thr 50 55 60Glu Leu Asn Gln Leu Phe Asn Glu Ile Asp Arg Ile Ala Gly Ala Thr65 70 75 80Glu Phe Asn Thr Lys Asn Leu Leu Ala Val Ser Thr Gly Leu Val Val 85 90 95Thr Leu Gln Val Gly Ala Asn Ala Gly Gln Val Ile Ala Phe Thr Ile 100 105 110Asp Asn Ala Gly Thr Ala Ser Leu Gly Leu Ser Ser Ala Asp Leu Ala 115 120 125Ile Asn Asp Asn Ala Ser Ala Ser Ala Phe Ile Ser Lys Val Asp Ser 130 135 140Ala Leu Gln Lys Val Ser Thr Tyr Arg Ala Asn Leu Gly Ser Ile Gln145 150 155 160Asn Arg Leu Glu His Thr Ile Ala Asn Leu Gly 165 170248146PRTArtificial SequenceSynthetic sequence 248Met Gly His His His His His His Ser Gly Leu Asn Gln Ala Ile Arg1 5 10 15Asn Ala Gln Asp Gly Ile Ser Leu Ile Gln Thr Ala Glu Gly Gly Leu 20 25 30Ser Glu Ile Gln Asn Ile Leu Gln Arg Met Arg Glu Leu Gly Val Gln 35 40 45Ala Ala Asn Gly Thr Leu Asn Asn Gln Asp Ile Ser Ala Ile Thr Thr 50 55 60Glu Leu Asn Gln Leu Phe Asn Glu Ile Asp Arg Ile Ala Gly Ala Thr65 70 75 80Glu Phe Asn Thr Lys Asn Leu Leu Ala Ala Gly Thr Ala Ser Leu Gly 85 90 95Leu Ser Ser Ala Asp Leu Ala Ile Asn Asp Asn Ala Ser Ala Ser Ala 100 105 110Phe Ile Ser Lys Val Asp Ser Ala Leu Gln Lys Val Ser Thr Tyr Arg 115 120 125Ala Asn Leu Gly Ser Ile Gln Asn Arg Leu Glu His Thr Ile Ala Asn 130 135 140Leu Gly145249116PRTArtificial SequenceSynthetic sequence 249Met Gly His His His His His His Ser Ala Ser Ala Phe Ile Ser Lys1 5 10 15Val Asp Ser Ala Leu Gln Lys Val Ser Thr Tyr Arg Ala Asn Leu Gly 20 25 30Ser Ile Gln Asn Arg Leu Glu His Thr Ile Ala Asn Leu Gly Pro Asp 35 40 45Gly Leu Asn Gln Ala Ile Arg Asn Ala Gln Asp Gly Ile Ser Leu Ile 50 55 60Gln Thr Ala Glu Gly Gly Leu Ser Glu Ile Gln Asn Ile Leu Gln Arg65 70 75 80Met Arg Glu Leu Gly Val Gln Ala Ala Asn Gly Thr Leu Asn Asn Gln 85 90 95Asp Ile Ser Ala Ile Thr Thr Glu Leu Asn Gln Leu Phe Asn Glu Ile 100 105 110Asp Arg Ile Ala 115250103PRTArtificial SequenceSynthetic sequence 250Met Gly His His His His His His Ser Asn Asn Gln Asp Ile Ser Ala1 5 10 15Ile Thr Thr Glu Leu Asn Gln Leu Phe Asn Glu Ile Asp Arg Ile Ala 20 25 30Gly Ala Thr Gly Ser Gly Gly Leu Ser Glu Ile Gln Asn Ile Leu Gln 35 40 45Arg Met Arg Glu Leu Gly Val Gln Ala Ala Asn Gly Thr Leu Asn Gly 50 55 60Gly Ser Ala Ser Ala Phe Ile Ser Lys Val Asp Ser Ala Leu Gln Lys65 70 75 80Val Ser Thr Tyr Arg Ala Asn Leu Gly Ser Ile Gln Asn Arg Leu Glu 85 90 95His Thr Ile Ala Asn Leu Gly 100251170PRTArtificial SequenceSynthetic sequence 251Met Gly His His His His His His Ser Gly Leu Ala Gln Ala Ser Arg1 5 10 15Asn Ala Gln Asp Ala Ile Ser Ile Ala Gln Thr Ala Glu Gly Ala Leu 20 25 30Asp Glu Thr Gln Ser Ile Leu Gln Arg Val Arg Glu Leu Gly Val Gln 35 40 45Gly Ala Asn Gly Thr Leu Thr Ala Asp Asp Ile Asn Ala Leu Gln Ala 50 55 60Glu Val Asp Gln Leu Ile Ala Glu Ile Asp Arg Ile Ala Gly Ala Thr65 70 75 80Glu Phe Asn Thr Gln Asn Leu Leu Asp Gly Ser Phe Thr Thr Lys Ala 85 90 95Phe Gln Val Gly Ala Asn Ser Gly Gln Asn Met Thr Leu Thr Ile Gly 100 105 110Lys Met Asp Thr Thr Thr Leu Gly Leu Ser Ser Ala Asp Leu Ala Ile 115 120 125Asn Asp Asn Ala Phe Ala Asn Gly Ala Ile Ser Thr Val Asp Ser Ala 130 135 140Leu Gln Lys Val Ser Ala Glu Arg Ala Lys Leu Gly Ala Ile Gln Asn145 150 155 160Arg Leu Glu His Thr Ile Ala Asn Leu Gly 165 170252170PRTArtificial SequenceSynthetic sequence 252Met Gly His His His His His His Ser Gly Leu Ala Gln Ala Ser Arg1 5 10 15Gln Ala Gln Asp Ala Ile Ser Ile Ala Gln Thr Ala Glu Gly Ala Leu 20 25 30Asp Glu Thr Gln Ser Ile Leu Gln Arg Val Arg Glu Leu Gly Val Gln 35 40 45Gly Ala Asp Gly Thr Leu Thr Ala Asp Asp Ile Asp Ala Leu Gln Ala 50 55 60Glu Val Asp Gln Leu Ile Ala Glu Ile Asp Arg Ile Ala Gly Ala Thr65 70 75 80Glu Phe Ala Thr Gln Lys Leu Leu Asp Gly Ser Phe Thr Thr Lys Ala 85 90 95Phe Gln Val Gly Ala Ala Ser Gly Gln Asp Val Thr Leu Thr Ile Gly 100 105 110Lys Val Asp Thr Thr Thr Leu Gly Leu Ser Ser Ala Asp Leu Ala Ile 115 120 125Asp Ser Ala Ala Phe Ala Asp Gly Ala Ile Ser Thr Val Asp Ser Ala 130 135 140Leu Gln Lys Val Ser Ala Glu Arg Ala Lys Leu Gly Ala Ile Gln Asn145 150 155 160Arg Leu Glu His Thr Ile Ala Gln Leu Gly 165 170253174PRTArtificial SequenceSynthetic peptide accession number Q53970 253Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu145 150 155 160Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn 165 170254189PRTArtificial SequenceSynthetic peptide accession number P72151 254Met Ala Leu Thr Val Asn Thr Asn Ile Ala Ser Leu Asn Thr Gln Arg1 5 10 15Asn Leu Asn Ala Ser Ser Asn Asp Leu Asn Thr Ser Leu Gln Arg Leu 20 25 30Thr Thr Gly Tyr Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Leu 35 40 45Gln Ile Ser Asn Arg Leu Ser Asn Gln Ile Ser Gly Leu Asn Val Ala 50 55 60Thr Arg Asn Ala Asn Asp Gly Ile Ser Leu Ala Gln Thr Ala Glu Gly65 70 75 80Ala Leu Gln Gln Ser Thr Asn Ile Leu Gln Arg Ile Arg Asp Leu Ala 85 90 95Leu Gln Ser Ala Asn Gly Ser Asn Ser Asp Ala Asp Arg Ala Ala Leu 100 105 110Gln Lys Glu Val Ala Ala Gln Gln Ala Glu Leu Thr Arg Ile Ser Asp 115 120 125Thr Thr Thr Phe Gly Gly Arg Lys Leu Leu Asp Gly Ser Phe Gly Thr 130 135 140Thr Ser Phe Gln Val Gly Ser Asn Ala Tyr Glu Thr Ile Asp Ile Ser145 150 155 160Leu Gln Asn Ala Ser Ala Ser Ala Ile Gly Ser Tyr Gln Val Gly Ser 165 170 175Asn Gly Ala Gly Thr Val Ala Ser Val Ala Gly Thr Ala 180 185255179PRTArtificial SequenceSynthetic peptide accession number Q5X5M6 255Met Ala Gln Val Ile Asn Thr Asn Val Ala Ser Leu Thr Ala Gln Arg1 5 10 15Asn Leu Gly Val Ser Gly Asn Met Met Gln Thr Ser Ile Gln Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Leu 35 40 45Ala Ile Ser Gln Arg Met Thr Ala Gln Ile Arg Gly Met Asn Gln Ala 50 55 60Val Arg Asn Ala Asn Asp Gly Ile Ser Leu Ala Gln Val Ala Glu Gly65 70 75 80Ala Met Gln Glu Thr Thr Asn Ile Leu Gln Arg Met Arg Glu Leu Ser 85 90 95Val Gln Ala Ala Asn Ser Thr Asn Asn Ser Ser Asp Arg Ala Ser Ile 100 105 110Gln Ser Glu Ile Ser Gln Leu Lys Ser Glu Leu Glu Arg Ile Ala Gln 115 120 125Asn Thr Glu Phe Asn Gly Gln Arg Ile Leu Asp Gly Ser Phe Ser Gly 130 135 140Ala Ser Phe Gln Val Gly Ala Asn Ser Asn Gln Thr Ile Asn Phe Ser145 150 155 160Ile Gly Ser Ile Lys Ala Ser Ser Ile Gly Gly Ile Ala Thr Ala Thr 165 170 175Gly Thr Glu256174PRTArtificial SequenceSynthetic peptide accession number Q6VMV6 256Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Val Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Thr 85 90 95Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Ser Ser Ile 100 105 110Gln Ala Glu Ile Thr Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Glu 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ala Glu Asn Asn Glu Met 130 135 140Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asn Leu145 150 155 160Ala Lys Ile Asp Ala Lys Thr Leu Gly Leu Asp Gly Phe Asn 165 170257173PRTArtificial SequenceSynthetic peptide accession number P13713 257Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Met Ala Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Gly Thr Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ser Asn Arg Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Leu Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Val Asn Asp Asn Leu Gln Asn Ile Arg Arg Leu Thr 85 90 95Val Gln Ala Gln Asn Gly Ser Asn Ser Thr Ser Asp Leu Lys Ser Ile 100 105 110Gln Asp Glu Ile Thr Gln Arg Leu Ser Glu Ile Asn Arg Ile Ser Glu 115 120 125Gln Thr Asp Phe Asn Gly Val Lys Val Leu Ser Ser Asp Gln Lys Leu 130 135 140Thr Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Thr Asp Ile Asp Leu145 150 155 160Lys Lys Ile Asp Ala Lys Gln Leu Gly Met Asp Thr Phe 165 170258168PRTArtificial SequenceSynthetic peptide accession number Q93RK8 258Met Arg Ile Asn His Asn Ile Ala Ala Leu Asn Thr Ser Arg Gln Leu1 5 10 15Asn Ala Gly Ser Asn Ser Ala Ala Lys Asn Met Glu Lys Leu Ser Ser 20 25 30Gly Leu Arg Ile Asn Arg Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile 35 40 45Ser Glu Lys Met Arg Ser Gln Ile Arg Gly Leu Asp Met Ala Ser Lys 50 55 60Asn Ala Gln Asp Gly Ile Ser Leu Ile Gln Thr Ser Glu Gly Ala Leu65 70 75 80Asn Glu Thr His Ser Ile Leu Gln Arg Met Ser Glu Leu Ala Thr Gln 85 90 95Ala Ala Asn Asp Thr Asn Thr Asp Ser Asp Arg Ser Glu Leu Gln Lys 100 105 110Glu Met Asp Gln Leu Ala Ser Glu Val Thr Arg Ile Ser Thr Asp Thr 115 120 125Glu Phe Asn Thr Lys Lys Leu Leu Asp Gly Thr Ala Gln Asn Leu Thr 130 135 140Phe Gln Ile Gly Ala Asn Glu Gly Gln Thr Met Ser Leu Ser Ile Asn145 150 155 160Lys Met Asp Ser Glu Ser Leu Lys 165259192PRTArtificial SequenceSynthetic peptide accession number Q02551 259Met Lys Val Asn Thr Asn Ile Ile Ser Leu Lys Thr Gln Glu Tyr Leu1 5 10 15Arg Lys Asn Asn Glu Gly Met Thr Gln Ala Gln Arg Arg Leu Ala Ser 20 25 30Gly Lys Arg Ile Asn Ser Ser Leu Asp Asp Ala Ala Gly Leu Ala Val 35 40 45Val Thr Arg Met Asn Val Lys Ser Thr Gly Leu Asp Ala Ala Ser Lys 50 55 60Asn Ser Ser Met Gly Ile Asp Leu Leu Gln Thr Ala Asp Ser Ala Leu65 70 75 80Ser Ser Met Ser Ser Ile Leu Gln Arg Met Arg Gln Leu Ala Val Gln 85 90 95Ser Ser Asn Gly Ser Phe Ser Asp Glu Asp Arg Lys Gln Tyr Thr Ala 100 105 110Glu Phe Gly Ser Leu Ile Lys Glu Leu Asp His Val Ala Asp Thr Thr 115 120 125Asn Tyr Asn Asn Ile Lys Leu Leu Asp Gln Thr Ala Thr Gly Ala Ala 130 135 140Thr Gln Val Ser Ile Gln Ala Ser Asp Lys Ala Asn Asp Leu Ile Asn145 150 155 160Ile Asp Leu Phe Asn Ala Lys Gly Leu Ser Ala Gly Thr Ile Thr Leu 165 170 175Gly Ser Gly Ser Thr Val Ala Gly Tyr Ser Ala Leu Ser Val Ala Asp 180 185 190260174PRTArtificial SequenceSynthetic peptide accession number Q09012 260Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ala Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Val Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Ser Glu Ile Asn Asn Asn Leu Gln Arg Ile Arg Glu Leu Ser 85 90 95Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Asn Ser Ile 100 105 110Gln Asp Glu Ile Thr Gln Arg Leu Ser Glu Ile Asp Arg Val Ser Asn 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ala Ser Asp Gln Thr Met 130 135 140Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Glu Ile Ala Leu145 150 155 160Asp Lys Ile Asp Ala Lys Thr Leu Gly Leu Asp Asn Phe Ser 165 170261174PRTArtificial SequenceSynthetic peptide accession number Q8GNT8 261Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Met Ala Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ala Leu Gly Thr Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ser Asn Arg Phe Thr Ala Asn Ile Asn Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Leu Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Val Asn Asp Asn Leu Gln Asn Ile Arg Arg Leu Thr 85 90 95Val Gln Ala Gln Asn Gly Ser Asn Ser Ser Ser Asp Leu Gln Ser Ile 100 105

110Gln Asp Glu Ile Thr Gln Arg Leu Ser Glu Ile Asp Arg Ile Ser Gln 115 120 125Gln Thr Asp Phe Asn Gly Val Lys Val Leu Ser Lys Asp Gln Lys Leu 130 135 140Thr Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Asp Ile Asp Leu145 150 155 160Lys Asn Ile Asn Ala Gln Ser Leu Gly Leu Asp Lys Phe Asn 165 170262186PRTArtificial SequenceSynthetic peptide accession number Q9FAE7 262Met Ala Ser Thr Ile Asn Thr Asn Val Ser Ser Leu Thr Ala Gln Arg1 5 10 15Asn Leu Ser Leu Ser Gln Ser Ser Leu Asn Thr Ser Ile Gln Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Leu 35 40 45Ala Ile Ser Glu Arg Phe Thr Ser Gln Ile Arg Gly Leu Asn Gln Ala 50 55 60Val Arg Asn Ala Asn Asp Gly Ile Ser Leu Ala Gln Thr Ala Glu Gly65 70 75 80Ala Leu Lys Ser Thr Gly Asp Ile Leu Gln Arg Val Arg Glu Leu Ala 85 90 95Val Gln Ser Ala Asn Ala Thr Asn Ser Ser Gly Asp Arg Lys Ala Ile 100 105 110Gln Ala Glu Val Gly Gln Leu Leu Ser Glu Met Asp Arg Ile Ala Gly 115 120 125Asn Thr Glu Phe Asn Gly Gln Lys Leu Leu Asp Gly Ser Phe Gly Ser 130 135 140Ala Thr Phe Gln Val Gly Ala Asn Ala Asn Gln Thr Ile Thr Ala Thr145 150 155 160Thr Gly Asn Phe Arg Thr Asn Asn Tyr Gly Ala Gln Leu Thr Ala Ser 165 170 175Ala Ser Gly Ala Ala Thr Ser Gly Ala Ser 180 185263173PRTArtificial SequenceSynthetic peptide accession number Q8ZF76 263Met Ala Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn Asn1 5 10 15Leu Asn Lys Ser Gln Ser Ser Leu Gly Thr Ala Ile Glu Arg Leu Ser 20 25 30Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala 35 40 45Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala Ala 50 55 60Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ser65 70 75 80Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Thr Val 85 90 95Gln Ala Gln Asn Gly Ser Asn Ser Ser Ser Asp Leu Asp Ser Ile Gln 100 105 110Asp Glu Ile Ser Leu Arg Leu Ala Glu Ile Asp Arg Val Ser Asp Gln 115 120 125Thr Gln Phe Asn Gly Lys Lys Val Leu Ala Glu Asn Thr Thr Met Ser 130 135 140Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Asp Ile Asn Leu Gln145 150 155 160Lys Ile Asp Ser Lys Ser Leu Gly Leu Gly Ser Tyr Ser 165 170264174PRTArtificial SequenceSynthetic peptide accession number Q7N5J4 264Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn1 5 10 15Asn Leu Asn Arg Ser Gln Gly Thr Leu Gly Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ala Asn Val Arg Gly Leu Thr Gln Ala 50 55 60Ala Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Thr Asn Leu Gln Arg Ile Arg Glu Leu Thr 85 90 95Val Gln Ser Gln Asn Gly Ser Asn Ser Glu Ser Asp Ile Lys Ser Ile 100 105 110Gln Glu Glu Val Thr Gln Arg Leu Lys Glu Ile Asp Arg Ile Ser Glu 115 120 125Gln Thr Gln Phe Asn Gly Val Arg Val Leu Arg Glu Asp Ser Lys Met 130 135 140Thr Ile Gln Val Gly Ala Asn Asp Asn Glu Val Ile Asp Ile Asp Leu145 150 155 160Lys Lys Ile Asp Lys Glu Ala Leu Asn Leu Gly Lys Phe Thr 165 170265189PRTArtificial SequenceSynthetic peptide accession number O33578 265Met Thr Thr Ile Asn Thr Asn Ile Gly Ala Ile Ala Ala Gln Ala Asn1 5 10 15Met Thr Lys Val Asn Asp Gln Phe Asn Thr Ala Met Thr Arg Leu Ser 20 25 30Thr Gly Leu Arg Ile Asn Ala Ala Lys Asp Asp Ala Ala Gly Met Ala 35 40 45Ile Gly Glu Lys Met Thr Ala Gln Val Met Gly Leu Asn Gln Ala Ile 50 55 60Arg Asn Ala Gln Asp Gly Lys Asn Leu Val Asp Thr Thr Glu Gly Ala65 70 75 80His Val Glu Val Ser Ser Met Leu Gln Arg Leu Arg Glu Leu Ala Val 85 90 95Gln Ser Ser Asn Asp Thr Asn Thr Ala Ala Asp Arg Gly Ser Leu Ala 100 105 110Ala Glu Gly Lys Gln Leu Ile Ala Glu Ile Asn Arg Val Ala Glu Ser 115 120 125Thr Thr Phe Asn Gly Met Lys Val Leu Asp Gly Ser Phe Thr Gly Lys 130 135 140Gln Leu Gln Ile Gly Ala Asp Ser Gly Gln Thr Met Ala Ile Asn Val145 150 155 160Asp Ser Ala Ala Ala Thr Asp Ile Gly Ala His Lys Ile Ser Ser Ala 165 170 175Ser Thr Val Val Ala Asp Ala Ala Leu Thr Asp Thr Thr 180 185266175PRTArtificial SequenceSynthetic peptide accession number Q56826 266Met Ala Ser Val Ile Asn Thr Asn Asp Ser Ala Leu Leu Ala Gln Asn1 5 10 15Asn Leu Thr Lys Ser Lys Gly Ile Leu Gly Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ala Asn Val Lys Gly Leu Thr Gln Ala 50 55 60Ala Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Ile Arg Glu Leu Thr 85 90 95Val Gln Ser Glu Asn Gly Ser Asn Ser Lys Ser Asp Leu Asp Ser Ile 100 105 110Gln Lys Glu Val Thr Gln Arg Leu Glu Glu Ile Asp Arg Ile Ser Thr 115 120 125Gln Thr Gln Phe Asn Gly Ile Lys Val Leu Asn Gly Asp Val Thr Glu 130 135 140Met Lys Ile Gln Val Gly Ala Asn Asp Asn Glu Thr Ile Gly Ile Lys145 150 155 160Leu Gly Lys Ile Asn Ser Glu Lys Leu Asn Leu Lys Glu Phe Ser 165 170 175267175PRTArtificial SequenceSynthetic peptide accession number P42273 267Met Ala Gln Val Ile Asn Thr Asn Tyr Leu Ser Leu Val Thr Gln Asn1 5 10 15Asn Leu Asn Arg Ser Gln Ser Ala Leu Gly Asn Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Met Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Asn Gly Leu Thr Gln Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Val Ser Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Ile Arg Glu Leu Thr 85 90 95Val Gln Ala Lys Asn Gly Thr Asn Ser Asn Ser Asp Ile Asn Ser Ile 100 105 110Gln Asn Glu Val Asn Gln Arg Leu Asp Glu Ile Asn Arg Val Ser Glu 115 120 125Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gly Glu Lys Ser Lys 130 135 140Met Thr Ile Gln Val Gly Thr Asn Asp Asn Glu Val Ile Glu Phe Asn145 150 155 160Leu Asp Lys Ile Asp Asn Asp Thr Leu Gly Val Ala Ser Asp Lys 165 170 175268200PRTArtificial SequenceSynthetic peptide accession number O31059 268Met Val Val Gln His Asn Met Gln Ala Ala Asn Ala Ser Arg Met Leu1 5 10 15Gly Ile Thr Thr Gly Asp Gln Ser Lys Ser Thr Glu Lys Leu Ser Ser 20 25 30Gly Phe Lys Ile Asn Arg Ala Ala Asp Asp Ala Ala Gly Leu Ser Ile 35 40 45Ser Glu Lys Met Arg Lys Gln Ile Arg Gly Leu Asp Gln Ala Ser Thr 50 55 60Asn Ala Ser Asp Gly Ile Ser Ala Val Gln Thr Ala Glu Gly Ala Leu65 70 75 80Thr Glu Val His Ser Met Leu Gln Arg Met Asn Glu Leu Ala Val Gln 85 90 95Ala Ala Asn Gly Thr Asn Ser Glu Ser Asp Arg Ser Ser Ile Gln Asp 100 105 110Glu Ile Asn Gln Leu Thr Thr Glu Ile Asp Arg Val Ala Glu Thr Thr 115 120 125Lys Phe Asn Glu Thr Tyr Leu Leu Lys Gly Gly Asn Gly Asp Arg Thr 130 135 140Val Arg Val Tyr Ala His Asp Ala Gly Leu Val Gly Ser Leu Ser Gln145 150 155 160Asn Thr Thr Lys Ala Thr Phe Gln Met Arg Lys Leu Glu Ile Gly Asp 165 170 175Ser Tyr Thr Ile Gly Gly Thr Thr Tyr Lys Ile Gly Ala Glu Thr Val 180 185 190Lys Glu Ala Met Thr Ala Leu Lys 195 200269177PRTArtificial SequenceSynthetic peptide accession number Q7VZC2 269Met Ala Ala Val Ile Asn Thr Asn Tyr Leu Ser Leu Val Ala Gln Asn1 5 10 15Asn Leu Asn Lys Ser Gln Ser Ala Leu Gly Ser Ala Ile Glu Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45Ala Ile Ala Asn Arg Phe Thr Ala Asn Val Lys Gly Leu Thr Gln Ala 50 55 60Ala Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly65 70 75 80Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Ile Arg Glu Leu Thr 85 90 95Val Gln Ala Ser Asn Gly Thr Asn Ser Ala Ser Asp Ile Asp Ser Ile 100 105 110Gln Gln Glu Val Asn Gln Arg Leu Glu Glu Ile Asn Arg Ile Ala Glu 115 120 125Gln Thr Asp Phe Asn Gly Ile Lys Val Leu Lys Ser Asn Ala Thr Asp 130 135 140Met Thr Leu Ser Ile Gln Val Gly Ala Lys Asp Asn Glu Thr Ile Asp145 150 155 160Ile Lys Ile Asp Arg Asn Ser Asn Trp Asn Leu Tyr Asp Ala Val Gly 165 170 175Thr270167PRTArtificial SequenceSynthetic peptide accession number Q9F4A4 270Met Ile Ile Asn His Asn Met Asn Ala Leu Asn Ala His Arg Asn Met1 5 10 15Met Gly Asn Ile Ala Thr Ala Gly Lys Ser Met Glu Lys Leu Ser Ser 20 25 30Gly Leu Arg Ile Asn Arg Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile 35 40 45Ser Glu Lys Met Arg Gly Gln Ile Arg Gly Leu Asp Gln Ala Ser Arg 50 55 60Asn Ala Gln Asp Gly Ile Ser Leu Ile Gln Thr Ala Glu Gly Ala Leu65 70 75 80Ala Glu Thr His Ser Ile Leu Gln Arg Met Arg Glu Leu Ser Val Gln 85 90 95Ser Ala Asn Asp Thr Asn Val Ala Val Asp Arg Thr Ala Ile Gln Asp 100 105 110Glu Ile Asn Ser Leu Thr Glu Glu Ile Asn Arg Ile Ser Gly Asp Thr 115 120 125Glu Phe Asn Thr Gln Lys Leu Leu Asp Gly Gly Phe Lys Gly Glu Phe 130 135 140Gln Ile Gly Ala Asn Ser Asn Gln Thr Val Lys Leu Asp Ile Gly Asn145 150 155 160Met Ser Ala Ala Ser Leu Gly 165271178PRTArtificial SequenceSynthetic peptide accession number Q8P9C4 271Met Ala Gln Val Ile Asn Thr Asn Val Met Ser Leu Asn Ala Gln Arg1 5 10 15Asn Leu Asn Thr Asn Ser Ser Ser Met Ala Leu Ser Ile Gln Gln Leu 20 25 30Ser Ser Gly Lys Arg Ile Thr Ser Ala Ser Val Asp Ala Ala Gly Leu 35 40 45Ala Ile Ser Glu Arg Phe Thr Thr Gln Ile Arg Gly Leu Asp Val Ala 50 55 60Ser Arg Asn Ala Asn Asp Gly Ile Ser Leu Ala Gln Thr Ala Glu Gly65 70 75 80Ala Met Val Glu Ile Gly Asn Asn Leu Gln Arg Ile Arg Glu Leu Ser 85 90 95Val Gln Ser Ala Asn Ala Thr Asn Ser Ala Thr Asp Arg Glu Ala Leu 100 105 110Asn Ser Glu Val Lys Gln Leu Thr Ser Glu Ile Asp Arg Val Ala Asn 115 120 125Gln Thr Ser Phe Asn Gly Thr Lys Leu Leu Asn Gly Asp Phe Ser Gly 130 135 140Ala Leu Phe Gln Val Gly Ala Asp Ala Gly Gln Thr Ile Gly Ile Asn145 150 155 160Ser Ile Val Asp Ala Asn Val Asp Ser Leu Gly Lys Ala Asn Phe Ala 165 170 175Ala Ser272161PRTArtificial SequenceSynthetic peptide accession number Q82UA3 272Met Pro Gln Val Ile Asn Thr Asn Ile Ala Ser Leu Asn Ala Gln Arg1 5 10 15Asn Leu Asn Val Ser Gln Asn Ser Leu Ser Thr Ala Leu Gln Arg Leu 20 25 30Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Leu 35 40 45Ala Ile Ser Glu Arg Met Thr Ser Gln Ile Arg Gly Met Asn Gln Ala 50 55 60Ala Arg Asn Ala Asn Asp Gly Ile Ser Leu Ala Gln Thr Ala Glu Gly65 70 75 80Ala Leu Val Glu Ile Gly Asn Asn Leu Gln Arg Ile Arg Glu Leu Ala 85 90 95Val Gln Ser Ala Asn Ala Thr Asn Ser Glu Asp Asp Arg Glu Ala Leu 100 105 110Gln Lys Glu Val Thr Gln Leu Ile Asp Glu Ile Gln Arg Val Gly Glu 115 120 125Gln Thr Ser Phe Asn Gly Thr Lys Leu Leu Asp Gly Ser Phe Ala Ser 130 135 140Gln Ile Phe Gln Val Gly Ala Asn Glu Gly Glu Thr Ile Asp Phe Thr145 150 155 160Asp273178PRTArtificial SequenceSynthetic peptide accession number Q84IC5 273Gly Phe Arg Ile Asn Thr Asn Gly Ala Ser Leu Asn Ala Gln Val Asn1 5 10 15Ala Gly Leu Asn Ser Arg Asn Leu Asp Ser Ser Leu Ala Arg Leu Ser 20 25 30Ser Gly Leu Arg Ile Asn Ser Ala Ala Asp Asp Ala Ser Gly Leu Ala 35 40 45Ile Ala Asp Ser Leu Lys Thr Gln Ala Asn Ser Leu Gly Gln Ala Ile 50 55 60Asn Asn Ala Asn Asp Ala Asn Ser Met Leu Gln Ile Ala Asp Lys Ala65 70 75 80Met Asp Glu Gln Leu Lys Ile Leu Asp Thr Ile Lys Val Lys Ala Thr 85 90 95Gln Ala Ala Gln Asp Gly Gln Thr Ala Lys Thr Arg Ala Met Ile Gln 100 105 110Gly Glu Ile Asn Lys Leu Met Glu Glu Leu Asp Asn Ile Ala Asn Thr 115 120 125Thr Thr Tyr Asn Gly Lys Gln Leu Leu Ser Gly Ser Phe Ser Asn Ala 130 135 140Gln Phe Gln Ile Gly Asp Lys Ala Asn Gln Thr Val Asn Ala Thr Ile145 150 155 160Gly Ser Thr Asn Ser Ala Lys Val Gly Gln Thr Arg Phe Glu Thr Gly 165 170 175Ala Val27488PRTArtificial SequenceSynthetic polypeptide accession number Q53970 274Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg1 5 10 15Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 20 25 30Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro65 70 75 80Gln Asn Val Leu Ser Leu Leu Arg 8527588PRTArtificial SequenceSynthetic peptide accession number P72151 275Ala Ile Ala Val Val Asp Asn Ala Leu Ala Ala Ile Asp Ala Gln Arg1 5 10 15Ala Asp Leu Gly Ala Val Gln Asn Arg Phe Lys Asn Thr Ile Asp Asn 20 25 30Leu Thr Asn Ile Ser Glu Asn Ala Thr Asn Ala Arg Ser Arg Ile Lys 35 40 45Asp Thr Asp Phe Ala Ala Glu Thr Ala Ala Leu Ser Lys Asn Gln Val 50

55 60Leu Gln Gln Ala Gly Thr Ala Ile Leu Ala Gln Ala Asn Gln Leu Pro65 70 75 80Gln Ala Val Leu Ser Leu Leu Arg 8527689PRTArtificial SequenceSynthetic peptide accession number Q5X5M6 276Ala Ile Lys Arg Ile Asp Ala Ala Leu Asn Ser Val Asn Ser Asn Arg1 5 10 15Ala Asn Met Gly Ala Leu Gln Asn Arg Phe Glu Ser Thr Ile Ala Asn 20 25 30Leu Gln Asn Val Ser Asp Asn Leu Ser Ala Ala Arg Ser Arg Ile Gln 35 40 45Asp Ala Asp Tyr Ala Ala Glu Met Ala Ser Leu Thr Lys Asn Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ala Met Leu Ala Gln Ala Asn Ser Leu Pro65 70 75 80Gln Ser Val Leu Ser Leu Leu Gly Arg 8527789PRTArtificial SequenceSynthetic peptide accession number Q6VMV6 277Pro Leu Glu Thr Ile Asp Lys Ala Leu Ala Lys Val Asp Asn Leu Arg1 5 10 15Ser Asp Leu Gly Ala Val Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 20 25 30Leu Gly Asn Thr Val Asn Asn Leu Ser Ser Ala Arg Ser Arg Ile Arg 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Ala Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Thr Thr65 70 75 80Gln Asn Val Leu Ser Leu Leu Gln Gly 8527888PRTArtificial SequenceSynthetic peptide accession number P13713 278Pro Leu Ala Thr Leu Asp Lys Ala Leu Ala Gln Val Asp Gly Leu Arg1 5 10 15Ser Ser Leu Gly Ala Val Gln Asn Arg Phe Asp Ser Val Ile Asn Asn 20 25 30Leu Asn Ser Thr Val Asn Asn Leu Ser Ala Ser Gln Ser Arg Ile Gln 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Ala Asn Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Ser Thr65 70 75 80Gln Asn Val Leu Ser Leu Leu Arg 8527989PRTArtificial SequenceSynthetic peptide accession number Q93RK8misc_feature(6)..(6)Xaa can be any naturally occurring amino acid 279Ala Leu Thr Thr Ile Xaa Thr Ala Ile Asp Thr Val Ser Ser Glu Arg1 5 10 15Ala Lys Leu Gly Ala Val Gln Asn Arg Leu Glu His Thr Ile Asn Asn 20 25 30Leu Gly Thr Ser Ser Glu Asn Leu Thr Ser Ala Asx Ser Arg Ile Arg 35 40 45Asp Val Asp Met Ala Ser Glu Met Met Glu Tyr Thr Lys Asn Asn Ile 50 55 60Leu Thr Gln Ala Ser Gln Ala Met Leu Ala Gln Ala Asn Gln Gln Pro65 70 75 80Gln Gln Val Leu Gln Leu Leu Lys Gly 8528090PRTArtificial SequenceSynthetic peptide accession number Q02551 280Val Ile Gly Leu Ala Asp Ala Ala Leu Thr Lys Ile Met Lys Gln Arg1 5 10 15Ala Asp Met Gly Ala Tyr Tyr Asn Arg Leu Glu Tyr Thr Ala Lys Gly 20 25 30Leu Met Gly Ala Tyr Glu Asn Met Gln Ala Ser Glu Ser Arg Ile Arg 35 40 45Asp Ala Asp Met Ala Glu Glu Val Val Ser Leu Thr Thr Lys Gln Ile 50 55 60Leu Val Gln Ser Gly Thr Ala Met Leu Ala Gln Ala Asn Met Lys Pro65 70 75 80Asn Ser Val Leu Lys Leu Leu Gln Gln Ile 85 9028188PRTArtificial SequenceSynthetic peptide accession number Q09012 281Pro Leu Ser Lys Leu Asp Glu Ala Leu Ala Lys Val Asp Lys Leu Arg1 5 10 15Ser Ser Leu Gly Ala Val Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 20 25 30Leu Gly Asn Thr Val Asn Asp Leu Ser Ser Ala Arg Ser Arg Ile Glu 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Ala Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Thr Thr65 70 75 80Gln Asn Val Leu Ser Leu Leu Arg 8528288PRTArtificial SequenceSynthetic peptide accession number Q8GNT8 282Pro Leu Ala Thr Leu Asp Lys Ala Leu Ser Gln Val Asp Ile Leu Arg1 5 10 15Ser Gly Leu Gly Ala Val Gln Asn Arg Phe Asp Ser Val Ile Asn Asn 20 25 30Leu Asn Ser Thr Val Asn Asn Leu Ser Ala Ser Arg Ser Arg Ile Gln 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Ala Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Ser Thr65 70 75 80Gln Asn Val Leu Ser Leu Leu Arg 8528388PRTArtificial SequenceSynthetic peptide accession number Q9FAE7 283Ala Leu Lys Ile Ile Asp Ala Ala Leu Ser Ala Val Asn Gln Gln Arg1 5 10 15Ala Ser Phe Gly Ala Leu Gln Ser Arg Phe Glu Thr Thr Val Asn Asn 20 25 30Leu Gln Ser Thr Ser Glu Asn Met Ser Ala Ser Arg Ser Arg Ile Gln 35 40 45Asp Ala Asp Phe Ala Ala Glu Thr Ala Asn Leu Ser Arg Ser Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ala Met Val Ala Gln Ala Asn Gln Leu Pro65 70 75 80Gln Gly Val Leu Ser Leu Leu Lys 8528488PRTArtificial SequenceSynthetic peptide accession number Q8ZF76 284Pro Leu Glu Thr Leu Asp Asp Ala Ile Lys Gln Val Asp Gly Leu Arg1 5 10 15Ser Ser Leu Gly Ala Val Gln Asn Arg Phe Glu Ser Ala Val Thr Asn 20 25 30Leu Asn Asn Thr Val Thr Asn Leu Thr Ser Ala Arg Ser Arg Ile Glu 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Ala Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ser Gln Ala Asn Gln Val Pro65 70 75 80Gln Thr Val Leu Ser Leu Leu Asn 8528588PRTArtificial SequenceSynthetic peptide accession number Q7N5J4 285Pro Leu Glu Thr Leu Asp Ser Ala Leu Ala Gln Val Asp Ser Leu Arg1 5 10 15Ser Ser Leu Gly Ala Ile Gln Asn Arg Leu Glu Ser Thr Val Asn Asn 20 25 30Leu Asn Asn Thr Val Asn Asn Leu Ser Ala Ala Arg Ser Arg Ile Glu 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Arg Gly Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ala Val Leu Ala Gln Ala Met Gln Val Pro65 70 75 80Gln Asn Val Met Ser Leu Leu Arg 8528689PRTArtificial SequenceSynthetic peptide accession number O33578 286Ala Ile Gly Val Ile Asp Val Ala Leu Ser Lys Ile Ser Gln Ser Arg1 5 10 15Ser Glu Leu Gly Ala Val Ser Asn Arg Leu Asp Ser Thr Ile Ser Asn 20 25 30Leu Thr Asn Ile Ser Thr Ser Val Gln Ala Ala Lys Ser Gln Val Met 35 40 45Asp Ala Asp Phe Ala Ala Glu Ser Thr Asn Leu Ala Arg Ser Gln Ile 50 55 60Leu Ser Gln Ala Ser Thr Ala Met Leu Ala Gln Ala Asn Ser Ser Lys65 70 75 80Gln Asn Val Leu Ser Leu Leu Arg Gly 8528788PRTArtificial SequenceSynthetic peptide accession number Q56826 287Pro Leu Asp Thr Leu Asp Lys Ala Leu Ala Gln Val Asp Asp Asn Arg1 5 10 15Ser Ser Leu Gly Ala Val Gln Asn Arg Leu Glu Ser Thr Val Asn Asn 20 25 30Leu Asn Asn Thr Val Asn Asn Leu Ser Ala Ala Arg Ser Arg Ile Glu 35 40 45Asp Ala Asp Tyr Ala Val Glu Val Ser Asn Met Ser Arg Gly Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro65 70 75 80Gln Thr Val Leu Ser Leu Leu Arg 8528888PRTArtificial SequenceSynthetic peptide accession number P42273 288Ala Leu Ala Thr Leu Asp Asn Ala Ile Ser Lys Val Asp Glu Ser Arg1 5 10 15Ser Lys Leu Gly Ala Ile Gln Asn Arg Phe Gln Ser Thr Ile Asn Asn 20 25 30Leu Asn Asn Thr Val Asn Asn Leu Ser Ala Ser Arg Ser Arg Ile Leu 35 40 45Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Asn Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ala Val Leu Ala Gln Ala Asn Gln Val Pro65 70 75 80Gln Thr Val Leu Ser Leu Leu Arg 8528988PRTArtificial SequenceSynthetic peptide accession number O31059 289Ala Ile Asp Ala Ile Ser Asp Ala Leu Ala Lys Val Ser Ala Gln Arg1 5 10 15Ser Ala Leu Gly Ser Ile Gln Asn Arg Leu Glu His Ser Ile Ala Asn 20 25 30Leu Asp Asn Val Val Glu Asn Thr Asn Ala Ala Glu Ser Arg Ile Arg 35 40 45Asp Thr Asp Met Ala Asp Glu Met Val Thr Tyr Ser Lys Asn Asn Ile 50 55 60Leu Met Gln Ala Gly Gln Ser Met Leu Ala Gln Ala Asn Gln Ala Thr65 70 75 80Gln Gly Val Leu Ser Ile Leu Gln 8529088PRTArtificial SequenceSynthetic peptide accession number Q7VZC2 290Ala Leu Ser Lys Leu Asp Asp Ala Met Lys Ala Val Asp Glu Gln Arg1 5 10 15Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Glu Ser Thr Val Ala Asn 20 25 30Leu Asn Asn Thr Ile Thr Asn Leu Ser Ala Ala Arg Ser Arg Ile Glu 35 40 45Asp Ser Asp Tyr Ala Thr Glu Val Ser Asn Met Thr Lys Asn Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro65 70 75 80Gln Asn Val Leu Ser Leu Leu Arg 8529188PRTArtificial SequenceSynthetic peptide accession number Q9F4A4 291Ser Ile Lys Thr Ile Asn Ser Ala Ile Glu Gln Val Ser Thr Gln Arg1 5 10 15Ser Lys Leu Gly Ala Val Gln Asn Arg Leu Glu His Thr Ile Asn Asn 20 25 30Leu Asn Thr Ser Ser Glu Asn Leu Thr Ala Ala Glu Ser Arg Val Arg 35 40 45Asp Val Asp Met Ala Lys Glu Met Met Ala Phe Ser Lys Asn Asn Ile 50 55 60Leu Ser Gln Ala Ala Gln Ala Met Leu Gly Gln Ala Asn Gln Gln Pro65 70 75 80Gln Gly Val Leu Gln Leu Leu Arg 8529288PRTArtificial SequenceSynthetic peptide accession number Q8P9C4 292Ala Leu Glu Ile Val Asp Lys Ala Leu Thr Ser Val Asn Ser Ser Arg1 5 10 15Ala Asp Met Gly Ala Val Gln Asn Arg Phe Thr Ser Thr Leu Ala Asn 20 25 30Leu Ala Ala Thr Ser Glu Asn Leu Thr Ala Ser Arg Ser Arg Ile Ala 35 40 45Asp Thr Asp Tyr Ala Lys Thr Thr Ala Glu Leu Thr Arg Thr Gln Ile 50 55 60Leu Gln Gln Ala Gly Thr Ala Met Leu Ala Gln Ala Lys Ser Val Pro65 70 75 80Gln Asn Val Leu Ser Leu Leu Gln 8529384PRTArtificial SequenceSynthetic peptide accession number Q82UA3 293Ile Asp Asp Ala Leu Lys Ile Val Asn Ser Thr Arg Ala Asp Leu Gly1 5 10 15Ala Ile Gln Asn Arg Phe Ser Ser Ala Ile Ala Asn Leu Gln Thr Ser 20 25 30Ala Glu Asn Leu Ser Ala Ser Arg Ser Arg Ile Gln Asp Ala Asp Phe 35 40 45Ala Ala Glu Thr Ala Ala Leu Thr Arg Ala Gln Ile Leu Gln Gln Ala 50 55 60Gly Val Ala Met Leu Ser Gln Ala Asn Ala Leu Pro Asn Asn Val Leu65 70 75 80Ser Leu Leu Arg29489PRTArtificial SequenceSynthetic peptide accession number Q84IC5 294Val Met Asp Ile Ala Asp Thr Ala Ile Ala Asn Leu Asp Thr Ile Arg1 5 10 15Ala Asn Ile Gly Ala Thr Gln Asn Gln Ile Thr Ser Thr Ile Asn Asn 20 25 30Ile Ser Val Thr Gln Val Asn Val Lys Ala Ala Glu Ser Gln Ile Arg 35 40 45Asp Val Asp Phe Ala Ser Glu Lys Ser Ala Asn Tyr Ser Lys Ala Asn 50 55 60Ile Leu Ala Gln Ser Gly Ser Tyr Ala Met Ala Gln Ala Asn Ala Ala65 70 75 80Ser Gln Asn Val Leu Arg Leu Leu Gln 85

Claims

1-60. (canceled)

61. A composition comprising a polypeptide having an amino acid sequence that is about 95% identical to SEQ ID NO: 137.

62. The composition of claim 61, the composition comprising a polypeptide having an amino acid sequence that is about 98% sequence identical to SEQ ID NO: 137.

63. The composition of claim 61, the composition comprising a polypeptide having an amino acid sequence that is about 99% sequence identical to SEQ ID NO: 137.

64. The composition of claim 61, the composition comprising a polypeptide having an amino acid sequence that is SEQ ID NO: 137.

65. A pharmaceutical composition, the pharmaceutical composition comprising a polypeptide having the amino acid sequence of SEQ ID NO: 137, and a pharmaceutically acceptable carrier.

66. The composition of claim 61, wherein the composition has reduced antigenicity and immunogenicity as compared to the polypeptide SEQ ID NO: 2.

67. The composition of claim 61, wherein the composition demonstrates improved pharmacokinetics as compared to the polypeptide SEQ ID NO: 2.

68. The composition of claim 61, wherein the composition activates TLR5 signaling at a level the same as, or similar to, that of the polypeptide SEQ ID NO: 2.

69. The composition of claim 61, wherein the polypeptide further comprises a N-terminal tag.

70. The composition of claim 61, wherein the polypeptide further comprises a C-terminal tag.

71. The composition of claim 61, wherein the composition induces NF-.kappa.B mediated expression of one or more of the cytokines selected from IL-6, IL-12, keratinocyte chemoattractant (KC), IL-10, G-CSF, MCP-1, TNF-.alpha., MIG, and MIP-2.

72. A pharmaceutical composition comprising the composition of claim 61 and a pharmaceutically acceptable carrier.

73. A method of stimulating TLR5 signaling comprising administering to a subject in need thereof a composition comprising a polypeptide having an amino acid sequence that is about 95% sequence identical to SEQ ID NO: 137.

74. The method of claim 73, wherein the subject suffers from radiation-induced cellular damage.

75. The method of claim 73, wherein the subject has been subjected to a lethal dose of radiation.

76. The method of claim 73, wherein the subject is undergoing radiation treatment.

77. The method of claim 73, wherein the composition has reduced antigenicity and immunogenicity as compared to the polypeptide SEQ ID NO: 2.