EXTRACELLULAR MATRIX-PRODUCING COMPOSITION USING MAST4 GENE AND PREPARATION METHOD THEREFOR

Abstract

The present invention relates to a composition for producing an extracellular matrix from a eukaryotic cell, the composition comprising a polypeptide or compound capable of specifically binding to a microtubule associated serine/threonine kinase family member 4 (MAST4) protein or a fragment thereof or a polynucleotide, polypeptide or compound capable of specifically binding to a nucleic acid coding for the MAST4 protein or a fragment thereof, and a composition for promoting chondrogenesis, comprising the same composition.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a continuation of U.S. patent application Ser. No. 16/492,477, filed Sep. 9, 2019, which is a National Stage Entry of PCT Patent Application No. PCT/US2020/025689, filed Mar. 8, 2018, each of which is hereby incorporated by reference in their entirety.

TECHNICAL FIELD

[0002] The present disclosure relates to a composition for producing an extracellular matrix from eukaryotic cells using Microtubule Associated Serine/Threonine Kinase Family Member 4 (MAST4) gene, a method of producing the extracellular matrix from the eukaryotic cells, and a composition for promoting chondrogenesis, the composition including the above composition.

BACKGROUND ART

[0003] Since most bone formation begins from a cartilaginous template, successful skeletal development requires a perfect cooperation in both structural and molecular aspects. Articular cartilage is a highly organized tissue, and the mechanism of in-vivo chondrogenesis involved therein is still unknown. Interactions between collagen microfibers and other extracellular matrix component proteins are known to maintain the structural integrity of the cartilage, but the signaling mechanisms regulating their complex processes have not yet been clearly revealed. Therefore, identification of the existence and function of a master regulator that leads chondrogenesis is not only academically meaningful, but also contributes to the public health as well as to development of innovative therapeutics.

[0004] Microtubule associated serine/threonine kinase (MAST) 4 is known to be expressed in cartilage (BMC Genomics 2007, 8: 165), but its role has not been clearly elucidated. CN 105636614 discloses that MAST4 may be used for the treatment of cartilage, but this is based only on the stochastic results of MAST4 expression in the cartilage, and does not elucidate specific roles thereof.

[0005] The present inventors have found MAST4 as a novel central regulator that is involved in chondrogenesis, and provide a source technology for the development of substances that modulate the activity of MAST4.

PRIOR ART DOCUMENTS

[0006] Non-Patent Document: BMC Genomics 2007, 8:165

[0007] Patent Document: CN 105636614

DESCRIPTION OF EMBODIMENTS

Technical Problem

[0008] An aspect provides a composition for promoting production of an extracellular matrix from eukaryotic cells, the composition including a compound capable of specifically binding to Microtubule Associated Serine/Threonine Kinase Family Member 4 (MAST4) protein or a fragment thereof, or a compound capable of specifically binding to a nucleic acid encoding the MAST4 protein or the fragment thereof.

[0009] Another aspect provides a composition for promoting chondrogenesis of chondrocytes, the composition including a compound capable of specifically binding to MAST4 protein or a fragment thereof, or a compound capable of specifically binding to a nucleic acid encoding the MAST4 protein or the fragment thereof.

[0010] Still another aspect provides a method of producing an extracellular matrix from eukaryotic cells, the method including contacting the eukaryotic cells with the composition for promoting production of the extracellular matrix from eukaryotic cells.

Solution to Problem

[0011] According to an aspect, provided is a composition for promoting production of an extracellular matrix from eukaryotic cells, the composition including a compound capable of specifically binding to Microtubule Associated Serine/Threonine Kinase Family Member 4 (MAST4) protein or a fragment thereof, or a compound capable of specifically binding to a nucleic acid encoding the MAST4 protein or the fragment thereof.

[0012] According to another aspect, provided is a composition for promoting chondrogenesis of chondrocytes, the composition including a compound capable of specifically binding to MAST4 protein or a fragment thereof, or a compound capable of specifically binding to a nucleic acid encoding the MAST4 protein or the fragment thereof.

[0013] In a specific embodiment, the compound capable of specifically binding to the MAST4 protein or the fragment thereof, or the compound capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof includes those capable of at least partially binding to the protein or the fragment thereof, or the nucleic acid. Here, the compound may be a chemically synthesized compound, polypeptide, or polynucleotide, or a combination thereof. These compounds may inhibit activity or expression of MAST4 protein.

[0014] In a specific embodiment, the composition for promoting production of extracellular matrix from eukaryotic cells may be a composition for promoting chondrogenesis from eukaryotic cells.

[0015] In the composition, the activity inhibitor of MAST4 protein or the expression inhibitor of MAST4 protein includes any one, as long as it is able to inhibit expression of MAST4 gene or activity of MAST4 protein. The activity inhibitor or the expression inhibitor may be a polynucleotide complementary to the entire or a part of the MAST4 gene. The polynucleotide sequence may be RNA, DNA, or a hybrid thereof.

[0016] In a specific embodiment, the activity inhibition of the MAST4 protein may be kinase activity inhibition of the MAST4 protein.

[0017] MAST4 is a kinase capable of phosphorylating Ser or Thr of a target substrate, and the kinase activity inhibition of the MAST4 protein means blocking of phosphorylation of a target substrate of MAST4, specifically, blocking of phosphorylation of Ser or Thr.

[0018] In a specific embodiment, the polypeptide specifically binding to MAST4 protein or the fragment thereof, or the polypeptide specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof may be an antibody or an antigen-binding fragment thereof.

[0019] The term "antibody" means a specific immunoglobulin directed against an antigenic site. MAST4 gene is cloned into an expression vector to obtain the MAST4 protein encoded by the gene, and the antibody may be prepared from the protein according to a common method in the art. A type of the antibody includes a polyclonal antibody or a monoclonal antibody, and includes all immunoglobulin antibodies. The antibody includes not only complete forms having two full-length light chains and two full-length heavy chains but also functional fragments of antibody molecules which have a specific antigen binding site (binding domain) directed against an antigenic site to retain an antigen-binding function, although they do not have the intact complete antibody structure having two light chains and two heavy chains.

[0020] The term "polynucleotide" may be used in the same meaning as a nucleotide or a nucleic acid, unless otherwise mentioned, and refers to a deoxyribonucleotide or a ribonucleotide. The polynucleotide may include an analog of a natural nucleotide and an analog having a modified sugar or base moiety, unless otherwise mentioned. The polynucleotide may be modified by various methods known in the art, as needed. Examples of the modification may include methylation, capping, substitution of a natural nucleotide with one or more homologues, and modification between nucleotides, for example, modification to uncharged linkages (e.g., methylphosphonate, phosphotriester, phosphoroamidate, carbamate, etc.) or charged linkages (e.g., phosphorothioate, phosphorodithioate, etc.).

[0021] In a specific embodiment, as the compound capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof, the polynucleotide capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof may be microRNA (miRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), Piwi-interacting RNA (piRNA), small nuclear RNA (snRNA), or antisense oligonucleotide, each specific to the nucleic acid encoding the MAST4 protein or the fragment thereof, or a combination thereof.

[0022] In another specific embodiment, the compound capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof may include the polynucleotide capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof, and may be CRISPR-Cas including guide RNA specific to the nucleic acid encoding the MAST4 protein or the fragment thereof.

[0023] In a specific embodiment, the Cas may be Cas9.

[0024] Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) mean loci including many short direct repeats found in the genome of bacteria or archaea, of which genetic sequences are revealed. The CRISPR-Cas system includes Cas9 as an essential protein element which forms a complex with guide RNA (specifically, two RNAs, called CRISPR RNA (crRNA) and trans-activating crRNA (tracrRNA), included in guide RNA), and it serves as an active endonuclease.

[0025] In a specific embodiment, for the CRISPR-Cas system to specifically act on the target gene MAST4, the guide RNA may have a form of a dual RNA including CRISPR RNA (crRNA) and transactivating crRNA (tracrRNA) specific to the nucleic acid encoding the MAST4 protein, or a single strand guide RNA including parts of the crRNA and the tracrRNA and hybridizing with the nucleic acid encoding the MAST4 protein. The dual RNA and the single strand guide RNA may at least partially hybridize with the polynucleotide encoding the MAST4 protein, and specifically, may hybridize with a region corresponding to "5'-TACCCTGCCGCTGCCGCACC-3' (SEQ ID NO: 17)" in the polynucleotide sequence encoding the amino acid sequence of MAST4 protein.

[0026] Specifically, the guide RNA may be a dual RNA including crRNA and tracrRNA that hybridize with a target sequence selected from the nucleotide sequence encoding the MAST4 protein, or a single strand guide RNA including parts of the crRNA and the tracrRNA and hybridizing with the nucleotide encoding the MAST4 protein. The MAST4 gene which is the target sequence includes a polynucleotide sequence at least partially complementary to the crRNA or sgRNA, and a sequence including a protospacer-adjacent motif (PAM). The PAM may be a sequence well-known in the art, which may have a sequence suitable to be recognized by a nuclease protein. The MAST4 gene targeted by the CRISPR-Cas system may be endogenous DNA or artificial DNA. The nucleotide encoding the MAST4 protein may be specifically endogenous DNA of a eukaryotic cell, and more specifically, endogenous DNA of a chondrocyte.

[0027] In a specific embodiment, the crRNA or sgRNA may include twenty consecutive polynucleotides complementary to the target DNA. The target DNA of the complementary twenty consecutive polynucleotides may be 5'-TACCCTGCCGCTGCCGCACC-3' (SEQ ID NO: 17), and may be selected from the sequences marked in bold in SEQ ID NOS: 74, 76, and 77 of Table 6. A nucleic acid encoding the Cas9 protein or the Cas9 protein may be derived from a microorganism of the genus Streptococcus. The microorganism of the genus Streptococcus may be Streptococcus pyogenes. The PAM may mean 5'-NGG-3' trinucledotide, and the Cas9 protein may further include a nuclear localization signal (NLS) at the C-terminus or N-terminus to enhance the efficiency.

[0028] In the composition for promoting production of an extracellular matrix from eukaryotic cells of the present disclosure, the eukaryotic cells may be yeast cells, fungal cells, protozoa cells, plant cells, higher plant cells, insect cells, amphibian cells, or mammalian cells. The mammal may vary such as humans, monkeys, cows, horses, pigs, etc. The eukaryotic cells may include cultured cells (in vitro) isolated from an individual, graft cells, in vivo cells, or recombinant cells, but are not limited thereto. The eukaryotic cells isolated from an individual may be eukaryotic cells isolated from an individual the same as an individual into which the product including extracellular matrix produced from the eukaryotic cells is injected. In this case, it is advantageous in that side effects such as unnecessary hyperimmune reactions or rejection reactions including graft-versus-host reaction generated by injecting a product produced from a different individual may be prevented.

[0029] In a specific embodiment, the eukaryotic cells may be fibroblasts or chondrocytes.

[0030] In a specific embodiment, the composition for promoting the production of extracellular matrix from the eukaryotic cells and/or the composition for promoting chondrogenesis of chondrocytes may further include TGF-.beta.1. The present inventors confirmed that MAST4 expression in human chondrocytes is reduced by TGF-.beta.1, and as a result, production of extracellular matrix is promoted. Therefore, to more effectively and easily promote extracellular matrix in MAST4 knockout cells of eukaryotic cells (or chondrocytes), combination treatment with TGF-.beta.1 may be advantageous.

[0031] The MAST4 is a protein derived from a human (Homo sapiens) or a mouse (Musmusculus), but the same protein may also be expressed in other mammals such as monkeys, cows, horses, etc.

[0032] The human-derived MAST4 may include all of seven isoforms present in human cells. The seven isoforms may include amino acid sequences of NP_055998.1 (SEQ ID NO: 1), NP_942123.1 (SEQ ID NO: 2), NP_001158136.1 (SEQ ID NO: 3), NP_001277155.1 (SEQ ID NO: 4), NP_001277156.1 (SEQ ID NO: 5), NP_001277157.1 (SEQ ID NO: 6), or NP_001284580.1 (SEQ ID NO: 7), based on NCBI reference sequence, and a protein or a polypeptide having each of the amino acid sequences may be translated from mRNA including polynucleotide sequences of SEQ ID NOS: 8 to 14 each encoding the amino acid sequences of SEQ ID NOS: 1 to in the sequence of NM_015183.2, NM_198828.2, NM_001164664.1, NM_001290226.1, NM_001290227.1, NM_001290228.1, or NM_001297651.1.

[0033] The mouse-derived MAST4 may include an amino acid sequence of NP_780380.2 (SEQ ID NO: 15), based on NCBI reference sequence, and a protein or a polypeptide having the amino acid sequence may be translated from mRNA including a polynucleotide sequence of SEQ ID NO: 16 encoding the amino acid sequence of SEQ ID NO: 15 in the sequence of NM_175171.3.

[0034] An amino acid sequence or a polynucleotide sequence having biologically equivalent activity, even though it is not identical to the amino acid sequences of SEQ ID NOS: 1 to 7 and 15 and the polynucleotide sequences of SEQ ID NOs: 8 to 14 and 16, may also be regarded as the MAST4 protein or mRNA thereof.

[0035] Therefore, in a specific embodiment, the MAST4 protein may include any one sequence of SEQ ID NOS: 1 to 7 and 15, and the nucleotide sequence encoding the MAST4 protein may include any one sequence of SEQ ID NOS: 8 to 14 and 16.

[0036] The MAST4 protein or polypeptide may include an amino acid sequence having 60% or more, for example, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, or 100% sequence identity to SEQ ID NOS: 1 to 7 and 15. Further, the MAST4 protein may have an amino acid sequence having modification of 1 or more amino acids, 2 or more amino acids, 3 or more amino acids, 4 or more amino acids, 5 or more amino acids, 6 or more amino acids, or 7 or more amino acids in the amino acid sequences of SEQ ID NOS: 1 to 7 and 15.

[0037] Each polynucleotide encoding MAST4 may have a sequence having 60% or more, for example, 70% or more, 80% or more, 90% or more, 95% or more, 99% or more, or 100% sequence identity to SEQ ID NOS: 8 to 14 and 16. Further, the polynucleotide encoding MAST4 may be a polynucleotide having a different sequence of 1 or more nucleotides, 2 or more nucleotides, 3 or more nucleotides, 4 or more nucleotides, 5 or more nucleotides, 6 or more nucleotides, or 7 or more nucleotides in the sequences of SEQ ID NOS: 8 to 14 and 16.

[0038] The present inventors first demonstrated that production of extracellular matrix is increased and chondrogenesis is promoted by inhibiting MAST4 gene expression in chondrocytes.

[0039] Therefore, in a specific embodiment, the composition for promoting production of an extracellular matrix from eukaryotic cells or the composition for promoting chondrogenesis of chondrocytes of the present disclosure may prevent or treat a joint disease, or improve symptoms thereof.

[0040] Further, in a specific embodiment, the composition for promoting the production of extracellular matrix from the eukaryotic cells and/or the composition for promoting chondrogenesis of chondrocytes of the present disclosure may be to induce chondrogenesis.

[0041] Further, in a specific embodiment, the composition for promoting the production of extracellular matrix from the eukaryotic cells may be used for tissue regeneration or anti-aging.

[0042] The tissue regeneration refers to regeneration of the skin damaged or deformed by wounds, burns, injury, aging, chronic inflammation, diseases, genetic factors, etc., and includes all those used for medical or skin cosmetic purposes. The damage or deformation is caused by the loss or reduced production of extracellular matrix in a tissue, or impossibility of recovery of the extracellular matrix in the tissue by the above factors, and the damage or deformation means symptoms improved, alleviated, recovered, or cured by promoting the production of extracellular matrix by the composition of the present disclosure.

[0043] As a tissue including the skin ages, the production of extracellular matrix decreases, resulting in reduced elasticity of the tissue, and the tissue is easily deformed or damaged by external stimuli, and its recovery becomes slow. Accordingly, the composition of the present disclosure may promote the production of extracellular matrix, thereby preventing or recovering reduced elasticity, deformation, or damage of tissues caused by aging.

[0044] In another specific embodiment, the composition for tissue regeneration or anti-aging may be used as a component of fillers or collagen supplement cosmetics. In still another specific embodiment, the composition for tissue regeneration or anti-aging may be used as a component of functional cosmetics to block the adsorption of fine dust or minerals.

[0045] The composition for promoting the production of extracellular matrix from the eukaryotic cells or the composition for promoting chondrogenesis of chondrocytes of the present disclosure may further include a pharmaceutically acceptable salt or carrier.

[0046] The term "pharmaceutically acceptable salt" means any organic or inorganic addition salt of the compound in the composition of the present disclosure, whose concentration has effective action because it is relatively non-toxic and harmless to patients and whose side effects do not degrade the beneficial efficacy of the composition of the present disclosure. These salt may be selected from any one known to those skilled in the art.

[0047] The composition of the present disclosure may further include a pharmaceutically acceptable carrier. The composition including the pharmaceutically acceptable carrier may have various formulations for oral or parenteral administration. When formulated, the composition may be prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. Solid formulations for oral administration may include tablets, pills, powders, granules, capsules, troches, etc., and these solid formulations may be prepared by mixing one or more compounds of the present disclosure with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin. Moreover, in addition to simple excipients, lubricants such as magnesium stearate, talc, etc. may be used. Liquid formulations for oral administration may include suspensions, liquids for internal use, emulsions, syrups, etc. Various excipients such as wetting agents, sweeteners, flavoring agents, preservatives, etc. may be included, in addition to commonly used simple diluents such as water, liquid paraffin, etc.

[0048] Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, etc. The non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. As a base of a suppository, witepsol, macrogol, Tween 61, cocoa butter, laurin butter, glycerol, gelatin, etc. may be used.

[0049] An aspect provides a method of preventing, treating, or improving a joint disease, the method including administering the composition to a subject.

[0050] Another aspect provides a method of producing an extracellular matrix, the method including contacting eukaryotic cells with the composition for producing the extracellular matrix from eukaryotic cells of the present disclosure.

[0051] In a specific embodiment, the eukaryotic cells may be isolated from a subject. In a specific embodiment, the eukaryotic cells may be chondrocytes.

[0052] In a specific embodiment, the contacting with the eukaryotic cells may include co-transfecting or serial-transfecting the composition into the eukaryotic cells. To effectively deliver the composition of the present disclosure to the eukaryotic cells, various methods known in the art, such as microinjection, electroporation, DEAE-dextran treatment, lipofection, nanoparticle-mediated transfection, protein transduction domain-mediated transduction, virus-mediated gene delivery, and PEG-mediated transfection in protoplast, etc. may be used, but are not limited thereto.

[0053] In a specific embodiment, the contacting with the eukaryotic cells may include culturing the eukaryotic cells in the presence of the composition.

[0054] In a specific embodiment, the culturing includes culturing in the presence of a chondrogenic inducer.

[0055] In a specific embodiment, the method of producing the extracellular matrix of the present disclosure may further include isolating the extracellular matrix from the contacting product.

[0056] In another specific embodiment, the method of producing the extracellular matrix may include contacting chondrocytes with the composition for promoting chondrogenesis of the present disclosure.

[0057] Still another aspect provides a method of forming a cartilage, the method including contacting chondrocytes with the composition for promoting chondrogenesis of the present disclosure.

[0058] In a specific embodiment, the chondrocytes may be isolated from a subject.

[0059] In a specific embodiment, the chondrocytes may be derived from a subject to be transplanted with the produced cartilage.

[0060] Still another aspect provides a method of producing ECM, the method including culturing eukaryotic cells having increased extracellular matrix productivity of the present disclosure to produce ECM; and isolating ECM from the culture.

[0061] In a specific embodiment, the culturing may be culturing in the presence of a chondrogenic inducer.

[0062] In a specific embodiment, the chondrogenic inducer may be BMP.

Advantageous Effects of Disclosure

[0063] A composition for promoting production of an extracellular matrix according to an aspect may be injected into a subject who requires supply of the extracellular matrix, thereby preventing or treating diseases including a joint disease, and improving symptoms thereof, and the composition may be applied to a method of efficiently producing the extracellular matrix from eukaryotic cells.

[0064] A composition for promoting chondrogenesis of chondrocytes according to another aspect may be injected into a subject, thereby preventing or treating diseases including a joint disease, and improving symptoms thereof. The composition may promote chondrogenesis of chondrocytes isolated from the subject, and thus it may be applied to a method of efficiently producing various components including extracellular matrice which are produced by chondrogenesis.

[0065] According to a method of producing an extracellular matrix from eukaryotic cells according to still another aspect, the extracellular matrix may be efficiently produced from eukaryotic cells.

BRIEF DESCRIPTION OF DRAWINGS

[0066] FIG. 1 illustrates a method of preparing MAST4 knockout mice using a CRISPR/Cas9 system;

[0067] FIG. 2A shows RT-PCR results of examining changes in expression levels of respective genes in MAST4 knockout mouse type A and B, and FIG. 2B shows protein expression patterns in MAST4 knockout mice;

[0068] FIG. 3 shows identification of MAST4 knockout in C3H10T1/2 cells in which MAST4 was knocked out using the CRISPR/Cas9 system;

[0069] FIG. 4 shows RT-PCR results of examining changes in expression levels of respective genes in C3H10T1/2 cells in which MAST4 was knocked out using the CRISPR/Cas9 system;

[0070] FIG. 5 shows RT-PCR results of examining changes in expression levels of respective genes in a micromass culture to confirm chondrogenesis;

[0071] FIG. 6 shows alcian blue staining results of examining a difference in cartilage differentiation in C3H10T1/2 cells in which MAST4 was knocked out using the CRISPR/Cas9 system;

[0072] FIG. 7 shows sequence information of target genes used to knockout MAST4 of human cells;

[0073] FIG. 8A shows human chondrocytes in which MAST4 was knocked out using siRNA, and FIG. 8B shows expression levels of extracellular matrix factors in human chondrocytes in which MAST4 was knocked out using the CRISPR/Cas9 system;

[0074] FIG. 9A shows changes in the expression level of MAST4 after treatment of human primary chondrocytes with TGF-.beta.1, and expression levels of extracellular matrix factors thereby, FIG. 9B shows changes in the expression level of MAST4 after treatment of human primary chondrocytes with TGF-.beta.1, and expression levels of extracellular matrix factors thereby; and

[0075] FIG. 10 shows chondrogenesis and regeneration effects in the tibia of the MAST4 knockout mouse.

MODE OF DISCLOSURE

[0076] Hereinafter, the present disclosure will be described in more detail with reference to embodiments. However, these embodiments are for illustrative purposes only, and the scope of the present disclosure is not intended to be limited by these embodiments.

Example 1. Confirmation of Increased Expression of Cartilage Component in MAST4 Knockout Mouse

[0077] 1-1. Preparation of MAST4 Knockout Mouse Using CRISPR/Cas9 System

[0078] To examine whether an extracellular matrix as a cartilage component was increased by suppressing MAST4 expression, MAST4 knockout mice were prepared using a CRISPR/Cas9 system.

[0079] In detail, to prepare CRISPR knockout mice, pX330-U6-Chimeric_BB-CBh-hSpCas9 (Addgene, #42230), donated by Dr. Feng Zhang (Cong et al., 2013), was used as a plasmid capable of expressing Cas9 mRNA and guide RNA. Since MAST4 is a large protein of 7 kb or more, it was designed such that the gene editing was allowed to target two parts, exon 1 and exon 15. A guide RNA sequence targeting exon 1 of MAST4 is 5'-GGAAACTCTGTCGGAGGAAGGGG-3' and a sequence targeting exon 15 is 5'-GGCACAAAGAGTCCCGCCAGAGG-3'. The guide RNA sequence was used to prepare oligomers as in MAST4 CRISPR oligomers of the following Table in accordance with the manufacturer's protocol (http://crispr.mit.edu/, Zhang Feng Lab), and each oligomer was inserted into a px330 plasmid to clone two plasmids targeting exon 1 and exon 15, respectively.

TABLE-US-00001 TABLE 1 MAST4 exon 1 CRISPR F (SEQ ID NO: 18) 5'-caccGGAAACTCTGTCGGAGGAAG- 3' MAST4 exon 1 CRISPR R (SEQ ID NO: 19) 5'-aaacCTTCCTCCGACAGAGTTTCC-3' MAST4 exon 15 CRISPR F (SEQ ID NO: 5'-caccGGCACAAAGAGTCCCGCCAG- 20) 3' MAST4 exon 15 CRISPR R (SEQ ID NO: 5'-aaacCTGGCGGGACTCTTTGTGCC- 21) 3'

[0080] To obtain embryos, 5 IU of pregnant mare serum gonadotrophin (PMSG; Prospec, cat. No. HOR-272) was administered to a C57BL/6J female mouse 2 days before mating, and after 47 hours, 5 IU of humanchorionic gonadotrophin (hCG, Prospec, cat. HOR-250) was administered thereto . . . . Thereafter, the mouse was mated with C57BL/6J male mouse, and embryos were obtained from fallopian tubes. A microinjection mixture including 5 ng/.mu.l of the prepared plasmid and 10 ng of ssDNA donor was injected into the pronuclei of the embryos at a one-cell-stage with reference to an existing standard protocol (Gordon and Ruddle, 1981). The injected one-cell-embryos were transferred to pseudopregnant ICR mice.

[0081] Phenotypic analysis of born mice was performed for exon 1 and exon 15. Finally, two types of MAST4 knockout mice were obtained. Information about the two types of MAST4 knockout mice, type A and type B are shown as in FIG. 1 and the following Table 2 (5'.fwdarw.3').

TABLE-US-00002 TABLE 2 Type A MAST4 KO ATGGGGGAGAAAGTTTCCGAGGCGCCTGAGCCCGT (71 bp deletion in exon 1) GCCCCGGGGCTGCAGCGGACACGGCGCCCGGACCC (SEQ ID NO: 22) TAGTCTCTTCGGCGGCAGCCGTGTCCTCGGAGGGCG CTTCCTCAGCGGAGTCATCCTCTGGCTCGGAAACTCT GTCGGAGGAAGGGGAGCCCAGCCGCTTCTCCTGCA GGTCGCAGCCGCCGCGGCCGCCGGGCGGCGCCCT GGGAACCCGGCTACCCGCCGCGTGGGCTCCCGCGC GCGTGGCTCTGGAGCGTGGAGTCCCTACCCTGCCG CTGCCGCACCCGGGAGGAGCGGTGCTGCCGGTGCC CCAGGTCAGCAGCGCATCCCAAGAGGAGCAGGATGA AGAG Type B MAST4 KO ATGGGGGAGAAAGTTTCCGAGGCGCCTGAGCCCGT (90 bp deletion in exon 1) GCCCCGGGGCTGCAGCGGACACGGCGCCCGGACCC (SEQ ID NO: 23) TAGTCTCTTCGGCGGCAGCCGTGTCCTCGGAGGGCG CTTCCTCAGCGGAGTCATCCTCTGGCTCGGAAACTCT GTCGGAGGAAGGGGAGCCCAGCCGCTTCTCCTGCA GGTCGCAGCCGCCGCGGCCGCCGGGCGGCGCCCT GGGAACCCGGCTACCCGCCGCGTGGGCTCCCGCGC GCGTGGCTCTGGAGCGTGGAGTCCCTACCCTGCCG CTGCCGCACCCGGGAGGAGCGGTGCTGCCGGTGCC CCAGGTCAGCAGCGCATCCCAAGAGGAGCAGGATGA AGAG type A MAST4 KO GGCAGTCTACTTTGTTCGGCACAAAGAGTCCCGCCA (3 bp deletion in exon 15) GAGGTTTGCCATGAAGAAGATCAA (SEQ ID NO: 24) CAAGCAGAACCTCATCCTTCGGAACCAGATCCAGCA GGCCTTCGTGGAGCGAGACATCCT GACTTTCGCAGAGAACCCCTTTGTGGTCAGCATGTAT TGCTCCTTTGAAACGAGGCGTCA CTTATGCATGGTCATGGAGTATGTAGAAG type B MAST4 KO GGCAGTCTACTTTGTTCGGCACAAAGAGTCCCGCCA (13 bp deletion in exon 15) GAGGTTTGCCATGAAGAAGATCAA (SEQ ID NO: 25) CAAGCAGAACCTCATCCTTCGGAACCAGATCCAGCA GGCCTTCGTGGAGCGAGACATCCT GACTTTCGCAGAGAACCCCTTTGTGGTCAGCATGTAT TGCTCCTTTGAAACGAGGCGTCA CTTATGCATGGTCATGGAGTATGTAGAAG

[0082] Bases to be deleted in Table 2 are shown in bold.

[0083] 1-2. RNA-Sequencing for Confirmation of Change of Cartilage Component Expression in MAST4 Knockout Mouse

[0084] To examine changes in the extracellular matrix as a cartilage component in MAST4 knockout mice prepared in Example 1-1, RNA-sequencing was performed for respective genes.

[0085] In detail, 1 day-old-MAST4 knockout mice prepared in Example 1-1, hetero-type mice, and wild-type mice were sacrificed, and then their tibia was excised. Each of the excised tibias was placed in a dish containing DEPC-PBS on ice, and cartilage and bone in the tibia were separated using a needle under a dissecting microscope. The tissues separated from each group was immersed in 500 .mu.l of TRIzol (purchased from Invitrogen), which were then used as samples. RNA was extracted according to a method well known in the art, and quantified using a nanodrop (Thermo scientific).

[0086] RNA-sequencing was performed by Theragen Etex. In detail, mRNA was isolated from 2 .mu.g of total RNA extracted from the mouse of each group using oligo(dT). After fragmentation of the mRNA, single-stranded cDNA was synthesized through random hexamer priming. This single-strand cDNA was used as a template to synthesize a second strand, thereby synthesizing a double-stranded cDNA. To prepare blunt-ends, end repair was performed, and to ligate an adapter, A-tailing and adapter ligation were performed. Thereafter, cDNA library was amplified by polymerase chain reaction (PCR). A concentration and size of the final product were examined using 2100 BioAnalyzer. The produced library was finally quantified using a KAPA library quantification kit, and then sequence interpretation was performed using Hiseq2500. To remove low-quality sequences from the interpreted sequences, filtering was performed such that reads containing 10% or more of bases marked as `N`s in the sequence information or reads containing 40% or more of bases less than Q20 were removed, and reads whose average quality is Q20 or less were also removed. The whole filtering process was performed using the in-house program. The filtered sequences were aligned to a reference genome sequence (hg19) of the corresponding species using STAR v2.4.0b (Dobin et al, 2013).

[0087] Expression level was measured using Cufflinks v2.1.1 (Trapnell C. et al, 2010), and the calculated expression values were expressed as fragments read per kilobase of exon per million fragments mapped (FPKM). Ensemble 72 was used as a genetic information database, and a non-coding gene region was removed with expression-mask option. To increase measurement accuracy of the expression levels, multi-read-correction and frag-bias-correct options were additionally used, and all other options were set to default values.

[0088] To examine genes which were changed by MAST4 knockout, expression values of the samples of each group, which were obtained through Cufflinks, were used. Genes, of which expression values were twice or more, as compared with those of wild-type MAST4, and which had a significance of P value <0.01, were selected, and the expression values of the selected genes and their differences are listed in Table 3.

[0089] As a result, it was confirmed that expression of many genes associated with extracellular matrix as a cartilage component was increased as in the following Table 3. However, in all of the two types of MAST4 knockout mice, reduced expression of mmp8 and mmp9 which are extracellular matrix-degrading enzymes was observed.

[0090] 1-3. RT-PCR for Confirmation of Change of Cartilage Component Expression in MAST4 Knockout Mouse

[0091] To more specifically examine changes in the extracellular matrix as a cartilage component in MAST4 knockout mice prepared in Example 1-1, a part of genes showing changes in the expression in the RNA sequencing results of Example 1-2 was selected and subjected to RT-PCR.

[0092] In detail, RT-PCR was performed using a set of primers of the following Table 4 and AccuPower PCR premix (BIONEER, Korea) according to the manufacturer's instructions.

[0093] As a result, results were consistent with the RNA sequencing results of Example 1-2, and it was confirmed that expression of genes associated with extracellular matrix as a cartilage component was increased (FIG. 2).

[0094] 1-4. Confirmation of Expression Level of Chondrocyte Marker in MAST4 Knockout Mouse

[0095] To examine the effect of MAST4 knockout on chondrocytes, Col2a1 which is known as a chondrocyte marker was stained with fluorescence in the mouse tibia.

[0096] In detail, the tibia tissue was obtained from the mouse model of Example 1-1, and fixed with 4% paraformaldehyde (PFA, Wako, Osaka, JAPAN) in 0.01 M phosphate buffer saline (PBS, pH 7.4) at 4.degree. C. overnight. The tissue was decalcified with 10% EDTA, and embedded in paraffin (Leica Biosystems, MO, USA), and sectioned 6 mm in thickness. The sample slide was stained with hematoxylin and eosin, and the tissue section was incubated with a primary antibody at 4.degree. C. overnight. The primary antibody targets ColI2a1 (Abcam, Cambridge, UK). After washing with PBS, the tissue section was sequentially incubated with AlexaFluor 488 (Invitrogen, CA, USA) at room temperature for 2 hours. Each image was obtained using a confocal microscope LSM700 (Carl Zeiss, Oberkochen, Germany), and a representative sample section was stained with freshly prepared Russell-Movatmodified pentachrome (American MasterTech, CA, USA).

[0097] As a result, FIG. 10 is an enlargement of a specific area of the observed sample, where Col2a1 (fluorescent green zone/grey background zone) was significantly increased in the tibia of the MAST4 knockout mouse model. TOPRO-3 (areas marked by red dots/gray dots) shows staining of the nuclei of chondrocytes. Therefore, it was confirmed that chondrogenesis and cartilage regeneration may be promoted by MAST4 knockout.

Example 2. Confirmation of Increased Expression of Cartilage Component in MAST4 Knockout Cells

[0098] 2-1. Preparation of MAST4 Knockout Cells Using CRISPR/Cas9 System

[0099] To examine whether increased extracellular matrix in the MAST4 knockout mice is also reproduced in vitro, MAST4 knockout cells were prepared using the CRISPR/Cas9 system.

[0100] In detail, C3H/10T1/2, Clone 8 (ATCCCCL-226.TM.) which is a mouse-derived fibroblast cell and is able to differentiate into chondrocytes was purchased ((C3H10T1/2 cell) provided by prof. Seon-Yong Jeong's lab, Department of Medical Genetics, School of Medicine, Ajou University). To knockout the cells, lentiCRISPR v2 (Plasmid #52961), pVSVg (AddGene 8454), and psPAX2 (AddGene 12260) were purchased from Addgene, and oligomers of the following Table 5 were used to insert guide RNA targeting exon 1 of mouse MAST4 gene (ENSMUSG00000034751) into LentiCRISPR v2 plasmid according to the manufacturer's instructions (lentiCRISPRv2 and lentiGuide oligo cloning protocol), thereby preparing a plasmid expressing guide RNA and Cas9 enzyme at the same time (as a control group, a plasmid having no guideRNA and expressing only Cas9 was used).

TABLE-US-00003 TABLE 5 Oligomer Sequence mMAST4 CRISPR exon 1 sgRNA F 5'-CACCGTACCCTGCCGCTGCCGCACC-3' (SEQ ID NO: 70) mMAST4 CRISPR exon 1 sgRNA R 5'-AAACGGTGCGGCAGCGGCAGGGTAC-3' (SEQ ID NO: 71) mouse MAST4 exon 1 5'- (SEQ ID NO: 72) ATGGGGGAGAAAGTTTCCGAGGCGCCTG AGCCCGTGCCCCGGGGCTGCAGCGGACA CGGCGCCCGGACCCTAGTCTCTTCGGCG GCAGCCGTGTCCTCGGAGGGCGCTTCCT CAGCGGAGTCATCCTCTGGCTCGGAAACT CTGTCGGAGGAAGGGGAGCCCAGCCGCT TCTCCTGCAGGTCGCAGCCGCCGCGGCC GCCGGGCGGCGCCCTGGGAACCCGGCT ACCCGCCGCGTGGGCTCCCGCGCGCGT GGCTCTGGAGCGTGGAGTCCCTACCCTG CCGCTGCCGCACCCGGGAGGAGCGGTG CTGCCGGTGCCCCAGGTCAGCAGCGCAT CCCAAGAGGAGCAGGATGAAGAG-3'

[0101] This method is a lentivirus-based CRISPR knockout method. To prepare a virus, the three plasmids prepared above (LentiCRISPR v2 (+guide RNA): guide RNA+Cas9 expressing plasmid, pVSVg: Virus envelop plasmid, psPAX2: Virus packaging plasmid) were transfected into 293T cells using a polyethyenimine (PEI) reagent. 18 hours later, the medium was replaced with a fresh medium, and only the medium was collected, and viruses were obtained using a 0.45 .mu.m filter. The obtained viruses were transfected into a 6-well dish to which C3H10T/12 was seeded. 24 hours after treatment with 1 ml of virus+1 ml of DMEM/FBS+2 .mu.l of polybren, the medium was replaced with fresh DMEM/FBS. 24 hours later, only infected cells were selected by treatment with puromycin, and subcultured to 40% confluency in a 10 cm dish. Since gene editing by CRISPR may randomly occur in cells, single colony selection was performed. Cells were seeded in 10 cm dishes such that 50 cells existed in each dish. When cells formed colonies over time, these colonies were defined as one clone, and genomic DNA was extracted from each clone. PCR was performed using primers specifically amplifying exon 1 (F: 5'->3' CTGTGGTCCAACCTCTGTCA, R: 5'->3' ATCGGCTCAGTGACACTTCC). The amplified PCR products were analyzed by the sequencing company. As a result of sequencing analysis, cells in which gene editing by frameshift was identified were used in the experiment, together with control cells. The sequences targeted by the prepared guide RNA were are in bold in Table 5. As a result of sequencing the MAST4 knockout results, deletion of two nucleotides occurred in mouse MAST4 exon 1, indicating frameshift induction.

[0102] 2-2. RT-PCR for Confirmation of Change of Cartilage Component Expression in MAST4 Knockout Cells

[0103] To examine changes in the extracellular matrix as a cartilage component in MAST4 knockout mice prepared in Example 1-1, RT-PCR was performed for respective genes.

[0104] 10 .mu.l of a medium containing total 10.sup.5 cells was put in the center of 12 wells, and incubated for 2 hours. 1 ml of DMEM containing 10% FBS was added to each well. 24 hours later, cells were harvested, and RNA was extracted using an easy-BLUE.TM. Total RNA Extraction Kit (Intron, Cat 17061) according to the manufacturer's instructions. Next, cDNA was synthesized using M-MLV reverse transcriptase (Promega, M1705) according to the manufacturer's instructions. Primers used in RT-PCR are as described in Table 4.

[0105] As a result, increased expression of extracellular matrix-associated genes was also found in MAST4 knockout cells, as consistent with the results of Example 1-2 and Example 1-3 (FIG. 4), indicating that the same results as in the MAST4 knockout mouse were also obtained in vitro.

Example 3. Micromass Culture of MAST4 Knockout Cells and Confirmation of Increased Cartilage Differentiation Activity

[0106] 3-1. Micromass Culture of MAST4 Knockout Cells

[0107] To evaluate chondrogenic ability of the MAST4 knockout cells of Example 2-2, micromass culture was performed.

[0108] In detail, MAST4 knockout cells were prepared as in Example 2-1, and micromass culture was performed with reference to a known method (Differentiation and Mineralization of Murine Mesenchymal C3H10T1/2 Cells in Micromass Culture, 2010, Rani Roy). First, 10 .mu.l of a medium containing total 10.sup.5 fibroblast cells were put in the center of each well of a 12-well plate, and incubated for 2 hours. 1 ml of DMEM containing 10% FBS was added to each well. Thereafter, 100 ng/ml, 500 ng/ml, or 1000 ng/ml of BMP2 was added to each culture depending on the purpose of cartilage induction, respectively. Thereafter, the medium was replaced with a fresh medium every three days.

[0109] 3-2. Confirmation of Reproduction of Effects of Micromass-Cultured MAST4 Knockout Cells

[0110] To examine whether production of extracellular matrix as a cartilage component was also increased in the MAST4 knockout cells cultured according to Example 3-1, as in the MAST4 knockout cells of Example 2-2, and finally, chondrogenic ability was increased therein, RT-PCR was performed.

[0111] In detail, cells, which were cultured for 0 day, 3 days, and 6 days from the day when the cells were seeded in a plate for micromass culture, were harvested, respectively, and RNA was extracted therefrom on the same day. RT-PCR was performed for respective genes, as in Example 1-3, and whether or not production of the cartilage component was increased was examined.

[0112] As a result, as consistent with the results observed in the MAST4 knockout cells of Example 2-2, expression of extracellular matrix components was increased, and at the same time, differentiation into chondrocytes began with aggrecan expression on day 3 after induction using BMP2, and as a result, it was confirmed that chondrogenic ability was increased (FIG. 5). In particular, when MAST4 was knock-outed, some genes (hapIn1) showed no significant difference in the expression on day 3, but all of the indicated extracellular matrix-associated genes showed overexpression on day 6. In contrast, in the control group, some proteins were less expressed or rather decreased on day 6 (e.g., Matn3, or Comp). The MAST4 knockout cells were found to be useful in the overexpression of all various extracellular matrices.

[0113] 3-3. Confirmation of Chondrogenesis of Mass-Cultured MAST4 Knockout Cells

[0114] With regard to the overexpression of the respective extracellular matrix-associated genes observed in Example 3-2, to examine whether or not the expression was actually increased at the level of isolated proteins, not at the gene expression level, alcian blue staining was performed.

[0115] In detail, plates of cells corresponding to each date were washed twice with PBS and fixed for 15 minutes by adding 1 ml of 4% paraformaldehyde. Then, 1 ml of 1% alcian blue 8-GX (Sigma-Aldrich, A5268) dissolved in 0.1 N HCl (pH 1.0) was added and stained overnight. After washing twice with 500 .mu.l of 0.1 N HCl, images were obtained.

[0116] As a result, in the case of MAST4 knockout cells, chondrogenesis was increased from day 3, and extracellular matrix secretion was increased, and the degree was increased with increasing BMP2 concentration (FIG. 6).

Example 4. Confirmation of Effect of Suppression of MAST4 Expression in Human Cells

Example 4-1. Confirmation of Effect of Suppression of MAST4 Expression in Human Cells

[0117] It was examined whether the results confirmed in the knockout mouse model and mouse cells were also induced in human cells.

[0118] In detail, human primary chondrocytes (donated by College of Medicine, Inha University) were knocked-out by transient transfection with MAST4 siRNA(h) (sc-106201; Santa Cruz biotechnology) (FIG. 8A) or MAST4 expression was knocked-out by the CRISPR/Cas9 system. MAST4 siRNA was transfected using a Lipofectamine RNAiMAX transfection reagent of ThermoFisher SCIENTIFIC, and information of primers used herein is as described in the following Table 6. Preparation and treatment of the CRISPR/Cas9 system were performed in the same manner as in Example 1-1 with reference to GeneArt.TM. Precision gRNA Synthesis Kit (A29377) of ThermoScientific, and information of primers used herein is as described in the following Table 6.

[0119] For high transfection efficiency, siRNA transfection was performed by a reverse transfection technique in which cell planting and transfection are performed at the same time, and a transfection reagent was Lipofectamine RNAiMAX transfection reagent of ThermoFisher SCIENTIFIC. In detail, 15 nM of MAST4 siRNA and 4.5 .mu.l of Lipofectamine RNAiMax were mixed in 40 .mu.l of Gibco.TM. Opti-MEM.TM., and incubated for 15 minutes. Thereafter, human primary chondrocytes of 1.5.times.10.sup.5 cell/well were plated together with 2 ml of a medium (FBS 10%) containing no gentamicin in a 6-well plate (ColI coated plate), and the siRNA mixture was added thereto. 72 hours later, the cells were harvested and RNA was isolated. Human primary chondrocytes were cultured in a collagen I-coated flask (175, Col I Straight Vent 356487, Corning) under conditions of DMEM (17-205-CVR Corning), FBS Qualified (USA origin 500 mL 26140-079, Gibco), L-glutamine (200 mM) (100.times.25030-081, Gibco), and gentamicin (5 ug/ml) (10 mL 15700-060, Thermofisher).

[0120] Knockout was performed by targeting 20 nt on the genome of MAST4 (target sequences are marked in bold), and specifically, #1 and #3 target Exon5, and #2 targets Exon 8. #1 and #3 were prepared in the reverse direction, and #2 was prepared in the forward direction. The human MAST4 gene used in the preparation of CRISPR/Cas9 system was with reference to MAST4 ENSG00000069020 (http://asia.ensembl.org/). Information of targeted Exon sequences and NGG PAM sequences (grey box) on which CRISPR deletion occurred are shown in detail in FIG. 7.

TABLE-US-00004 TABLE 6 hMAST4 CR#1 F (SEQ ID NO: 73) 5'-TAATACGACTCACTATAG GAGTGTGGTCGAGGCAATGC-3' hMAST4 CR#1 R (SEQ ID NO: 74) 5'-TTCTAGCTCTAAAAC GCATTGCCTCGACCACACTC-3' hMAST4 CR#2 F (SEQ ID NO: 75) 5'-TAATACGACTCACTATAG GTAACTCGTCTGGTGTTGGT-3' hMAST4 CR#2 R (SEQ ID NO: 76) 5'-TTCTAGCTCTAAAAC ACCAACACCAGACGAGTTAC-3' hMAST4 CR#3 F (SEQ ID NO: 77) 5'-TAATACGACTCACTATAG AGCAACCGGAAAAGCTTAAT-3' hMAST4 CR#3 R (SEQ ID NO: 78) 5'-TTCTAGCTCTAAAAC ATTAAGCTTTTCCGGTTGCT-3' HumanAcanRT Forward (336) 5'-gaatcaactgctgcagacca-3' (SEQ ID NO: 82) HumanAcan RT Reverse (336) 5'-gtgccagatcatcaccacac-3' (SEQ ID NO: 83) HumanCol9a1RT Forward (467) 5'-CGTGGATTTCCAGGCCGTGG-3' (SEQ ID NO: 84) HumanCol9a1RT Reverse (467) 5'-TCGCTGTCCTTGATCACCAG-3' (SEQ ID NO: 85) HumanGapdhRT Forward (156) 5'-TGGCAAAGTGGAGATTGTTGCC-3' (SEQ ID NO: 86) HumanGapdhRT Reverse (156) 5'-AAGATGGTGATGGGCTTCCCG-3' (SEQ ID NO: 87)

[0121] As a result, as shown in FIG. 8A, when MAST4 siRNA was transfected, MAST4 expression was decreased, and at this time, expression of extracellular matrix factors such as Acan was increased. Further, as shown in FIG. 8B, when MAST4 was knocked out, expression of extracellular matrix factors such as Acan and Col9a1 was increased. These results are the same as those demonstrated in the previous mouse models and mouse cells. Therefore, with regard to other extracellular matrix factors and chondrogenic effects, the same results as those demonstrated in the mouse may be also obtained by suppressing MAST4 expression in human cells.

Example 4-2. Suppression of MAST4 Expression by TGF-.beta.1 in Human Cells and Confirmation of Effect Thereof

[0122] It was examined whether suppression of MAST4 expression as confirmed in Example 4-1 was induced by TGF-.beta.1 and expression of extracellular matrix factors was affected thereby.

[0123] In detail, the human primary chondrocytes of Example 4-1 were treated with TGF-.beta.1, and an expression level thereof was measured by RT-PCR as in Examples 1-2 and 1-3 and Western blotting.

[0124] As a result, as shown in FIG. 9, when TGF-.beta.1 (5 ng/ml) was treated for 24 hours, 48 hours, or 72 hours, respectively, MAST4 expression was suppressed, and as a result, expression of extracellular matrix factors was increased. When co-treatment with TGF-.beta.1 (5 ng/ml) and TEW-7197 which is a TGF-.beta.1 inhibitor was performed (FIG. 9B), Acan expression increased by TGF-.beta.1 was suppressed and the inhibitory effect on MAST4 expression was also decreased, as compared with single treatment with TGF-.beta.1.

Sequence CWU 1

1

9312434PRTHomo sapiens 1Met Asp Glu Ser Ser Ile Leu Arg Arg Arg Gly Leu Gln Lys Glu Leu1 5 10 15Ser Leu Pro Arg Arg Gly Ser Leu Ile Asp Ser Gln Lys Trp Asn Cys 20 25 30Leu Val Lys Arg Cys Arg Thr Ser Asn Arg Lys Ser Leu Ile Gly Asn 35 40 45Gly Gln Ser Pro Ala Leu Pro Arg Pro His Ser Pro Leu Ser Ala His 50 55 60Ala Gly Asn Ser Pro Gln Asp Ser Pro Arg Asn Phe Ser Pro Ser Ala65 70 75 80Ser Ala His Phe Ser Phe Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser 85 90 95Leu Ala Ser Leu Pro Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser 100 105 110Thr Val Ser Ser Ser Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro 115 120 125Tyr Gln Pro Thr Pro Asp Glu Leu His Phe Leu Ser Lys His Phe Cys 130 135 140Thr Thr Glu Ser Ile Ala Thr Glu Asn Arg Cys Arg Asn Thr Pro Met145 150 155 160Arg Pro Arg Ser Arg Ser Leu Ser Pro Gly Arg Ser Pro Ala Cys Cys 165 170 175Asp His Glu Ile Ile Met Met Asn His Val Tyr Lys Glu Arg Phe Pro 180 185 190Lys Ala Thr Ala Gln Met Glu Glu Arg Leu Lys Glu Ile Ile Thr Ser 195 200 205Tyr Ser Pro Asp Asn Val Leu Pro Leu Ala Asp Gly Val Leu Ser Phe 210 215 220Thr His His Gln Ile Ile Glu Leu Ala Arg Asp Cys Leu Asp Lys Ser225 230 235 240His Gln Gly Leu Ile Thr Ser Arg Tyr Phe Leu Glu Leu Gln His Lys 245 250 255Leu Asp Lys Leu Leu Gln Glu Ala His Asp Arg Ser Glu Ser Gly Glu 260 265 270Leu Ala Phe Ile Lys Gln Leu Val Arg Lys Ile Leu Ile Val Ile Ala 275 280 285Arg Pro Ala Arg Leu Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe 290 295 300Tyr Tyr Leu Leu Glu Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly305 310 315 320Ile Lys Thr Asp Ile Pro Arg Tyr Ile Ile Ser Gln Leu Gly Leu Asn 325 330 335Lys Asp Pro Leu Glu Glu Met Ala His Leu Gly Asn Tyr Asp Ser Gly 340 345 350Thr Ala Glu Thr Pro Glu Thr Asp Glu Ser Val Ser Ser Ser Asn Ala 355 360 365Ser Leu Lys Leu Arg Arg Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile 370 375 380Lys Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Tyr Phe Val Arg His385 390 395 400Lys Glu Ser Arg Gln Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn 405 410 415Leu Ile Leu Arg Asn Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile 420 425 430Leu Thr Phe Ala Glu Asn Pro Phe Val Val Ser Met Tyr Cys Ser Phe 435 440 445Glu Thr Arg Arg His Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly 450 455 460Asp Cys Ala Thr Leu Met Lys Asn Met Gly Pro Leu Pro Val Asp Met465 470 475 480Ala Arg Met Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His 485 490 495Asn Tyr Gly Ile Val His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val 500 505 510Thr Ser Met Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val 515 520 525Gly Leu Met Ser Met Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys 530 535 540Asp Ala Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr545 550 555 560Ile Ala Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp 565 570 575Trp Trp Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val 580 585 590Pro Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser 595 600 605Asp Glu Ile Asn Trp Pro Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala 610 615 620Gln Asp Leu Ile Thr Leu Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu625 630 635 640Gly Thr Gly Gly Ala Tyr Glu Val Lys Gln His Arg Phe Phe Arg Ser 645 650 655Leu Asp Trp Asn Ser Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln 660 665 670Leu Glu Ser Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys 675 680 685Tyr His His Met Glu Thr Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp 690 695 700Phe Asn Val Glu Ile Arg Gln Phe Ser Ser Cys Ser His Arg Phe Ser705 710 715 720Lys Val Phe Ser Ser Ile Asp Arg Ile Thr Gln Asn Ser Ala Glu Glu 725 730 735Lys Glu Asp Ser Val Asp Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr 740 745 750Glu Thr Leu Ser Trp Ser Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser 755 760 765Thr Ser Asn Ser Ser Asp Thr Glu Ser Asn Arg His Lys Leu Ser Ser 770 775 780Gly Leu Leu Pro Lys Leu Ala Ile Ser Thr Glu Gly Glu Gln Asp Glu785 790 795 800Ala Ala Ser Cys Pro Gly Asp Pro His Glu Glu Pro Gly Lys Pro Ala 805 810 815Leu Pro Pro Glu Glu Cys Ala Gln Glu Glu Pro Glu Val Thr Thr Pro 820 825 830Ala Ser Thr Ile Ser Ser Ser Thr Leu Ser Val Gly Ser Phe Ser Glu 835 840 845His Leu Asp Gln Ile Asn Gly Arg Ser Glu Cys Val Asp Ser Thr Asp 850 855 860Asn Ser Ser Lys Pro Ser Ser Glu Pro Ala Ser His Met Ala Arg Gln865 870 875 880Arg Leu Glu Ser Thr Glu Lys Lys Lys Ile Ser Gly Lys Val Thr Lys 885 890 895Ser Leu Ser Ala Ser Ala Leu Ser Leu Met Ile Pro Gly Asp Met Phe 900 905 910Ala Val Ser Pro Leu Gly Ser Pro Met Ser Pro His Ser Leu Ser Ser 915 920 925Asp Pro Ser Ser Ser Arg Asp Ser Ser Pro Ser Arg Asp Ser Ser Ala 930 935 940Ala Ser Ala Ser Pro His Gln Pro Ile Val Ile His Ser Ser Gly Lys945 950 955 960Asn Tyr Gly Phe Thr Ile Arg Ala Ile Arg Val Tyr Val Gly Asp Ser 965 970 975Asp Ile Tyr Thr Val His His Ile Val Trp Asn Val Glu Glu Gly Ser 980 985 990Pro Ala Cys Gln Ala Gly Leu Lys Ala Gly Asp Leu Ile Thr His Ile 995 1000 1005Asn Gly Glu Pro Val His Gly Leu Val His Thr Glu Val Ile Glu Leu 1010 1015 1020Leu Leu Lys Ser Gly Asn Lys Val Ser Ile Thr Thr Thr Pro Phe Glu1025 1030 1035 1040Asn Thr Ser Ile Lys Thr Gly Pro Ala Arg Arg Asn Ser Tyr Lys Ser 1045 1050 1055Arg Met Val Arg Arg Ser Lys Lys Ser Lys Lys Lys Glu Ser Leu Glu 1060 1065 1070Arg Arg Arg Ser Leu Phe Lys Lys Leu Ala Lys Gln Pro Ser Pro Leu 1075 1080 1085Leu His Thr Ser Arg Ser Phe Ser Cys Leu Asn Arg Ser Leu Ser Ser 1090 1095 1100Gly Glu Ser Leu Pro Gly Ser Pro Thr His Ser Leu Ser Pro Arg Ser1105 1110 1115 1120Pro Thr Pro Ser Tyr Arg Ser Thr Pro Asp Phe Pro Ser Gly Thr Asn 1125 1130 1135Ser Ser Gln Ser Ser Ser Pro Ser Ser Ser Ala Pro Asn Ser Pro Ala 1140 1145 1150Gly Ser Gly His Ile Arg Pro Ser Thr Leu His Gly Leu Ala Pro Lys 1155 1160 1165Leu Gly Gly Gln Arg Tyr Arg Ser Gly Arg Arg Lys Ser Ala Gly Asn 1170 1175 1180Ile Pro Leu Ser Pro Leu Ala Arg Thr Pro Ser Pro Thr Pro Gln Pro1185 1190 1195 1200Thr Ser Pro Gln Arg Ser Pro Ser Pro Leu Leu Gly His Ser Leu Gly 1205 1210 1215Asn Ser Lys Ile Ala Gln Ala Phe Pro Ser Lys Met His Ser Pro Pro 1220 1225 1230Thr Ile Val Arg His Ile Val Arg Pro Lys Ser Ala Glu Pro Pro Arg 1235 1240 1245Ser Pro Leu Leu Lys Arg Val Gln Ser Glu Glu Lys Leu Ser Pro Ser 1250 1255 1260Tyr Gly Ser Asp Lys Lys His Leu Cys Ser Arg Lys His Ser Leu Glu1265 1270 1275 1280Val Thr Gln Glu Glu Val Gln Arg Glu Gln Ser Gln Arg Glu Ala Pro 1285 1290 1295Leu Gln Ser Leu Asp Glu Asn Val Cys Asp Val Pro Pro Leu Ser Arg 1300 1305 1310Ala Arg Pro Val Glu Gln Gly Cys Leu Lys Arg Pro Val Ser Arg Lys 1315 1320 1325Val Gly Arg Gln Glu Ser Val Asp Asp Leu Asp Arg Asp Lys Leu Lys 1330 1335 1340Ala Lys Val Val Val Lys Lys Ala Asp Gly Phe Pro Glu Lys Gln Glu1345 1350 1355 1360Ser His Gln Lys Ser His Gly Pro Gly Ser Asp Leu Glu Asn Phe Ala 1365 1370 1375Leu Phe Lys Leu Glu Glu Arg Glu Lys Lys Val Tyr Pro Lys Ala Val 1380 1385 1390Glu Arg Ser Ser Thr Phe Glu Asn Lys Ala Ser Met Gln Glu Ala Pro 1395 1400 1405Pro Leu Gly Ser Leu Leu Lys Asp Ala Leu His Lys Gln Ala Ser Val 1410 1415 1420Arg Ala Ser Glu Gly Ala Met Ser Asp Gly Arg Val Pro Ala Glu His1425 1430 1435 1440Arg Gln Gly Gly Gly Asp Phe Arg Arg Ala Pro Ala Pro Gly Thr Leu 1445 1450 1455Gln Asp Gly Leu Cys His Ser Leu Asp Arg Gly Ile Ser Gly Lys Gly 1460 1465 1470Glu Gly Thr Glu Lys Ser Ser Gln Ala Lys Glu Leu Leu Arg Cys Glu 1475 1480 1485Lys Leu Asp Ser Lys Leu Ala Asn Ile Asp Tyr Leu Arg Lys Lys Met 1490 1495 1500Ser Leu Glu Asp Lys Glu Asp Asn Leu Cys Pro Val Leu Lys Pro Lys1505 1510 1515 1520Met Thr Ala Gly Ser His Glu Cys Leu Pro Gly Asn Pro Val Arg Pro 1525 1530 1535Thr Gly Gly Gln Gln Glu Pro Pro Pro Ala Ser Glu Ser Arg Ala Phe 1540 1545 1550Val Ser Ser Thr His Ala Ala Gln Met Ser Ala Val Ser Phe Val Pro 1555 1560 1565Leu Lys Ala Leu Thr Gly Arg Val Asp Ser Gly Thr Glu Lys Pro Gly 1570 1575 1580Leu Val Ala Pro Glu Ser Pro Val Arg Lys Ser Pro Ser Glu Tyr Lys1585 1590 1595 1600Leu Glu Gly Arg Ser Val Ser Cys Leu Lys Pro Ile Glu Gly Thr Leu 1605 1610 1615Asp Ile Ala Leu Leu Ser Gly Pro Gln Ala Ser Lys Thr Glu Leu Pro 1620 1625 1630Ser Pro Glu Ser Ala Gln Ser Pro Ser Pro Ser Gly Asp Val Arg Ala 1635 1640 1645Ser Val Pro Pro Val Leu Pro Ser Ser Ser Gly Lys Lys Asn Asp Thr 1650 1655 1660Thr Ser Ala Arg Glu Leu Ser Pro Ser Ser Leu Lys Met Asn Lys Ser1665 1670 1675 1680Tyr Leu Leu Glu Pro Trp Phe Leu Pro Pro Ser Arg Gly Leu Gln Asn 1685 1690 1695Ser Pro Ala Val Ser Leu Pro Asp Pro Glu Phe Lys Arg Asp Arg Lys 1700 1705 1710Gly Pro His Pro Thr Ala Arg Ser Pro Gly Thr Val Met Glu Ser Asn 1715 1720 1725Pro Gln Gln Arg Glu Gly Ser Ser Pro Lys His Gln Asp His Thr Thr 1730 1735 1740Asp Pro Lys Leu Leu Thr Cys Leu Gly Gln Asn Leu His Ser Pro Asp1745 1750 1755 1760Leu Ala Arg Pro Arg Cys Pro Leu Pro Pro Glu Ala Ser Pro Ser Arg 1765 1770 1775Glu Lys Pro Gly Leu Arg Glu Ser Ser Glu Arg Gly Pro Pro Thr Ala 1780 1785 1790Arg Ser Glu Arg Ser Ala Ala Arg Ala Asp Thr Cys Arg Glu Pro Ser 1795 1800 1805Met Glu Leu Cys Phe Pro Glu Thr Ala Lys Thr Ser Asp Asn Ser Lys 1810 1815 1820Asn Leu Leu Ser Val Gly Arg Thr His Pro Asp Phe Tyr Thr Gln Thr1825 1830 1835 1840Gln Ala Met Glu Lys Ala Trp Ala Pro Gly Gly Lys Thr Asn His Lys 1845 1850 1855Asp Gly Pro Gly Glu Ala Arg Pro Pro Pro Arg Asp Asn Ser Ser Leu 1860 1865 1870His Ser Ala Gly Ile Pro Cys Glu Lys Glu Leu Gly Lys Val Arg Arg 1875 1880 1885Gly Val Glu Pro Lys Pro Glu Ala Leu Leu Ala Arg Arg Ser Leu Gln 1890 1895 1900Pro Pro Gly Ile Glu Ser Glu Lys Ser Glu Lys Leu Ser Ser Phe Pro1905 1910 1915 1920Ser Leu Gln Lys Asp Gly Ala Lys Glu Pro Glu Arg Lys Glu Gln Pro 1925 1930 1935Leu Gln Arg His Pro Ser Ser Ile Pro Pro Pro Pro Leu Thr Ala Lys 1940 1945 1950Asp Leu Ser Ser Pro Ala Ala Arg Gln His Cys Ser Ser Pro Ser His 1955 1960 1965Ala Ser Gly Arg Glu Pro Gly Ala Lys Pro Ser Thr Ala Glu Pro Ser 1970 1975 1980Ser Ser Pro Gln Asp Pro Pro Lys Pro Val Ala Ala His Ser Glu Ser1985 1990 1995 2000Ser Ser His Lys Pro Arg Pro Gly Pro Asp Pro Gly Pro Pro Lys Thr 2005 2010 2015Lys His Pro Asp Arg Ser Leu Ser Ser Gln Lys Pro Ser Val Gly Ala 2020 2025 2030Thr Lys Gly Lys Glu Pro Ala Thr Gln Ser Leu Gly Gly Ser Ser Arg 2035 2040 2045Glu Gly Lys Gly His Ser Lys Ser Gly Pro Asp Val Phe Pro Ala Thr 2050 2055 2060Pro Gly Ser Gln Asn Lys Ala Ser Asp Gly Ile Gly Gln Gly Glu Gly2065 2070 2075 2080Gly Pro Ser Val Pro Leu His Thr Asp Arg Ala Pro Leu Asp Ala Lys 2085 2090 2095Pro Gln Pro Thr Ser Gly Gly Arg Pro Leu Glu Val Leu Glu Lys Pro 2100 2105 2110Val His Leu Pro Arg Pro Gly His Pro Gly Pro Ser Glu Pro Ala Asp 2115 2120 2125Gln Lys Leu Ser Ala Val Gly Glu Lys Gln Thr Leu Ser Pro Lys His 2130 2135 2140Pro Lys Pro Ser Thr Val Lys Asp Cys Pro Thr Leu Cys Lys Gln Thr2145 2150 2155 2160Asp Asn Arg Gln Thr Asp Lys Ser Pro Ser Gln Pro Ala Ala Asn Thr 2165 2170 2175Asp Arg Arg Ala Glu Gly Lys Lys Cys Thr Glu Ala Leu Tyr Ala Pro 2180 2185 2190Ala Glu Gly Asp Lys Leu Glu Ala Gly Leu Ser Phe Val His Ser Glu 2195 2200 2205Asn Arg Leu Lys Gly Ala Glu Arg Pro Ala Ala Gly Val Gly Lys Gly 2210 2215 2220Phe Pro Glu Ala Arg Gly Lys Gly Pro Gly Pro Gln Lys Pro Pro Thr2225 2230 2235 2240Glu Ala Asp Lys Pro Asn Gly Met Lys Arg Ser Pro Ser Ala Thr Gly 2245 2250 2255Gln Ser Ser Phe Arg Ser Thr Ala Leu Pro Glu Lys Ser Leu Ser Cys 2260 2265 2270Ser Ser Ser Phe Pro Glu Thr Arg Ala Gly Val Arg Glu Ala Ser Ala 2275 2280 2285Ala Ser Ser Asp Thr Ser Ser Ala Lys Ala Ala Gly Gly Met Leu Glu 2290 2295 2300Leu Pro Ala Pro Ser Asn Arg Asp His Arg Lys Ala Gln Pro Ala Gly2305 2310 2315 2320Glu Gly Arg Thr His Met Thr Lys Ser Asp Ser Leu Pro Ser Phe Arg 2325 2330 2335Val Ser Thr Leu Pro Leu Glu Ser His His Pro Asp Pro Asn Thr Met 2340 2345 2350Gly Gly Ala Ser His Arg Asp Arg Ala Leu Ser Val Thr Ala Thr Val 2355 2360 2365Gly Glu Thr Lys Gly Lys Asp Pro Ala Pro Ala Gln Pro Pro Pro Ala 2370 2375 2380Arg Lys Gln Asn Val Gly Arg Asp Val Thr Lys Pro Ser Pro Ala Pro2385 2390 2395 2400Asn Thr Asp Arg Pro Ile Ser Leu Ser Asn Glu Lys Asp Phe Val Val 2405 2410 2415Arg Gln Arg Arg Gly Lys Glu Ser Leu Arg Ser Ser Pro His Lys Lys 2420 2425 2430Ala Leu2250PRTHomo sapiens 2Met Gly Glu Lys Val Ser Glu Ala Pro Glu Pro Val Pro Arg Gly Cys1 5 10 15Ser Gly His Gly Ser Arg Thr Pro Ala Ser Ala Leu Val Ala Ala Ser

20 25 30Ser Pro Gly Ala Ser Ser Ala Glu Ser Ser Ser Gly Ser Glu Thr Leu 35 40 45Ser Glu Glu Gly Glu Pro Gly Gly Phe Ser Arg Glu His Gln Pro Pro 50 55 60Pro Pro Pro Pro Leu Gly Gly Thr Leu Gly Ala Arg Ala Pro Ala Ala65 70 75 80Trp Ala Pro Ala Ser Val Leu Leu Glu Arg Gly Val Leu Ala Leu Pro 85 90 95Pro Pro Leu Pro Gly Gly Ala Val Pro Pro Ala Pro Arg Gly Ser Ser 100 105 110Ala Ser Gln Glu Glu Gln Asp Glu Glu Leu Asp His Ile Leu Ser Pro 115 120 125Pro Pro Met Pro Phe Arg Lys Cys Ser Asn Pro Asp Val Ala Ser Gly 130 135 140Pro Gly Lys Ser Leu Lys Tyr Lys Arg Gln Leu Ser Glu Asp Gly Arg145 150 155 160Gln Leu Arg Arg Gly Ser Leu Gly Gly Ala Leu Thr Gly Arg Tyr Leu 165 170 175Leu Pro Asn Pro Val Ala Gly Gln Ala Trp Pro Ala Ser Ala Glu Thr 180 185 190Ser Asn Leu Val Arg Met Arg Ser Gln Ala Leu Gly Gln Ser Ala Pro 195 200 205Ser Leu Thr Ala Ser Leu Lys Glu Leu Ser Leu Pro Arg Arg Gly Ser 210 215 220Leu Ile Asp Ser Gln Lys Trp Asn Cys Leu Val Lys Arg Pro Val Cys225 230 235 240Pro Asn Ala Gly Arg Thr Ser Pro Leu Gly 245 25032623PRTHomo sapiens 3Met Gly Glu Lys Val Ser Glu Ala Pro Glu Pro Val Pro Arg Gly Cys1 5 10 15Ser Gly His Gly Ser Arg Thr Pro Ala Ser Ala Leu Val Ala Ala Ser 20 25 30Ser Pro Gly Ala Ser Ser Ala Glu Ser Ser Ser Gly Ser Glu Thr Leu 35 40 45Ser Glu Glu Gly Glu Pro Gly Gly Phe Ser Arg Glu His Gln Pro Pro 50 55 60Pro Pro Pro Pro Leu Gly Gly Thr Leu Gly Ala Arg Ala Pro Ala Ala65 70 75 80Trp Ala Pro Ala Ser Val Leu Leu Glu Arg Gly Val Leu Ala Leu Pro 85 90 95Pro Pro Leu Pro Gly Gly Ala Val Pro Pro Ala Pro Arg Gly Ser Ser 100 105 110Ala Ser Gln Glu Glu Gln Asp Glu Glu Leu Asp His Ile Leu Ser Pro 115 120 125Pro Pro Met Pro Phe Arg Lys Cys Ser Asn Pro Asp Val Ala Ser Gly 130 135 140Pro Gly Lys Ser Leu Lys Tyr Lys Arg Gln Leu Ser Glu Asp Gly Arg145 150 155 160Gln Leu Arg Arg Gly Ser Leu Gly Gly Ala Leu Thr Gly Arg Tyr Leu 165 170 175Leu Pro Asn Pro Val Ala Gly Gln Ala Trp Pro Ala Ser Ala Glu Thr 180 185 190Ser Asn Leu Val Arg Met Arg Ser Gln Ala Leu Gly Gln Ser Ala Pro 195 200 205Ser Leu Thr Ala Ser Leu Lys Glu Leu Ser Leu Pro Arg Arg Gly Ser 210 215 220Phe Cys Arg Thr Ser Asn Arg Lys Ser Leu Ile Gly Asn Gly Gln Ser225 230 235 240Pro Ala Leu Pro Arg Pro His Ser Pro Leu Ser Ala His Ala Gly Asn 245 250 255Ser Pro Gln Asp Ser Pro Arg Asn Phe Ser Pro Ser Ala Ser Ala His 260 265 270Phe Ser Phe Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser Leu Ala Ser 275 280 285Leu Pro Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr Val Ser 290 295 300Ser Ser Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro Tyr Gln Pro305 310 315 320Thr Pro Asp Glu Leu His Phe Leu Ser Lys His Phe Cys Thr Thr Glu 325 330 335Ser Ile Ala Thr Glu Asn Arg Cys Arg Asn Thr Pro Met Arg Pro Arg 340 345 350Ser Arg Ser Leu Ser Pro Gly Arg Ser Pro Ala Cys Cys Asp His Glu 355 360 365Ile Ile Met Met Asn His Val Tyr Lys Glu Arg Phe Pro Lys Ala Thr 370 375 380Ala Gln Met Glu Glu Arg Leu Lys Glu Ile Ile Thr Ser Tyr Ser Pro385 390 395 400Asp Asn Val Leu Pro Leu Ala Asp Gly Val Leu Ser Phe Thr His His 405 410 415Gln Ile Ile Glu Leu Ala Arg Asp Cys Leu Asp Lys Ser His Gln Gly 420 425 430Leu Ile Thr Ser Arg Tyr Phe Leu Glu Leu Gln His Lys Leu Asp Lys 435 440 445Leu Leu Gln Glu Ala His Asp Arg Ser Glu Ser Gly Glu Leu Ala Phe 450 455 460Ile Lys Gln Leu Val Arg Lys Ile Leu Ile Val Ile Ala Arg Pro Ala465 470 475 480Arg Leu Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr Tyr Leu 485 490 495Leu Glu Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly Ile Lys Thr 500 505 510Asp Ile Pro Arg Tyr Ile Ile Ser Gln Leu Gly Leu Asn Lys Asp Pro 515 520 525Leu Glu Glu Met Ala His Leu Gly Asn Tyr Asp Ser Gly Thr Ala Glu 530 535 540Thr Pro Glu Thr Asp Glu Ser Val Ser Ser Ser Asn Ala Ser Leu Lys545 550 555 560Leu Arg Arg Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile Lys Leu Ile 565 570 575Ser Asn Gly Ala Tyr Gly Ala Val Tyr Phe Val Arg His Lys Glu Ser 580 585 590Arg Gln Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu 595 600 605Arg Asn Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe 610 615 620Ala Glu Asn Pro Phe Val Val Ser Met Tyr Cys Ser Phe Glu Thr Arg625 630 635 640Arg His Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala 645 650 655Thr Leu Met Lys Asn Met Gly Pro Leu Pro Val Asp Met Ala Arg Met 660 665 670Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly 675 680 685Ile Val His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr Ser Met 690 695 700Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly Leu Met705 710 715 720Ser Met Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg 725 730 735Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro 740 745 750Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala 755 760 765Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe 770 775 780Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Ile785 790 795 800Asn Trp Pro Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala Gln Asp Leu 805 810 815Ile Thr Leu Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu Gly Thr Gly 820 825 830Gly Ala Tyr Glu Val Lys Gln His Arg Phe Phe Arg Ser Leu Asp Trp 835 840 845Asn Ser Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser 850 855 860Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys Tyr His His865 870 875 880Met Glu Thr Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp Phe Asn Val 885 890 895Glu Ile Arg Gln Phe Ser Ser Cys Ser His Arg Phe Ser Lys Val Phe 900 905 910Ser Ser Ile Asp Arg Ile Thr Gln Asn Ser Ala Glu Glu Lys Glu Asp 915 920 925Ser Val Asp Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr Glu Thr Leu 930 935 940Ser Trp Ser Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser Thr Ser Asn945 950 955 960Ser Ser Asp Thr Glu Ser Asn Arg His Lys Leu Ser Ser Gly Leu Leu 965 970 975Pro Lys Leu Ala Ile Ser Thr Glu Gly Glu Gln Asp Glu Ala Ala Ser 980 985 990Cys Pro Gly Asp Pro His Glu Glu Pro Gly Lys Pro Ala Leu Pro Pro 995 1000 1005Glu Glu Cys Ala Gln Glu Glu Pro Glu Val Thr Thr Pro Ala Ser Thr 1010 1015 1020Ile Ser Ser Ser Thr Leu Ser Val Gly Ser Phe Ser Glu His Leu Asp1025 1030 1035 1040Gln Ile Asn Gly Arg Ser Glu Cys Val Asp Ser Thr Asp Asn Ser Ser 1045 1050 1055Lys Pro Ser Ser Glu Pro Ala Ser His Met Ala Arg Gln Arg Leu Glu 1060 1065 1070Ser Thr Glu Lys Lys Lys Ile Ser Gly Lys Val Thr Lys Ser Leu Ser 1075 1080 1085Ala Ser Ala Leu Ser Leu Met Ile Pro Gly Asp Met Phe Ala Val Ser 1090 1095 1100Pro Leu Gly Ser Pro Met Ser Pro His Ser Leu Ser Ser Asp Pro Ser1105 1110 1115 1120Ser Ser Arg Asp Ser Ser Pro Ser Arg Asp Ser Ser Ala Ala Ser Ala 1125 1130 1135Ser Pro His Gln Pro Ile Val Ile His Ser Ser Gly Lys Asn Tyr Gly 1140 1145 1150Phe Thr Ile Arg Ala Ile Arg Val Tyr Val Gly Asp Ser Asp Ile Tyr 1155 1160 1165Thr Val His His Ile Val Trp Asn Val Glu Glu Gly Ser Pro Ala Cys 1170 1175 1180Gln Ala Gly Leu Lys Ala Gly Asp Leu Ile Thr His Ile Asn Gly Glu1185 1190 1195 1200Pro Val His Gly Leu Val His Thr Glu Val Ile Glu Leu Leu Leu Lys 1205 1210 1215Ser Gly Asn Lys Val Ser Ile Thr Thr Thr Pro Phe Glu Asn Thr Ser 1220 1225 1230Ile Lys Thr Gly Pro Ala Arg Arg Asn Ser Tyr Lys Ser Arg Met Val 1235 1240 1245Arg Arg Ser Lys Lys Ser Lys Lys Lys Glu Ser Leu Glu Arg Arg Arg 1250 1255 1260Ser Leu Phe Lys Lys Leu Ala Lys Gln Pro Ser Pro Leu Leu His Thr1265 1270 1275 1280Ser Arg Ser Phe Ser Cys Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser 1285 1290 1295Leu Pro Gly Ser Pro Thr His Ser Leu Ser Pro Arg Ser Pro Thr Pro 1300 1305 1310Ser Tyr Arg Ser Thr Pro Asp Phe Pro Ser Gly Thr Asn Ser Ser Gln 1315 1320 1325Ser Ser Ser Pro Ser Ser Ser Ala Pro Asn Ser Pro Ala Gly Ser Gly 1330 1335 1340His Ile Arg Pro Ser Thr Leu His Gly Leu Ala Pro Lys Leu Gly Gly1345 1350 1355 1360Gln Arg Tyr Arg Ser Gly Arg Arg Lys Ser Ala Gly Asn Ile Pro Leu 1365 1370 1375Ser Pro Leu Ala Arg Thr Pro Ser Pro Thr Pro Gln Pro Thr Ser Pro 1380 1385 1390Gln Arg Ser Pro Ser Pro Leu Leu Gly His Ser Leu Gly Asn Ser Lys 1395 1400 1405Ile Ala Gln Ala Phe Pro Ser Lys Met His Ser Pro Pro Thr Ile Val 1410 1415 1420Arg His Ile Val Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu1425 1430 1435 1440Leu Lys Arg Val Gln Ser Glu Glu Lys Leu Ser Pro Ser Tyr Gly Ser 1445 1450 1455Asp Lys Lys His Leu Cys Ser Arg Lys His Ser Leu Glu Val Thr Gln 1460 1465 1470Glu Glu Val Gln Arg Glu Gln Ser Gln Arg Glu Ala Pro Leu Gln Ser 1475 1480 1485Leu Asp Glu Asn Val Cys Asp Val Pro Pro Leu Ser Arg Ala Arg Pro 1490 1495 1500Val Glu Gln Gly Cys Leu Lys Arg Pro Val Ser Arg Lys Val Gly Arg1505 1510 1515 1520Gln Glu Ser Val Asp Asp Leu Asp Arg Asp Lys Leu Lys Ala Lys Val 1525 1530 1535Val Val Lys Lys Ala Asp Gly Phe Pro Glu Lys Gln Glu Ser His Gln 1540 1545 1550Lys Ser His Gly Pro Gly Ser Asp Leu Glu Asn Phe Ala Leu Phe Lys 1555 1560 1565Leu Glu Glu Arg Glu Lys Lys Val Tyr Pro Lys Ala Val Glu Arg Ser 1570 1575 1580Ser Thr Phe Glu Asn Lys Ala Ser Met Gln Glu Ala Pro Pro Leu Gly1585 1590 1595 1600Ser Leu Leu Lys Asp Ala Leu His Lys Gln Ala Ser Val Arg Ala Ser 1605 1610 1615Glu Gly Ala Met Ser Asp Gly Arg Val Pro Ala Glu His Arg Gln Gly 1620 1625 1630Gly Gly Asp Phe Arg Arg Ala Pro Ala Pro Gly Thr Leu Gln Asp Gly 1635 1640 1645Leu Cys His Ser Leu Asp Arg Gly Ile Ser Gly Lys Gly Glu Gly Thr 1650 1655 1660Glu Lys Ser Ser Gln Ala Lys Glu Leu Leu Arg Cys Glu Lys Leu Asp1665 1670 1675 1680Ser Lys Leu Ala Asn Ile Asp Tyr Leu Arg Lys Lys Met Ser Leu Glu 1685 1690 1695Asp Lys Glu Asp Asn Leu Cys Pro Val Leu Lys Pro Lys Met Thr Ala 1700 1705 1710Gly Ser His Glu Cys Leu Pro Gly Asn Pro Val Arg Pro Thr Gly Gly 1715 1720 1725Gln Gln Glu Pro Pro Pro Ala Ser Glu Ser Arg Ala Phe Val Ser Ser 1730 1735 1740Thr His Ala Ala Gln Met Ser Ala Val Ser Phe Val Pro Leu Lys Ala1745 1750 1755 1760Leu Thr Gly Arg Val Asp Ser Gly Thr Glu Lys Pro Gly Leu Val Ala 1765 1770 1775Pro Glu Ser Pro Val Arg Lys Ser Pro Ser Glu Tyr Lys Leu Glu Gly 1780 1785 1790Arg Ser Val Ser Cys Leu Lys Pro Ile Glu Gly Thr Leu Asp Ile Ala 1795 1800 1805Leu Leu Ser Gly Pro Gln Ala Ser Lys Thr Glu Leu Pro Ser Pro Glu 1810 1815 1820Ser Ala Gln Ser Pro Ser Pro Ser Gly Asp Val Arg Ala Ser Val Pro1825 1830 1835 1840Pro Val Leu Pro Ser Ser Ser Gly Lys Lys Asn Asp Thr Thr Ser Ala 1845 1850 1855Arg Glu Leu Ser Pro Ser Ser Leu Lys Met Asn Lys Ser Tyr Leu Leu 1860 1865 1870Glu Pro Trp Phe Leu Pro Pro Ser Arg Gly Leu Gln Asn Ser Pro Ala 1875 1880 1885Val Ser Leu Pro Asp Pro Glu Phe Lys Arg Asp Arg Lys Gly Pro His 1890 1895 1900Pro Thr Ala Arg Ser Pro Gly Thr Val Met Glu Ser Asn Pro Gln Gln1905 1910 1915 1920Arg Glu Gly Ser Ser Pro Lys His Gln Asp His Thr Thr Asp Pro Lys 1925 1930 1935Leu Leu Thr Cys Leu Gly Gln Asn Leu His Ser Pro Asp Leu Ala Arg 1940 1945 1950Pro Arg Cys Pro Leu Pro Pro Glu Ala Ser Pro Ser Arg Glu Lys Pro 1955 1960 1965Gly Leu Arg Glu Ser Ser Glu Arg Gly Pro Pro Thr Ala Arg Ser Glu 1970 1975 1980Arg Ser Ala Ala Arg Ala Asp Thr Cys Arg Glu Pro Ser Met Glu Leu1985 1990 1995 2000Cys Phe Pro Glu Thr Ala Lys Thr Ser Asp Asn Ser Lys Asn Leu Leu 2005 2010 2015Ser Val Gly Arg Thr His Pro Asp Phe Tyr Thr Gln Thr Gln Ala Met 2020 2025 2030Glu Lys Ala Trp Ala Pro Gly Gly Lys Thr Asn His Lys Asp Gly Pro 2035 2040 2045Gly Glu Ala Arg Pro Pro Pro Arg Asp Asn Ser Ser Leu His Ser Ala 2050 2055 2060Gly Ile Pro Cys Glu Lys Glu Leu Gly Lys Val Arg Arg Gly Val Glu2065 2070 2075 2080Pro Lys Pro Glu Ala Leu Leu Ala Arg Arg Ser Leu Gln Pro Pro Gly 2085 2090 2095Ile Glu Ser Glu Lys Ser Glu Lys Leu Ser Ser Phe Pro Ser Leu Gln 2100 2105 2110Lys Asp Gly Ala Lys Glu Pro Glu Arg Lys Glu Gln Pro Leu Gln Arg 2115 2120 2125His Pro Ser Ser Ile Pro Pro Pro Pro Leu Thr Ala Lys Asp Leu Ser 2130 2135 2140Ser Pro Ala Ala Arg Gln His Cys Ser Ser Pro Ser His Ala Ser Gly2145 2150 2155 2160Arg Glu Pro Gly Ala Lys Pro Ser Thr Ala Glu Pro Ser Ser Ser Pro 2165 2170 2175Gln Asp Pro Pro Lys Pro Val Ala Ala His Ser Glu Ser Ser Ser His 2180 2185 2190Lys Pro Arg Pro Gly Pro Asp Pro Gly Pro Pro Lys Thr Lys His Pro 2195 2200 2205Asp Arg Ser Leu Ser Ser Gln Lys Pro Ser Val Gly Ala Thr Lys Gly 2210 2215 2220Lys Glu Pro Ala Thr Gln Ser Leu Gly Gly Ser Ser Arg Glu Gly Lys2225 2230

2235 2240Gly His Ser Lys Ser Gly Pro Asp Val Phe Pro Ala Thr Pro Gly Ser 2245 2250 2255Gln Asn Lys Ala Ser Asp Gly Ile Gly Gln Gly Glu Gly Gly Pro Ser 2260 2265 2270Val Pro Leu His Thr Asp Arg Ala Pro Leu Asp Ala Lys Pro Gln Pro 2275 2280 2285Thr Ser Gly Gly Arg Pro Leu Glu Val Leu Glu Lys Pro Val His Leu 2290 2295 2300Pro Arg Pro Gly His Pro Gly Pro Ser Glu Pro Ala Asp Gln Lys Leu2305 2310 2315 2320Ser Ala Val Gly Glu Lys Gln Thr Leu Ser Pro Lys His Pro Lys Pro 2325 2330 2335Ser Thr Val Lys Asp Cys Pro Thr Leu Cys Lys Gln Thr Asp Asn Arg 2340 2345 2350Gln Thr Asp Lys Ser Pro Ser Gln Pro Ala Ala Asn Thr Asp Arg Arg 2355 2360 2365Ala Glu Gly Lys Lys Cys Thr Glu Ala Leu Tyr Ala Pro Ala Glu Gly 2370 2375 2380Asp Lys Leu Glu Ala Gly Leu Ser Phe Val His Ser Glu Asn Arg Leu2385 2390 2395 2400Lys Gly Ala Glu Arg Pro Ala Ala Gly Val Gly Lys Gly Phe Pro Glu 2405 2410 2415Ala Arg Gly Lys Gly Pro Gly Pro Gln Lys Pro Pro Thr Glu Ala Asp 2420 2425 2430Lys Pro Asn Gly Met Lys Arg Ser Pro Ser Ala Thr Gly Gln Ser Ser 2435 2440 2445Phe Arg Ser Thr Ala Leu Pro Glu Lys Ser Leu Ser Cys Ser Ser Ser 2450 2455 2460Phe Pro Glu Thr Arg Ala Gly Val Arg Glu Ala Ser Ala Ala Ser Ser2465 2470 2475 2480Asp Thr Ser Ser Ala Lys Ala Ala Gly Gly Met Leu Glu Leu Pro Ala 2485 2490 2495Pro Ser Asn Arg Asp His Arg Lys Ala Gln Pro Ala Gly Glu Gly Arg 2500 2505 2510Thr His Met Thr Lys Ser Asp Ser Leu Pro Ser Phe Arg Val Ser Thr 2515 2520 2525Leu Pro Leu Glu Ser His His Pro Asp Pro Asn Thr Met Gly Gly Ala 2530 2535 2540Ser His Arg Asp Arg Ala Leu Ser Val Thr Ala Thr Val Gly Glu Thr2545 2550 2555 2560Lys Gly Lys Asp Pro Ala Pro Ala Gln Pro Pro Pro Ala Arg Lys Gln 2565 2570 2575Asn Val Gly Arg Asp Val Thr Lys Pro Ser Pro Ala Pro Asn Thr Asp 2580 2585 2590Arg Pro Ile Ser Leu Ser Asn Glu Lys Asp Phe Val Val Arg Gln Arg 2595 2600 2605Arg Gly Lys Glu Ser Leu Arg Ser Ser Pro His Lys Lys Ala Leu 2610 2615 262042417PRTHomo sapiens 4Met Lys Ala Gln Arg Glu Arg Leu Gln Ile Pro Gly Leu Thr Leu Asp1 5 10 15Cys Arg Thr Ser Asn Arg Lys Ser Leu Ile Gly Asn Gly Gln Ser Pro 20 25 30Ala Leu Pro Arg Pro His Ser Pro Leu Ser Ala His Ala Gly Asn Ser 35 40 45Pro Gln Asp Ser Pro Arg Asn Phe Ser Pro Ser Ala Ser Ala His Phe 50 55 60Ser Phe Ala Arg Arg Asn Asp Arg Thr Asp Gly Arg Arg Trp Ser Leu65 70 75 80Ala Ser Leu Pro Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr 85 90 95Val Ser Ser Ser Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro Tyr 100 105 110Gln Pro Thr Pro Asp Glu Leu His Phe Leu Ser Lys His Phe Cys Thr 115 120 125Thr Glu Ser Ile Ala Thr Glu Asn Arg Cys Arg Asn Thr Pro Met Arg 130 135 140Pro Arg Ser Arg Ser Leu Ser Pro Gly Arg Ser Pro Ala Cys Cys Asp145 150 155 160His Glu Ile Ile Met Met Asn His Val Tyr Lys Glu Arg Phe Pro Lys 165 170 175Ala Thr Ala Gln Met Glu Glu Arg Leu Lys Glu Ile Ile Thr Ser Tyr 180 185 190Ser Pro Asp Asn Val Leu Pro Leu Ala Asp Gly Val Leu Ser Phe Thr 195 200 205His His Gln Ile Ile Glu Leu Ala Arg Asp Cys Leu Asp Lys Ser His 210 215 220Gln Gly Leu Ile Thr Ser Arg Tyr Phe Leu Glu Leu Gln His Lys Leu225 230 235 240Asp Lys Leu Leu Gln Glu Ala His Asp Arg Ser Glu Ser Gly Glu Leu 245 250 255Ala Phe Ile Lys Gln Leu Val Arg Lys Ile Leu Ile Val Ile Ala Arg 260 265 270Pro Ala Arg Leu Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr 275 280 285Tyr Leu Leu Glu Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly Ile 290 295 300Lys Thr Asp Ile Pro Arg Tyr Ile Ile Ser Gln Leu Gly Leu Asn Lys305 310 315 320Asp Pro Leu Glu Glu Met Ala His Leu Gly Asn Tyr Asp Ser Gly Thr 325 330 335Ala Glu Thr Pro Glu Thr Asp Glu Ser Val Ser Ser Ser Asn Ala Ser 340 345 350Leu Lys Leu Arg Arg Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile Lys 355 360 365Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Tyr Phe Val Arg His Lys 370 375 380Glu Ser Arg Gln Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu385 390 395 400Ile Leu Arg Asn Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu 405 410 415Thr Phe Ala Glu Asn Pro Phe Val Val Ser Met Tyr Cys Ser Phe Glu 420 425 430Thr Arg Arg His Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp 435 440 445Cys Ala Thr Leu Met Lys Asn Met Gly Pro Leu Pro Val Asp Met Ala 450 455 460Arg Met Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn465 470 475 480Tyr Gly Ile Val His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr 485 490 495Ser Met Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly 500 505 510Leu Met Ser Met Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp 515 520 525Ala Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile 530 535 540Ala Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp545 550 555 560Trp Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro 565 570 575Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp 580 585 590Glu Ile Asn Trp Pro Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala Gln 595 600 605Asp Leu Ile Thr Leu Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu Gly 610 615 620Thr Gly Gly Ala Tyr Glu Val Lys Gln His Arg Phe Phe Arg Ser Leu625 630 635 640Asp Trp Asn Ser Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu 645 650 655Glu Ser Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys Tyr 660 665 670His His Met Glu Thr Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp Phe 675 680 685Asn Val Glu Ile Arg Gln Phe Ser Ser Cys Ser His Arg Phe Ser Lys 690 695 700Val Phe Ser Ser Ile Asp Arg Ile Thr Gln Asn Ser Ala Glu Glu Lys705 710 715 720Glu Asp Ser Val Asp Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr Glu 725 730 735Thr Leu Ser Trp Ser Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser Thr 740 745 750Ser Asn Ser Ser Asp Thr Glu Ser Asn Arg His Lys Leu Ser Ser Gly 755 760 765Leu Leu Pro Lys Leu Ala Ile Ser Thr Glu Gly Glu Gln Asp Glu Ala 770 775 780Ala Ser Cys Pro Gly Asp Pro His Glu Glu Pro Gly Lys Pro Ala Leu785 790 795 800Pro Pro Glu Glu Cys Ala Gln Glu Glu Pro Glu Val Thr Thr Pro Ala 805 810 815Ser Thr Ile Ser Ser Ser Thr Leu Ser Val Gly Ser Phe Ser Glu His 820 825 830Leu Asp Gln Ile Asn Gly Arg Ser Glu Cys Val Asp Ser Thr Asp Asn 835 840 845Ser Ser Lys Pro Ser Ser Glu Pro Ala Ser His Met Ala Arg Gln Arg 850 855 860Leu Glu Ser Thr Glu Lys Lys Lys Ile Ser Gly Lys Val Thr Lys Ser865 870 875 880Leu Ser Ala Ser Ala Leu Ser Leu Met Ile Pro Gly Asp Met Phe Ala 885 890 895Val Ser Pro Leu Gly Ser Pro Met Ser Pro His Ser Leu Ser Ser Asp 900 905 910Pro Ser Ser Ser Arg Asp Ser Ser Pro Ser Arg Asp Ser Ser Ala Ala 915 920 925Ser Ala Ser Pro His Gln Pro Ile Val Ile His Ser Ser Gly Lys Asn 930 935 940Tyr Gly Phe Thr Ile Arg Ala Ile Arg Val Tyr Val Gly Asp Ser Asp945 950 955 960Ile Tyr Thr Val His His Ile Val Trp Asn Val Glu Glu Gly Ser Pro 965 970 975Ala Cys Gln Ala Gly Leu Lys Ala Gly Asp Leu Ile Thr His Ile Asn 980 985 990Gly Glu Pro Val His Gly Leu Val His Thr Glu Val Ile Glu Leu Leu 995 1000 1005Leu Lys Ser Gly Asn Lys Val Ser Ile Thr Thr Thr Pro Phe Glu Asn 1010 1015 1020Thr Ser Ile Lys Thr Gly Pro Ala Arg Arg Asn Ser Tyr Lys Ser Arg1025 1030 1035 1040Met Val Arg Arg Ser Lys Lys Ser Lys Lys Lys Glu Ser Leu Glu Arg 1045 1050 1055Arg Arg Ser Leu Phe Lys Lys Leu Ala Lys Gln Pro Ser Pro Leu Leu 1060 1065 1070His Thr Ser Arg Ser Phe Ser Cys Leu Asn Arg Ser Leu Ser Ser Gly 1075 1080 1085Glu Ser Leu Pro Gly Ser Pro Thr His Ser Leu Ser Pro Arg Ser Pro 1090 1095 1100Thr Pro Ser Tyr Arg Ser Thr Pro Asp Phe Pro Ser Gly Thr Asn Ser1105 1110 1115 1120Ser Gln Ser Ser Ser Pro Ser Ser Ser Ala Pro Asn Ser Pro Ala Gly 1125 1130 1135Ser Gly His Ile Arg Pro Ser Thr Leu His Gly Leu Ala Pro Lys Leu 1140 1145 1150Gly Gly Gln Arg Tyr Arg Ser Gly Arg Arg Lys Ser Ala Gly Asn Ile 1155 1160 1165Pro Leu Ser Pro Leu Ala Arg Thr Pro Ser Pro Thr Pro Gln Pro Thr 1170 1175 1180Ser Pro Gln Arg Ser Pro Ser Pro Leu Leu Gly His Ser Leu Gly Asn1185 1190 1195 1200Ser Lys Ile Ala Gln Ala Phe Pro Ser Lys Met His Ser Pro Pro Thr 1205 1210 1215Ile Val Arg His Ile Val Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser 1220 1225 1230Pro Leu Leu Lys Arg Val Gln Ser Glu Glu Lys Leu Ser Pro Ser Tyr 1235 1240 1245Gly Ser Asp Lys Lys His Leu Cys Ser Arg Lys His Ser Leu Glu Val 1250 1255 1260Thr Gln Glu Glu Val Gln Arg Glu Gln Ser Gln Arg Glu Ala Pro Leu1265 1270 1275 1280Gln Ser Leu Asp Glu Asn Val Cys Asp Val Pro Pro Leu Ser Arg Ala 1285 1290 1295Arg Pro Val Glu Gln Gly Cys Leu Lys Arg Pro Val Ser Arg Lys Val 1300 1305 1310Gly Arg Gln Glu Ser Val Asp Asp Leu Asp Arg Asp Lys Leu Lys Ala 1315 1320 1325Lys Val Val Val Lys Lys Ala Asp Gly Phe Pro Glu Lys Gln Glu Ser 1330 1335 1340His Gln Lys Ser His Gly Pro Gly Ser Asp Leu Glu Asn Phe Ala Leu1345 1350 1355 1360Phe Lys Leu Glu Glu Arg Glu Lys Lys Val Tyr Pro Lys Ala Val Glu 1365 1370 1375Arg Ser Ser Thr Phe Glu Asn Lys Ala Ser Met Gln Glu Ala Pro Pro 1380 1385 1390Leu Gly Ser Leu Leu Lys Asp Ala Leu His Lys Gln Ala Ser Val Arg 1395 1400 1405Ala Ser Glu Gly Ala Met Ser Asp Gly Arg Val Pro Ala Glu His Arg 1410 1415 1420Gln Gly Gly Gly Asp Phe Arg Arg Ala Pro Ala Pro Gly Thr Leu Gln1425 1430 1435 1440Asp Gly Leu Cys His Ser Leu Asp Arg Gly Ile Ser Gly Lys Gly Glu 1445 1450 1455Gly Thr Glu Lys Ser Ser Gln Ala Lys Glu Leu Leu Arg Cys Glu Lys 1460 1465 1470Leu Asp Ser Lys Leu Ala Asn Ile Asp Tyr Leu Arg Lys Lys Met Ser 1475 1480 1485Leu Glu Asp Lys Glu Asp Asn Leu Cys Pro Val Leu Lys Pro Lys Met 1490 1495 1500Thr Ala Gly Ser His Glu Cys Leu Pro Gly Asn Pro Val Arg Pro Thr1505 1510 1515 1520Gly Gly Gln Gln Glu Pro Pro Pro Ala Ser Glu Ser Arg Ala Phe Val 1525 1530 1535Ser Ser Thr His Ala Ala Gln Met Ser Ala Val Ser Phe Val Pro Leu 1540 1545 1550Lys Ala Leu Thr Gly Arg Val Asp Ser Gly Thr Glu Lys Pro Gly Leu 1555 1560 1565Val Ala Pro Glu Ser Pro Val Arg Lys Ser Pro Ser Glu Tyr Lys Leu 1570 1575 1580Glu Gly Arg Ser Val Ser Cys Leu Lys Pro Ile Glu Gly Thr Leu Asp1585 1590 1595 1600Ile Ala Leu Leu Ser Gly Pro Gln Ala Ser Lys Thr Glu Leu Pro Ser 1605 1610 1615Pro Glu Ser Ala Gln Ser Pro Ser Pro Ser Gly Asp Val Arg Ala Ser 1620 1625 1630Val Pro Pro Val Leu Pro Ser Ser Ser Gly Lys Lys Asn Asp Thr Thr 1635 1640 1645Ser Ala Arg Glu Leu Ser Pro Ser Ser Leu Lys Met Asn Lys Ser Tyr 1650 1655 1660Leu Leu Glu Pro Trp Phe Leu Pro Pro Ser Arg Gly Leu Gln Asn Ser1665 1670 1675 1680Pro Ala Val Ser Leu Pro Asp Pro Glu Phe Lys Arg Asp Arg Lys Gly 1685 1690 1695Pro His Pro Thr Ala Arg Ser Pro Gly Thr Val Met Glu Ser Asn Pro 1700 1705 1710Gln Gln Arg Glu Gly Ser Ser Pro Lys His Gln Asp His Thr Thr Asp 1715 1720 1725Pro Lys Leu Leu Thr Cys Leu Gly Gln Asn Leu His Ser Pro Asp Leu 1730 1735 1740Ala Arg Pro Arg Cys Pro Leu Pro Pro Glu Ala Ser Pro Ser Arg Glu1745 1750 1755 1760Lys Pro Gly Leu Arg Glu Ser Ser Glu Arg Gly Pro Pro Thr Ala Arg 1765 1770 1775Ser Glu Arg Ser Ala Ala Arg Ala Asp Thr Cys Arg Glu Pro Ser Met 1780 1785 1790Glu Leu Cys Phe Pro Glu Thr Ala Lys Thr Ser Asp Asn Ser Lys Asn 1795 1800 1805Leu Leu Ser Val Gly Arg Thr His Pro Asp Phe Tyr Thr Gln Thr Gln 1810 1815 1820Ala Met Glu Lys Ala Trp Ala Pro Gly Gly Lys Thr Asn His Lys Asp1825 1830 1835 1840Gly Pro Gly Glu Ala Arg Pro Pro Pro Arg Asp Asn Ser Ser Leu His 1845 1850 1855Ser Ala Gly Ile Pro Cys Glu Lys Glu Leu Gly Lys Val Arg Arg Gly 1860 1865 1870Val Glu Pro Lys Pro Glu Ala Leu Leu Ala Arg Arg Ser Leu Gln Pro 1875 1880 1885Pro Gly Ile Glu Ser Glu Lys Ser Glu Lys Leu Ser Ser Phe Pro Ser 1890 1895 1900Leu Gln Lys Asp Gly Ala Lys Glu Pro Glu Arg Lys Glu Gln Pro Leu1905 1910 1915 1920Gln Arg His Pro Ser Ser Ile Pro Pro Pro Pro Leu Thr Ala Lys Asp 1925 1930 1935Leu Ser Ser Pro Ala Ala Arg Gln His Cys Ser Ser Pro Ser His Ala 1940 1945 1950Ser Gly Arg Glu Pro Gly Ala Lys Pro Ser Thr Ala Glu Pro Ser Ser 1955 1960 1965Ser Pro Gln Asp Pro Pro Lys Pro Val Ala Ala His Ser Glu Ser Ser 1970 1975 1980Ser His Lys Pro Arg Pro Gly Pro Asp Pro Gly Pro Pro Lys Thr Lys1985 1990 1995 2000His Pro Asp Arg Ser Leu Ser Ser Gln Lys Pro Ser Val Gly Ala Thr 2005 2010 2015Lys Gly Lys Glu Pro Ala Thr Gln Ser Leu Gly Gly Ser Ser Arg Glu 2020 2025 2030Gly Lys Gly His Ser Lys Ser Gly Pro Asp Val Phe Pro Ala Thr Pro 2035 2040 2045Gly Ser Gln Asn Lys Ala Ser Asp Gly Ile Gly Gln Gly Glu Gly Gly 2050 2055 2060Pro Ser Val Pro Leu His Thr Asp Arg Ala Pro Leu Asp Ala Lys Pro2065 2070

2075 2080Gln Pro Thr Ser Gly Gly Arg Pro Leu Glu Val Leu Glu Lys Pro Val 2085 2090 2095His Leu Pro Arg Pro Gly His Pro Gly Pro Ser Glu Pro Ala Asp Gln 2100 2105 2110Lys Leu Ser Ala Val Gly Glu Lys Gln Thr Leu Ser Pro Lys His Pro 2115 2120 2125Lys Pro Ser Thr Val Lys Asp Cys Pro Thr Leu Cys Lys Gln Thr Asp 2130 2135 2140Asn Arg Gln Thr Asp Lys Ser Pro Ser Gln Pro Ala Ala Asn Thr Asp2145 2150 2155 2160Arg Arg Ala Glu Gly Lys Lys Cys Thr Glu Ala Leu Tyr Ala Pro Ala 2165 2170 2175Glu Gly Asp Lys Leu Glu Ala Gly Leu Ser Phe Val His Ser Glu Asn 2180 2185 2190Arg Leu Lys Gly Ala Glu Arg Pro Ala Ala Gly Val Gly Lys Gly Phe 2195 2200 2205Pro Glu Ala Arg Gly Lys Gly Pro Gly Pro Gln Lys Pro Pro Thr Glu 2210 2215 2220Ala Asp Lys Pro Asn Gly Met Lys Arg Ser Pro Ser Ala Thr Gly Gln2225 2230 2235 2240Ser Ser Phe Arg Ser Thr Ala Leu Pro Glu Lys Ser Leu Ser Cys Ser 2245 2250 2255Ser Ser Phe Pro Glu Thr Arg Ala Gly Val Arg Glu Ala Ser Ala Ala 2260 2265 2270Ser Ser Asp Thr Ser Ser Ala Lys Ala Ala Gly Gly Met Leu Glu Leu 2275 2280 2285Pro Ala Pro Ser Asn Arg Asp His Arg Lys Ala Gln Pro Ala Gly Glu 2290 2295 2300Gly Arg Thr His Met Thr Lys Ser Asp Ser Leu Pro Ser Phe Arg Val2305 2310 2315 2320Ser Thr Leu Pro Leu Glu Ser His His Pro Asp Pro Asn Thr Met Gly 2325 2330 2335Gly Ala Ser His Arg Asp Arg Ala Leu Ser Val Thr Ala Thr Val Gly 2340 2345 2350Glu Thr Lys Gly Lys Asp Pro Ala Pro Ala Gln Pro Pro Pro Ala Arg 2355 2360 2365Lys Gln Asn Val Gly Arg Asp Val Thr Lys Pro Ser Pro Ala Pro Asn 2370 2375 2380Thr Asp Arg Pro Ile Ser Leu Ser Asn Glu Lys Asp Phe Val Val Arg2385 2390 2395 2400Gln Arg Arg Gly Lys Glu Ser Leu Arg Ser Ser Pro His Lys Lys Ala 2405 2410 2415Leu52362PRTHomo sapiens 5Met Asp Met Ser Asp Pro Asn Phe Trp Thr Val Leu Ser Asn Phe Thr1 5 10 15Leu Pro His Leu Arg Ser Gly Asn Arg Leu Arg Arg Thr Gln Ser Cys 20 25 30Arg Thr Ser Asn Arg Lys Ser Leu Ile Gly Asn Gly Gln Ser Pro Ala 35 40 45Leu Pro Arg Pro His Ser Pro Leu Ser Ala His Ala Gly Asn Ser Pro 50 55 60Gln Asp Ser Pro Arg Asn Phe Ser Pro Ser Ala Ser Ala His Phe Ser65 70 75 80Phe Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser Leu Ala Ser Leu Pro 85 90 95Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr Val Ser Ser Ser 100 105 110Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro Tyr Gln Pro Thr Pro 115 120 125Asp Glu Leu His Phe Leu Ser Lys His Phe Cys Thr Thr Glu Ser Ile 130 135 140Ala Thr Glu Asn Arg Cys Arg Asn Thr Pro Met Arg Pro Arg Ser Arg145 150 155 160Ser Leu Ser Pro Gly Arg Ser Pro Ala Cys Cys Asp His Glu Ile Ile 165 170 175Met Met Asn His Val Tyr Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln 180 185 190Met Glu Glu Arg Leu Lys Glu Ile Ile Thr Ser Tyr Ser Pro Asp Asn 195 200 205Val Leu Pro Leu Ala Asp Gly Val Leu Ser Phe Thr His His Gln Ile 210 215 220Ile Glu Leu Ala Arg Asp Cys Leu Asp Lys Ser His Gln Gly Leu Ile225 230 235 240Thr Ser Arg Tyr Phe Leu Glu Leu Gln His Lys Leu Asp Lys Leu Leu 245 250 255Gln Glu Ala His Asp Arg Ser Glu Ser Gly Glu Leu Ala Phe Ile Lys 260 265 270Gln Leu Val Arg Lys Ile Leu Ile Val Ile Ala Arg Pro Ala Arg Leu 275 280 285Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr Tyr Leu Leu Glu 290 295 300Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly Ile Lys Thr Asp Ile305 310 315 320Pro Arg Tyr Ile Ile Ser Gln Leu Gly Leu Asn Lys Asp Pro Leu Glu 325 330 335Glu Met Ala His Leu Gly Asn Tyr Asp Ser Gly Thr Ala Glu Thr Pro 340 345 350Glu Thr Asp Glu Ser Val Ser Ser Ser Asn Ala Ser Leu Lys Leu Arg 355 360 365Arg Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn 370 375 380Gly Ala Tyr Gly Ala Val Tyr Phe Val Arg His Lys Glu Ser Arg Gln385 390 395 400Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn 405 410 415Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu 420 425 430Asn Pro Phe Val Val Ser Met Tyr Cys Ser Phe Glu Thr Arg Arg His 435 440 445Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu 450 455 460Met Lys Asn Met Gly Pro Leu Pro Val Asp Met Ala Arg Met Tyr Phe465 470 475 480Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val 485 490 495His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr Ser Met Gly His 500 505 510Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly Leu Met Ser Met 515 520 525Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe 530 535 540Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro Glu Val545 550 555 560Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala Met Gly 565 570 575Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp 580 585 590Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Ile Asn Trp 595 600 605Pro Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala Gln Asp Leu Ile Thr 610 615 620Leu Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu Gly Thr Gly Gly Ala625 630 635 640Tyr Glu Val Lys Gln His Arg Phe Phe Arg Ser Leu Asp Trp Asn Ser 645 650 655Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp 660 665 670Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys Tyr His His Met Glu 675 680 685Thr Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp Phe Asn Val Glu Ile 690 695 700Arg Gln Phe Ser Ser Cys Ser His Arg Phe Ser Lys Val Phe Ser Ser705 710 715 720Ile Asp Arg Ile Thr Gln Asn Ser Ala Glu Glu Lys Glu Asp Ser Val 725 730 735Asp Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr Glu Thr Leu Ser Trp 740 745 750Ser Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser Thr Ser Asn Ser Ser 755 760 765Asp Thr Glu Ser Asn Arg His Lys Leu Ser Ser Gly Leu Leu Pro Lys 770 775 780Leu Ala Ile Ser Thr Glu Gly Glu Gln Asp Glu Ala Ala Ser Cys Pro785 790 795 800Gly Asp Pro His Glu Glu Pro Gly Lys Pro Ala Leu Pro Pro Glu Glu 805 810 815Cys Ala Gln Glu Glu Pro Glu Val Thr Thr Pro Ala Ser Thr Ile Ser 820 825 830Ser Ser Thr Leu Ser Asp Met Phe Ala Val Ser Pro Leu Gly Ser Pro 835 840 845Met Ser Pro His Ser Leu Ser Ser Asp Pro Ser Ser Ser Arg Asp Ser 850 855 860Ser Pro Ser Arg Asp Ser Ser Ala Ala Ser Ala Ser Pro His Gln Pro865 870 875 880Ile Val Ile His Ser Ser Gly Lys Asn Tyr Gly Phe Thr Ile Arg Ala 885 890 895Ile Arg Val Tyr Val Gly Asp Ser Asp Ile Tyr Thr Val His His Ile 900 905 910Val Trp Asn Val Glu Glu Gly Ser Pro Ala Cys Gln Ala Gly Leu Lys 915 920 925Ala Gly Asp Leu Ile Thr His Ile Asn Gly Glu Pro Val His Gly Leu 930 935 940Val His Thr Glu Val Ile Glu Leu Leu Leu Lys Ser Gly Asn Lys Val945 950 955 960Ser Ile Thr Thr Thr Pro Phe Glu Asn Thr Ser Ile Lys Thr Gly Pro 965 970 975Ala Arg Arg Asn Ser Tyr Lys Ser Arg Met Val Arg Arg Ser Lys Lys 980 985 990Ser Lys Lys Lys Glu Ser Leu Glu Arg Arg Arg Ser Leu Phe Lys Lys 995 1000 1005Leu Ala Lys Gln Pro Ser Pro Leu Leu His Thr Ser Arg Ser Phe Ser 1010 1015 1020Cys Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser Leu Pro Gly Ser Pro1025 1030 1035 1040Thr His Ser Leu Ser Pro Arg Ser Pro Thr Pro Ser Tyr Arg Ser Thr 1045 1050 1055Pro Asp Phe Pro Ser Gly Thr Asn Ser Ser Gln Ser Ser Ser Pro Ser 1060 1065 1070Ser Ser Ala Pro Asn Ser Pro Ala Gly Ser Gly His Ile Arg Pro Ser 1075 1080 1085Thr Leu His Gly Leu Ala Pro Lys Leu Gly Gly Gln Arg Tyr Arg Ser 1090 1095 1100Gly Arg Arg Lys Ser Ala Gly Asn Ile Pro Leu Ser Pro Leu Ala Arg1105 1110 1115 1120Thr Pro Ser Pro Thr Pro Gln Pro Thr Ser Pro Gln Arg Ser Pro Ser 1125 1130 1135Pro Leu Leu Gly His Ser Leu Gly Asn Ser Lys Ile Ala Gln Ala Phe 1140 1145 1150Pro Ser Lys Met His Ser Pro Pro Thr Ile Val Arg His Ile Val Arg 1155 1160 1165Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu Leu Lys Arg Val Gln 1170 1175 1180Ser Glu Glu Lys Leu Ser Pro Ser Tyr Gly Ser Asp Lys Lys His Leu1185 1190 1195 1200Cys Ser Arg Lys His Ser Leu Glu Val Thr Gln Glu Glu Val Gln Arg 1205 1210 1215Glu Gln Ser Gln Arg Glu Ala Pro Leu Gln Ser Leu Asp Glu Asn Val 1220 1225 1230Cys Asp Val Pro Pro Leu Ser Arg Ala Arg Pro Val Glu Gln Gly Cys 1235 1240 1245Leu Lys Arg Pro Val Ser Arg Lys Val Gly Arg Gln Glu Ser Val Asp 1250 1255 1260Asp Leu Asp Arg Asp Lys Leu Lys Ala Lys Val Val Val Lys Lys Ala1265 1270 1275 1280Asp Gly Phe Pro Glu Lys Gln Glu Ser His Gln Lys Ser His Gly Pro 1285 1290 1295Gly Ser Asp Leu Glu Asn Phe Ala Leu Phe Lys Leu Glu Glu Arg Glu 1300 1305 1310Lys Lys Val Tyr Pro Lys Ala Val Glu Arg Ser Ser Thr Phe Glu Asn 1315 1320 1325Lys Ala Ser Met Gln Glu Ala Pro Pro Leu Gly Ser Leu Leu Lys Asp 1330 1335 1340Ala Leu His Lys Gln Ala Ser Val Arg Ala Ser Glu Gly Ala Met Ser1345 1350 1355 1360Asp Gly Arg Val Pro Ala Glu His Arg Gln Gly Gly Gly Asp Phe Arg 1365 1370 1375Arg Ala Pro Ala Pro Gly Thr Leu Gln Asp Gly Leu Cys His Ser Leu 1380 1385 1390Asp Arg Gly Ile Ser Gly Lys Gly Glu Gly Thr Glu Lys Ser Ser Gln 1395 1400 1405Ala Lys Glu Leu Leu Arg Cys Glu Lys Leu Asp Ser Lys Leu Ala Asn 1410 1415 1420Ile Asp Tyr Leu Arg Lys Lys Met Ser Leu Glu Asp Lys Glu Asp Asn1425 1430 1435 1440Leu Cys Pro Val Leu Lys Pro Lys Met Thr Ala Gly Ser His Glu Cys 1445 1450 1455Leu Pro Gly Asn Pro Val Arg Pro Thr Gly Gly Gln Gln Glu Pro Pro 1460 1465 1470Pro Ala Ser Glu Ser Arg Ala Phe Val Ser Ser Thr His Ala Ala Gln 1475 1480 1485Met Ser Ala Val Ser Phe Val Pro Leu Lys Ala Leu Thr Gly Arg Val 1490 1495 1500Asp Ser Gly Thr Glu Lys Pro Gly Leu Val Ala Pro Glu Ser Pro Val1505 1510 1515 1520Arg Lys Ser Pro Ser Glu Tyr Lys Leu Glu Gly Arg Ser Val Ser Cys 1525 1530 1535Leu Lys Pro Ile Glu Gly Thr Leu Asp Ile Ala Leu Leu Ser Gly Pro 1540 1545 1550Gln Ala Ser Lys Thr Glu Leu Pro Ser Pro Glu Ser Ala Gln Ser Pro 1555 1560 1565Ser Pro Ser Gly Asp Val Arg Ala Ser Val Pro Pro Val Leu Pro Ser 1570 1575 1580Ser Ser Gly Lys Lys Asn Asp Thr Thr Ser Ala Arg Glu Leu Ser Pro1585 1590 1595 1600Ser Ser Leu Lys Met Asn Lys Ser Tyr Leu Leu Glu Pro Trp Phe Leu 1605 1610 1615Pro Pro Ser Arg Gly Leu Gln Asn Ser Pro Ala Val Ser Leu Pro Asp 1620 1625 1630Pro Glu Phe Lys Arg Asp Arg Lys Gly Pro His Pro Thr Ala Arg Ser 1635 1640 1645Pro Gly Thr Val Met Glu Ser Asn Pro Gln Gln Arg Glu Gly Ser Ser 1650 1655 1660Pro Lys His Gln Asp His Thr Thr Asp Pro Lys Leu Leu Thr Cys Leu1665 1670 1675 1680Gly Gln Asn Leu His Ser Pro Asp Leu Ala Arg Pro Arg Cys Pro Leu 1685 1690 1695Pro Pro Glu Ala Ser Pro Ser Arg Glu Lys Pro Gly Leu Arg Glu Ser 1700 1705 1710Ser Glu Arg Gly Pro Pro Thr Ala Arg Ser Glu Arg Ser Ala Ala Arg 1715 1720 1725Ala Asp Thr Cys Arg Glu Pro Ser Met Glu Leu Cys Phe Pro Glu Thr 1730 1735 1740Ala Lys Thr Ser Asp Asn Ser Lys Asn Leu Leu Ser Val Gly Arg Thr1745 1750 1755 1760His Pro Asp Phe Tyr Thr Gln Thr Gln Ala Met Glu Lys Ala Trp Ala 1765 1770 1775Pro Gly Gly Lys Thr Asn His Lys Asp Gly Pro Gly Glu Ala Arg Pro 1780 1785 1790Pro Pro Arg Asp Asn Ser Ser Leu His Ser Ala Gly Ile Pro Cys Glu 1795 1800 1805Lys Glu Leu Gly Lys Val Arg Arg Gly Val Glu Pro Lys Pro Glu Ala 1810 1815 1820Leu Leu Ala Arg Arg Ser Leu Gln Pro Pro Gly Ile Glu Ser Glu Lys1825 1830 1835 1840Ser Glu Lys Leu Ser Ser Phe Pro Ser Leu Gln Lys Asp Gly Ala Lys 1845 1850 1855Glu Pro Glu Arg Lys Glu Gln Pro Leu Gln Arg His Pro Ser Ser Ile 1860 1865 1870Pro Pro Pro Pro Leu Thr Ala Lys Asp Leu Ser Ser Pro Ala Ala Arg 1875 1880 1885Gln His Cys Ser Ser Pro Ser His Ala Ser Gly Arg Glu Pro Gly Ala 1890 1895 1900Lys Pro Ser Thr Ala Glu Pro Ser Ser Ser Pro Gln Asp Pro Pro Lys1905 1910 1915 1920Pro Val Ala Ala His Ser Glu Ser Ser Ser His Lys Pro Arg Pro Gly 1925 1930 1935Pro Asp Pro Gly Pro Pro Lys Thr Lys His Pro Asp Arg Ser Leu Ser 1940 1945 1950Ser Gln Lys Pro Ser Val Gly Ala Thr Lys Gly Lys Glu Pro Ala Thr 1955 1960 1965Gln Ser Leu Gly Gly Ser Ser Arg Glu Gly Lys Gly His Ser Lys Ser 1970 1975 1980Gly Pro Asp Val Phe Pro Ala Thr Pro Gly Ser Gln Asn Lys Ala Ser1985 1990 1995 2000Asp Gly Ile Gly Gln Gly Glu Gly Gly Pro Ser Val Pro Leu His Thr 2005 2010 2015Asp Arg Ala Pro Leu Asp Ala Lys Pro Gln Pro Thr Ser Gly Gly Arg 2020 2025 2030Pro Leu Glu Val Leu Glu Lys Pro Val His Leu Pro Arg Pro Gly His 2035 2040 2045Pro Gly Pro Ser Glu Pro Ala Asp Gln Lys Leu Ser Ala Val Gly Glu 2050 2055 2060Lys Gln Thr Leu Ser Pro Lys His Pro Lys Pro Ser Thr Val Lys Asp2065 2070 2075 2080Cys Pro Thr Leu Cys Lys Gln Thr Asp Asn Arg Gln Thr Asp Lys Ser 2085 2090 2095Pro Ser Gln Pro Ala Ala Asn Thr Asp Arg Arg Ala Glu Gly Lys Lys 2100 2105 2110Cys Thr Glu Ala Leu Tyr Ala Pro Ala Glu Gly Asp Lys Leu

Glu Ala 2115 2120 2125Gly Leu Ser Phe Val His Ser Glu Asn Arg Leu Lys Gly Ala Glu Arg 2130 2135 2140Pro Ala Ala Gly Val Gly Lys Gly Phe Pro Glu Ala Arg Gly Lys Gly2145 2150 2155 2160Pro Gly Pro Gln Lys Pro Pro Thr Glu Ala Asp Lys Pro Asn Gly Met 2165 2170 2175Lys Arg Ser Pro Ser Ala Thr Gly Gln Ser Ser Phe Arg Ser Thr Ala 2180 2185 2190Leu Pro Glu Lys Ser Leu Ser Cys Ser Ser Ser Phe Pro Glu Thr Arg 2195 2200 2205Ala Gly Val Arg Glu Ala Ser Ala Ala Ser Ser Asp Thr Ser Ser Ala 2210 2215 2220Lys Ala Ala Gly Gly Met Leu Glu Leu Pro Ala Pro Ser Asn Arg Asp2225 2230 2235 2240His Arg Lys Ala Gln Pro Ala Gly Glu Gly Arg Thr His Met Thr Lys 2245 2250 2255Ser Asp Ser Leu Pro Ser Phe Arg Val Ser Thr Leu Pro Leu Glu Ser 2260 2265 2270His His Pro Asp Pro Asn Thr Met Gly Gly Ala Ser His Arg Asp Arg 2275 2280 2285Ala Leu Ser Val Thr Ala Thr Val Gly Glu Thr Lys Gly Lys Asp Pro 2290 2295 2300Ala Pro Ala Gln Pro Pro Pro Ala Arg Lys Gln Asn Val Gly Arg Asp2305 2310 2315 2320Val Thr Lys Pro Ser Pro Ala Pro Asn Thr Asp Arg Pro Ile Ser Leu 2325 2330 2335Ser Asn Glu Lys Asp Phe Val Val Arg Gln Arg Arg Gly Lys Glu Ser 2340 2345 2350Leu Arg Ser Ser Pro His Lys Lys Ala Leu 2355 23606238PRTHomo sapiens 6Met Gly Glu Lys Val Ser Glu Ala Pro Glu Pro Val Pro Arg Gly Cys1 5 10 15Ser Gly His Gly Ser Arg Thr Pro Ala Ser Ala Leu Val Ala Ala Ser 20 25 30Ser Pro Gly Ala Ser Ser Ala Glu Ser Ser Ser Gly Ser Glu Thr Leu 35 40 45Ser Glu Glu Gly Glu Pro Gly Gly Phe Ser Arg Glu His Gln Pro Pro 50 55 60Pro Pro Pro Pro Leu Gly Gly Thr Leu Gly Ala Arg Ala Pro Ala Ala65 70 75 80Trp Ala Pro Ala Ser Val Leu Leu Glu Arg Gly Val Leu Ala Leu Pro 85 90 95Pro Pro Leu Pro Gly Gly Ala Val Pro Pro Ala Pro Arg Gly Ser Ser 100 105 110Ala Ser Gln Glu Glu Gln Asp Glu Glu Leu Asp His Ile Leu Ser Pro 115 120 125Pro Pro Met Pro Phe Arg Lys Cys Ser Asn Pro Asp Val Ala Ser Gly 130 135 140Pro Gly Lys Ser Leu Lys Tyr Lys Arg Gln Leu Ser Glu Asp Gly Arg145 150 155 160Gln Leu Arg Arg Gly Ser Leu Gly Gly Ala Leu Thr Gly Arg Tyr Leu 165 170 175Leu Pro Asn Pro Val Ala Gly Gln Ala Trp Pro Ala Ser Ala Glu Thr 180 185 190Ser Asn Leu Val Arg Met Arg Ser Gln Ala Leu Gly Gln Ser Ala Pro 195 200 205Ser Leu Thr Ala Ser Leu Lys Glu Leu Ser Leu Pro Arg Arg Gly Ser 210 215 220Phe Pro Val Cys Pro Asn Ala Gly Arg Thr Ser Pro Leu Gly225 230 23572429PRTHomo sapiens 7Met Asp Met Ser Asp Pro Asn Phe Trp Thr Val Leu Ser Asn Phe Thr1 5 10 15Leu Pro His Leu Arg Ser Gly Asn Arg Leu Arg Arg Thr Gln Ser Cys 20 25 30Arg Thr Ser Asn Arg Lys Ser Leu Ile Gly Asn Gly Gln Ser Pro Ala 35 40 45Leu Pro Arg Pro His Ser Pro Leu Ser Ala His Ala Gly Asn Ser Pro 50 55 60Gln Asp Ser Pro Arg Asn Phe Ser Pro Ser Ala Ser Ala His Phe Ser65 70 75 80Phe Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser Leu Ala Ser Leu Pro 85 90 95Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr Val Ser Ser Ser 100 105 110Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro Tyr Gln Pro Thr Pro 115 120 125Asp Glu Leu His Phe Leu Ser Lys His Phe Cys Thr Thr Glu Ser Ile 130 135 140Ala Thr Glu Asn Arg Cys Arg Asn Thr Pro Met Arg Pro Arg Ser Arg145 150 155 160Ser Leu Ser Pro Gly Arg Ser Pro Ala Cys Cys Asp His Glu Ile Ile 165 170 175Met Met Asn His Val Tyr Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln 180 185 190Met Glu Glu Arg Leu Lys Glu Ile Ile Thr Ser Tyr Ser Pro Asp Asn 195 200 205Val Leu Pro Leu Ala Asp Gly Val Leu Ser Phe Thr His His Gln Ile 210 215 220Ile Glu Leu Ala Arg Asp Cys Leu Asp Lys Ser His Gln Gly Leu Ile225 230 235 240Thr Ser Arg Tyr Phe Leu Glu Leu Gln His Lys Leu Asp Lys Leu Leu 245 250 255Gln Glu Ala His Asp Arg Ser Glu Ser Gly Glu Leu Ala Phe Ile Lys 260 265 270Gln Leu Val Arg Lys Ile Leu Ile Val Ile Ala Arg Pro Ala Arg Leu 275 280 285Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr Tyr Leu Leu Glu 290 295 300Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly Ile Lys Thr Asp Ile305 310 315 320Pro Arg Tyr Ile Ile Ser Gln Leu Gly Leu Asn Lys Asp Pro Leu Glu 325 330 335Glu Met Ala His Leu Gly Asn Tyr Asp Ser Gly Thr Ala Glu Thr Pro 340 345 350Glu Thr Asp Glu Ser Val Ser Ser Ser Asn Ala Ser Leu Lys Leu Arg 355 360 365Arg Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn 370 375 380Gly Ala Tyr Gly Ala Val Tyr Phe Val Arg His Lys Glu Ser Arg Gln385 390 395 400Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn 405 410 415Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu 420 425 430Asn Pro Phe Val Val Ser Met Tyr Cys Ser Phe Glu Thr Arg Arg His 435 440 445Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu 450 455 460Met Lys Asn Met Gly Pro Leu Pro Val Asp Met Ala Arg Met Tyr Phe465 470 475 480Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val 485 490 495His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr Ser Met Gly His 500 505 510Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly Leu Met Ser Met 515 520 525Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe 530 535 540Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro Glu Val545 550 555 560Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala Met Gly 565 570 575Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp 580 585 590Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Ile Asn Trp 595 600 605Pro Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala Gln Asp Leu Ile Thr 610 615 620Leu Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu Gly Thr Gly Gly Ala625 630 635 640Tyr Glu Val Lys Gln His Arg Phe Phe Arg Ser Leu Asp Trp Asn Ser 645 650 655Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp 660 665 670Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys Tyr His His Met Glu 675 680 685Thr Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp Phe Asn Val Glu Ile 690 695 700Arg Gln Phe Ser Ser Cys Ser His Arg Phe Ser Lys Val Phe Ser Ser705 710 715 720Ile Asp Arg Ile Thr Gln Asn Ser Ala Glu Glu Lys Glu Asp Ser Val 725 730 735Asp Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr Glu Thr Leu Ser Trp 740 745 750Ser Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser Thr Ser Asn Ser Ser 755 760 765Asp Thr Glu Ser Asn Arg His Lys Leu Ser Ser Gly Leu Leu Pro Lys 770 775 780Leu Ala Ile Ser Thr Glu Gly Glu Gln Asp Glu Ala Ala Ser Cys Pro785 790 795 800Gly Asp Pro His Glu Glu Pro Gly Lys Pro Ala Leu Pro Pro Glu Glu 805 810 815Cys Ala Gln Glu Glu Pro Glu Val Thr Thr Pro Ala Ser Thr Ile Ser 820 825 830Ser Ser Thr Leu Ser Val Gly Ser Phe Ser Glu His Leu Asp Gln Ile 835 840 845Asn Gly Arg Ser Glu Cys Val Asp Ser Thr Asp Asn Ser Ser Lys Pro 850 855 860Ser Ser Glu Pro Ala Ser His Met Ala Arg Gln Arg Leu Glu Ser Thr865 870 875 880Glu Lys Lys Lys Ile Ser Gly Lys Val Thr Lys Ser Leu Ser Ala Ser 885 890 895Ala Leu Ser Leu Met Ile Pro Gly Asp Met Phe Ala Val Ser Pro Leu 900 905 910Gly Ser Pro Met Ser Pro His Ser Leu Ser Ser Asp Pro Ser Ser Ser 915 920 925Arg Asp Ser Ser Pro Ser Arg Asp Ser Ser Ala Ala Ser Ala Ser Pro 930 935 940His Gln Pro Ile Val Ile His Ser Ser Gly Lys Asn Tyr Gly Phe Thr945 950 955 960Ile Arg Ala Ile Arg Val Tyr Val Gly Asp Ser Asp Ile Tyr Thr Val 965 970 975His His Ile Val Trp Asn Val Glu Glu Gly Ser Pro Ala Cys Gln Ala 980 985 990Gly Leu Lys Ala Gly Asp Leu Ile Thr His Ile Asn Gly Glu Pro Val 995 1000 1005His Gly Leu Val His Thr Glu Val Ile Glu Leu Leu Leu Lys Ser Gly 1010 1015 1020Asn Lys Val Ser Ile Thr Thr Thr Pro Phe Glu Asn Thr Ser Ile Lys1025 1030 1035 1040Thr Gly Pro Ala Arg Arg Asn Ser Tyr Lys Ser Arg Met Val Arg Arg 1045 1050 1055Ser Lys Lys Ser Lys Lys Lys Glu Ser Leu Glu Arg Arg Arg Ser Leu 1060 1065 1070Phe Lys Lys Leu Ala Lys Gln Pro Ser Pro Leu Leu His Thr Ser Arg 1075 1080 1085Ser Phe Ser Cys Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser Leu Pro 1090 1095 1100Gly Ser Pro Thr His Ser Leu Ser Pro Arg Ser Pro Thr Pro Ser Tyr1105 1110 1115 1120Arg Ser Thr Pro Asp Phe Pro Ser Gly Thr Asn Ser Ser Gln Ser Ser 1125 1130 1135Ser Pro Ser Ser Ser Ala Pro Asn Ser Pro Ala Gly Ser Gly His Ile 1140 1145 1150Arg Pro Ser Thr Leu His Gly Leu Ala Pro Lys Leu Gly Gly Gln Arg 1155 1160 1165Tyr Arg Ser Gly Arg Arg Lys Ser Ala Gly Asn Ile Pro Leu Ser Pro 1170 1175 1180Leu Ala Arg Thr Pro Ser Pro Thr Pro Gln Pro Thr Ser Pro Gln Arg1185 1190 1195 1200Ser Pro Ser Pro Leu Leu Gly His Ser Leu Gly Asn Ser Lys Ile Ala 1205 1210 1215Gln Ala Phe Pro Ser Lys Met His Ser Pro Pro Thr Ile Val Arg His 1220 1225 1230Ile Val Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu Leu Lys 1235 1240 1245Arg Val Gln Ser Glu Glu Lys Leu Ser Pro Ser Tyr Gly Ser Asp Lys 1250 1255 1260Lys His Leu Cys Ser Arg Lys His Ser Leu Glu Val Thr Gln Glu Glu1265 1270 1275 1280Val Gln Arg Glu Gln Ser Gln Arg Glu Ala Pro Leu Gln Ser Leu Asp 1285 1290 1295Glu Asn Val Cys Asp Val Pro Pro Leu Ser Arg Ala Arg Pro Val Glu 1300 1305 1310Gln Gly Cys Leu Lys Arg Pro Val Ser Arg Lys Val Gly Arg Gln Glu 1315 1320 1325Ser Val Asp Asp Leu Asp Arg Asp Lys Leu Lys Ala Lys Val Val Val 1330 1335 1340Lys Lys Ala Asp Gly Phe Pro Glu Lys Gln Glu Ser His Gln Lys Ser1345 1350 1355 1360His Gly Pro Gly Ser Asp Leu Glu Asn Phe Ala Leu Phe Lys Leu Glu 1365 1370 1375Glu Arg Glu Lys Lys Val Tyr Pro Lys Ala Val Glu Arg Ser Ser Thr 1380 1385 1390Phe Glu Asn Lys Ala Ser Met Gln Glu Ala Pro Pro Leu Gly Ser Leu 1395 1400 1405Leu Lys Asp Ala Leu His Lys Gln Ala Ser Val Arg Ala Ser Glu Gly 1410 1415 1420Ala Met Ser Asp Gly Arg Val Pro Ala Glu His Arg Gln Gly Gly Gly1425 1430 1435 1440Asp Phe Arg Arg Ala Pro Ala Pro Gly Thr Leu Gln Asp Gly Leu Cys 1445 1450 1455His Ser Leu Asp Arg Gly Ile Ser Gly Lys Gly Glu Gly Thr Glu Lys 1460 1465 1470Ser Ser Gln Ala Lys Glu Leu Leu Arg Cys Glu Lys Leu Asp Ser Lys 1475 1480 1485Leu Ala Asn Ile Asp Tyr Leu Arg Lys Lys Met Ser Leu Glu Asp Lys 1490 1495 1500Glu Asp Asn Leu Cys Pro Val Leu Lys Pro Lys Met Thr Ala Gly Ser1505 1510 1515 1520His Glu Cys Leu Pro Gly Asn Pro Val Arg Pro Thr Gly Gly Gln Gln 1525 1530 1535Glu Pro Pro Pro Ala Ser Glu Ser Arg Ala Phe Val Ser Ser Thr His 1540 1545 1550Ala Ala Gln Met Ser Ala Val Ser Phe Val Pro Leu Lys Ala Leu Thr 1555 1560 1565Gly Arg Val Asp Ser Gly Thr Glu Lys Pro Gly Leu Val Ala Pro Glu 1570 1575 1580Ser Pro Val Arg Lys Ser Pro Ser Glu Tyr Lys Leu Glu Gly Arg Ser1585 1590 1595 1600Val Ser Cys Leu Lys Pro Ile Glu Gly Thr Leu Asp Ile Ala Leu Leu 1605 1610 1615Ser Gly Pro Gln Ala Ser Lys Thr Glu Leu Pro Ser Pro Glu Ser Ala 1620 1625 1630Gln Ser Pro Ser Pro Ser Gly Asp Val Arg Ala Ser Val Pro Pro Val 1635 1640 1645Leu Pro Ser Ser Ser Gly Lys Lys Asn Asp Thr Thr Ser Ala Arg Glu 1650 1655 1660Leu Ser Pro Ser Ser Leu Lys Met Asn Lys Ser Tyr Leu Leu Glu Pro1665 1670 1675 1680Trp Phe Leu Pro Pro Ser Arg Gly Leu Gln Asn Ser Pro Ala Val Ser 1685 1690 1695Leu Pro Asp Pro Glu Phe Lys Arg Asp Arg Lys Gly Pro His Pro Thr 1700 1705 1710Ala Arg Ser Pro Gly Thr Val Met Glu Ser Asn Pro Gln Gln Arg Glu 1715 1720 1725Gly Ser Ser Pro Lys His Gln Asp His Thr Thr Asp Pro Lys Leu Leu 1730 1735 1740Thr Cys Leu Gly Gln Asn Leu His Ser Pro Asp Leu Ala Arg Pro Arg1745 1750 1755 1760Cys Pro Leu Pro Pro Glu Ala Ser Pro Ser Arg Glu Lys Pro Gly Leu 1765 1770 1775Arg Glu Ser Ser Glu Arg Gly Pro Pro Thr Ala Arg Ser Glu Arg Ser 1780 1785 1790Ala Ala Arg Ala Asp Thr Cys Arg Glu Pro Ser Met Glu Leu Cys Phe 1795 1800 1805Pro Glu Thr Ala Lys Thr Ser Asp Asn Ser Lys Asn Leu Leu Ser Val 1810 1815 1820Gly Arg Thr His Pro Asp Phe Tyr Thr Gln Thr Gln Ala Met Glu Lys1825 1830 1835 1840Ala Trp Ala Pro Gly Gly Lys Thr Asn His Lys Asp Gly Pro Gly Glu 1845 1850 1855Ala Arg Pro Pro Pro Arg Asp Asn Ser Ser Leu His Ser Ala Gly Ile 1860 1865 1870Pro Cys Glu Lys Glu Leu Gly Lys Val Arg Arg Gly Val Glu Pro Lys 1875 1880 1885Pro Glu Ala Leu Leu Ala Arg Arg Ser Leu Gln Pro Pro Gly Ile Glu 1890 1895 1900Ser Glu Lys Ser Glu Lys Leu Ser Ser Phe Pro Ser Leu Gln Lys Asp1905 1910 1915 1920Gly Ala Lys Glu Pro Glu Arg Lys Glu Gln Pro Leu Gln Arg His Pro 1925 1930 1935Ser Ser Ile Pro Pro Pro Pro Leu Thr Ala Lys Asp Leu Ser Ser Pro 1940 1945 1950Ala Ala Arg Gln His Cys Ser Ser Pro Ser His Ala Ser Gly Arg Glu 1955 1960 1965Pro Gly Ala Lys Pro Ser Thr Ala Glu Pro Ser Ser Ser Pro Gln Asp 1970 1975 1980Pro

Pro Lys Pro Val Ala Ala His Ser Glu Ser Ser Ser His Lys Pro1985 1990 1995 2000Arg Pro Gly Pro Asp Pro Gly Pro Pro Lys Thr Lys His Pro Asp Arg 2005 2010 2015Ser Leu Ser Ser Gln Lys Pro Ser Val Gly Ala Thr Lys Gly Lys Glu 2020 2025 2030Pro Ala Thr Gln Ser Leu Gly Gly Ser Ser Arg Glu Gly Lys Gly His 2035 2040 2045Ser Lys Ser Gly Pro Asp Val Phe Pro Ala Thr Pro Gly Ser Gln Asn 2050 2055 2060Lys Ala Ser Asp Gly Ile Gly Gln Gly Glu Gly Gly Pro Ser Val Pro2065 2070 2075 2080Leu His Thr Asp Arg Ala Pro Leu Asp Ala Lys Pro Gln Pro Thr Ser 2085 2090 2095Gly Gly Arg Pro Leu Glu Val Leu Glu Lys Pro Val His Leu Pro Arg 2100 2105 2110Pro Gly His Pro Gly Pro Ser Glu Pro Ala Asp Gln Lys Leu Ser Ala 2115 2120 2125Val Gly Glu Lys Gln Thr Leu Ser Pro Lys His Pro Lys Pro Ser Thr 2130 2135 2140Val Lys Asp Cys Pro Thr Leu Cys Lys Gln Thr Asp Asn Arg Gln Thr2145 2150 2155 2160Asp Lys Ser Pro Ser Gln Pro Ala Ala Asn Thr Asp Arg Arg Ala Glu 2165 2170 2175Gly Lys Lys Cys Thr Glu Ala Leu Tyr Ala Pro Ala Glu Gly Asp Lys 2180 2185 2190Leu Glu Ala Gly Leu Ser Phe Val His Ser Glu Asn Arg Leu Lys Gly 2195 2200 2205Ala Glu Arg Pro Ala Ala Gly Val Gly Lys Gly Phe Pro Glu Ala Arg 2210 2215 2220Gly Lys Gly Pro Gly Pro Gln Lys Pro Pro Thr Glu Ala Asp Lys Pro2225 2230 2235 2240Asn Gly Met Lys Arg Ser Pro Ser Ala Thr Gly Gln Ser Ser Phe Arg 2245 2250 2255Ser Thr Ala Leu Pro Glu Lys Ser Leu Ser Cys Ser Ser Ser Phe Pro 2260 2265 2270Glu Thr Arg Ala Gly Val Arg Glu Ala Ser Ala Ala Ser Ser Asp Thr 2275 2280 2285Ser Ser Ala Lys Ala Ala Gly Gly Met Leu Glu Leu Pro Ala Pro Ser 2290 2295 2300Asn Arg Asp His Arg Lys Ala Gln Pro Ala Gly Glu Gly Arg Thr His2305 2310 2315 2320Met Thr Lys Ser Asp Ser Leu Pro Ser Phe Arg Val Ser Thr Leu Pro 2325 2330 2335Leu Glu Ser His His Pro Asp Pro Asn Thr Met Gly Gly Ala Ser His 2340 2345 2350Arg Asp Arg Ala Leu Ser Val Thr Ala Thr Val Gly Glu Thr Lys Gly 2355 2360 2365Lys Asp Pro Ala Pro Ala Gln Pro Pro Pro Ala Arg Lys Gln Asn Val 2370 2375 2380Gly Arg Asp Val Thr Lys Pro Ser Pro Ala Pro Asn Thr Asp Arg Pro2385 2390 2395 2400Ile Ser Leu Ser Asn Glu Lys Asp Phe Val Val Arg Gln Arg Arg Gly 2405 2410 2415Lys Glu Ser Leu Arg Ser Ser Pro His Lys Lys Ala Leu 2420 242587305DNAHomo sapiens 8atggatgagt ccagcattct aagacgaaga gggctccaga aggagctgag tctccccaga 60agaggaagtt tgatagattc ccagaagtgg aattgcttgg tcaaacgttg ccgaacaagc 120aaccggaaaa gcttaatagg caatgggcag tcaccagcat tgcctcgacc acactcacct 180ctctctgctc atgcaggaaa tagccctcaa gatagtccaa gaaatttctc ccccagtgcc 240tcagcccatt tttcatttgc acggaggact gatggacgcc gctggtcgtt ggcttctctc 300ccttcctctg gctatgggac aaacacaccc agctctacgg tctcttcatc ctgttcctcc 360caggagaagt tgcatcagtt accataccaa ccaacaccag acgagttaca cttcttatca 420aaacatttct gtaccaccga aagcatcgcc actgagaaca gatgcaggaa cacgccgatg 480cgcccccgtt cccgaagtct gagccctgga cgttctcccg cctgctgtga ccatgaaata 540attatgatga accatgtcta caaagaaagg ttcccaaagg ctacagctca gatggaagaa 600cgtctaaagg aaattatcac cagctactct cctgacaacg ttctaccctt agcagatgga 660gtgcttagtt tcactcacca ccagattatt gaactggctc gagattgctt ggataaatcc 720caccagggcc tcatcacctc acgatacttc cttgaattac agcacaaatt agataagttg 780ctacaggagg ctcatgatcg ttcagaaagt ggagaattgg catttattaa acaactagtt 840cgaaagatcc taattgttat tgcccgccct gctcggttat tagagtgcct ggaatttgat 900ccggaagaat tttactacct attggaagca gcagaaggcc atgccaaaga aggacagggt 960attaaaaccg acattcccag gtacatcatt agccaactgg gactcaataa ggatcccttg 1020gaagaaatgg ctcatttggg aaactacgat agtgggacag cagaaacacc agaaacagat 1080gaatcagtga gtagctctaa tgcctccctg aaacttcgaa ggaaacctcg ggaaagtgat 1140tttgaaacga ttaaattgat tagcaatgga gcctatgggg cagtctactt tgttcggcat 1200aaagaatccc ggcagaggtt tgccatgaag aagattaata aacagaacct catccttcga 1260aaccagatcc agcaggcctt tgtggagcgg gatatcctga cttttgcaga aaaccccttt 1320gttgtcagca tgtattgctc ctttgaaaca aggcgccact tgtgcatggt catggaatat 1380gtggaagggg gagactgtgc tactttaatg aaaaacatgg gtcctctccc tgttgatatg 1440gccagaatgt actttgctga gacggtcttg gccttggaat atttacataa ttatggaatt 1500gtacacaggg atttgaaacc agacaacttg ttggttacct ccatggggca cataaagctg 1560acagattttg gattatctaa ggtgggacta atgagcatga ctaccaacct ttacgagggt 1620catattgaga aggatgctag agagttcctg gataaacagg tctgtggcac acctgaatac 1680attgcaccag aagtgattct gaggcagggt tatggaaagc cggtggactg gtgggccatg 1740gggattatcc tctatgaatt tctggttgga tgcgtgccat tctttgggga tactccagag 1800gagctatttg gacaagtcat cagtgatgag atcaactggc ctgagaagga tgaggcaccc 1860ccacctgatg cccaggatct gattacctta ctcctcaggc agaatcccct ggagaggctg 1920ggaacaggtg gtgcatatga agtcaaacag catcgattct tccgttcttt agactggaac 1980agtttgctga gacagaaggc agaatttatt ccccaactgg aatctgagga tgacacaagt 2040tattttgata ctcggtctga gaagtatcat catatggaaa cggaggaaga agatgacaca 2100aatgatgaag actttaatgt ggaaataagg cagttttctt catgttcaca caggttttca 2160aaagttttca gcagtataga tcgaatcact cagaattcag cagaagagaa ggaagactct 2220gtggacaaaa ccaaaagcac caccttgcca tccacagaaa cactgagctg gagttcagaa 2280tattctgaaa tgcaacagct atcaacatcc aactcttcag atactgaaag caacagacat 2340aaactcagtt ctggcctact tcccaaactg gctatttcaa cagagggaga gcaagatgaa 2400gctgcctcct gccctggaga cccccatgag gagccaggaa agccagccct tcctcctgaa 2460gagtgtgccc aggaggagcc tgaggtcacc accccagcca gcaccatcag cagctccacc 2520ctgtcagttg gcagtttttc agagcacttg gatcagataa atggacgaag cgagtgtgtg 2580gacagtacag ataattcctc aaagccatcc agtgaacccg cttctcacat ggctcggcag 2640cgattagaaa gcacagaaaa aaagaaaatc tcggggaaag tcacaaagtc cctctctgcc 2700agtgctcttt ccctcatgat cccaggagat atgtttgctg tttcccctct gggaagtcca 2760atgtctcccc attccctgtc ctcggaccct tcttcttcac gagattcctc tcccagccga 2820gattcctcag cagcttctgc cagtccacat cagccgattg tgatccacag ttcggggaag 2880aactacggct ttaccatccg agccatccgg gtgtatgtgg gagacagtga catctataca 2940gtgcaccata tcgtctggaa tgtagaagaa ggaagtccgg catgccaggc aggactgaag 3000gctggagatc ttatcactca catcaatgga gaaccagtgc atggacttgt ccacacagaa 3060gttatagaac tcctactgaa gagtgggaat aaggtgtcaa tcactactac cccatttgaa 3120aacacatcaa tcaaaactgg accagccagg agaaacagct ataagagccg gatggtgagg 3180cggagcaaga aatccaagaa gaaagaaagt ctcgaaagga ggagatctct tttcaaaaag 3240ctagccaagc agccttctcc tttactccac accagccgaa gtttctcctg cttgaacaga 3300tccctgtcat cgggtgagag cctcccaggt tcccccactc atagcttgtc tccccggtct 3360ccaacaccaa gctaccgctc cacccctgac ttcccatctg gtactaattc ctcccagagc 3420agctccccta gttctagtgc ccccaattcc ccagcagggt ccgggcacat ccggcccagc 3480actctccacg gtcttgcacc caaactcggc gggcagcggt accggtccgg aaggcgaaag 3540tccgccggca acatcccact gtccccgctg gcccggacgc cctctccaac cccgcaaccc 3600acctccccgc agcggtcacc atcccctctt ctgggacact cactgggcaa ttccaagatc 3660gcgcaagcct ttcccagcaa gatgcactcc ccgcccacca tcgtcagaca catcgtgagg 3720cccaagagtg cggagccccc caggtccccg ctgctcaagc gcgtgcagtc cgaggagaag 3780ctgtcgccct cttacggcag tgacaagaag cacctgtgct cccgcaagca cagcctggag 3840gtgacccaag aggaggtgca gcgggagcag tcccagcggg aggcgccgct gcagagcctg 3900gatgagaacg tgtgcgacgt gccgccgctc agccgcgccc ggccagtgga gcaaggctgc 3960ctgaaacgcc cagtctcccg gaaggtgggc cgccaggagt ctgtggacga cctggaccgc 4020gacaagctga aggccaaggt ggtggtgaag aaagcagacg gcttcccaga gaaacaggaa 4080tcccaccaga aatcccatgg acccgggagt gatttggaaa actttgctct gtttaagctg 4140gaagagagag agaagaaagt ctatccgaag gctgtggaaa ggtcaagtac ttttgaaaac 4200aaagcgtcta tgcaggaggc gccaccgctg ggcagcctgc tgaaggatgc tcttcacaag 4260caggccagcg tgcgcgccag cgagggtgcg atgtcggatg gccgggtgcc tgcggagcac 4320cgccagggtg gcggggactt cagacgggcc cccgctcctg gcaccctcca ggatggtctc 4380tgccactccc tcgacagggg catctctggg aagggggaag gcacggagaa gtcctcccag 4440gccaaggagc ttctccgatg tgaaaagtta gacagcaagc tggccaacat cgattacctc 4500cgaaagaaaa tgtcacttga ggacaaagag gacaacctct gccctgtgct gaagcccaag 4560atgacagctg gctcccacga atgcctgcca gggaacccag tccgacccac gggtgggcag 4620caggagcccc cgccggcttc tgagagccga gcttttgtca gcagcaccca tgcagctcag 4680atgagtgccg tctcttttgt tcccctcaag gccttaacag gccgggtgga cagtggaacg 4740gagaagcctg gcttggttgc tcctgagtcc cctgttagga agagcccctc cgagtataag 4800ctggaaggta ggtctgtctc atgcctgaag ccgatcgagg gcactctgga cattgctctc 4860ctgtccggac ctcaggcctc caagacagaa ctgccttccc cagagtctgc acagagcccc 4920agcccaagtg gtgacgtgag ggcctctgtg ccaccagttc tccccagcag cagtgggaaa 4980aagaacgata ccaccagtgc aagagagctt tctccttcca gcttaaagat gaataaatcc 5040tacctgctgg agccttggtt cctgcccccc agccgaggtc tccagaattc accagcagtt 5100tccctgcctg acccagagtt caagagggac aggaaaggtc cccatcctac tgccaggagc 5160cctggaacag tcatggaaag caatccccaa cagagagagg gcagctcccc taaacaccaa 5220gaccacacca ctgaccccaa gcttctgacc tgcctggggc agaacctcca cagccctgac 5280ctggccaggc cacgctgccc gctcccacct gaagcttccc cctcaaggga gaagccaggc 5340ctgagggaat cgtctgaaag aggccctccc acagccagaa gcgagcgctc tgctgcgagg 5400gctgacacat gcagagagcc ctccatggaa ctgtgctttc cagaaactgc gaaaaccagt 5460gacaactcca aaaatctcct ctctgtggga aggacccacc cagatttcta tacacagacc 5520caggccatgg agaaagcatg ggcgccgggt gggaaaacga accacaaaga tggcccaggt 5580gaggcgaggc ccccgcccag agacaactcc tctctgcact cagctggaat tccctgtgag 5640aaggagctgg gcaaggtgag gcgtggcgtg gaacccaagc ccgaagcgct tcttgccagg 5700cggtctctgc agccacctgg aattgagagt gagaagagtg aaaagctctc cagtttccca 5760tctttgcaga aagatggtgc caaggaacct gaaaggaagg agcagcctct acaaaggcat 5820cccagcagca tccctccgcc ccctctgacg gccaaagacc tgtccagccc ggctgccagg 5880cagcattgca gttccccaag ccacgcttct ggcagagagc cgggggccaa gcccagcact 5940gcagagccca gctcgagccc ccaggaccct cccaagcctg ttgctgcgca cagtgaaagc 6000agcagccaca agccccggcc tggccctgac ccgggccctc caaagactaa gcaccccgac 6060cggtccctct cctctcagaa accaagtgtc ggggccacaa agggcaaaga gcctgccact 6120cagtccctcg gtggctctag cagagagggg aagggccaca gtaagagtgg gccggatgtg 6180tttcctgcta ccccaggctc ccagaacaaa gccagcgatg ggattggcca gggagaaggt 6240gggccctctg tcccactgca cactgacagg gctcctctag acgccaagcc acaacccacc 6300agtggtgggc ggcccctgga ggtgctggag aagcctgtgc atttgccaag gccgggacac 6360ccagggccta gtgagccagc ggaccagaaa ctgtccgctg ttggtgaaaa gcaaaccctg 6420tctccaaagc accccaaacc atccactgtg aaagattgcc ccaccctgtg caaacagaca 6480gacaacagac agacagacaa aagcccgagt cagccggccg ccaacaccga cagaagggcg 6540gaagggaaga aatgcactga agcactttat gctccagcag agggcgacaa gctcgaggcc 6600ggcctttcct ttgtgcatag cgagaaccgg ttgaaaggcg cggagcggcc agccgcgggg 6660gtggggaagg gcttccctga ggccagaggg aaagggcccg gtccccagaa gccaccgacg 6720gaggcagaca agcccaatgg catgaaacgg tccccctcag ccactgggca gagttctttc 6780cgatccacgg ccctcccgga aaagtctctg agctgctcct ccagcttccc tgaaaccagg 6840gccggagtta gagaggcctc tgcagccagc agcgacacct cttctgccaa ggccgccggg 6900ggcatgctgg agcttccagc ccccagcaac agggaccata ggaaggctca gcctgccggg 6960gagggccgaa cccacatgac aaagagtgac tccctgccct ccttccgggt ctccaccctg 7020cctctggagt cacaccaccc cgacccaaac accatgggcg gggccagcca ccgggacagg 7080gctctctcgg tgactgccac cgtaggggaa accaaaggga aggaccctgc cccagcccag 7140cctcccccag ctaggaaaca gaacgtgggc agagacgtga ccaagccatc cccagcccca 7200aacactgacc gccccatctc tctttctaat gagaaggact ttgtggtacg gcagaggcgg 7260gggaaagaga gtttgcgtag cagccctcac aaaaaggcct tgtaa 73059753DNAHomo sapiens 9atgggggaga aagtttcgga ggcgccagag ccggtgcccc gcggctgcag tggccacggc 60agccggactc cagcctctgc gctggtcgcc gcgtcctctc cgggtgcttc ctcggccgag 120tcctcctcgg gctcagaaac tctgtcggag gaaggggagc ccggcggctt ctccagagag 180catcagccgc cgccgccgcc gccgttggga ggcaccctgg gcgcccgggc gcccgccgcg 240tgggctccgg caagcgtgct gctggagcgc ggagtccttg cgctgccgcc gccgcttccc 300ggaggagctg tgccgcccgc gccccggggc agcagcgcgt cccaggagga gcaggacgag 360gagcttgacc acatattatc ccctccaccc atgccgtttc ggaaatgcag caacccagat 420gtggcttctg gccctggaaa atcactgaag tataaaagac agctgagtga ggatggaaga 480cagctaaggc gagggagcct gggaggagcc ctgactggga ggtaccttct tccaaacccg 540gtggcgggac aggcctggcc ggcctctgca gagacgtcca acctcgtgcg catgcgcagc 600caggccctgg gccagtcggc gccctcgctc accgccagcc tgaaggagct gagtctcccc 660agaagaggaa gtttgataga ttcccagaag tggaattgct tggtcaaacg ccctgtgtgt 720ccaaatgctg ggagaacatc accccttgga tga 753107872DNAHomo sapiens 10atgggggaga aagtttcgga ggcgccagag ccggtgcccc gcggctgcag tggccacggc 60agccggactc cagcctctgc gctggtcgcc gcgtcctctc cgggtgcttc ctcggccgag 120tcctcctcgg gctcagaaac tctgtcggag gaaggggagc ccggcggctt ctccagagag 180catcagccgc cgccgccgcc gccgttggga ggcaccctgg gcgcccgggc gcccgccgcg 240tgggctccgg caagcgtgct gctggagcgc ggagtccttg cgctgccgcc gccgcttccc 300ggaggagctg tgccgcccgc gccccggggc agcagcgcgt cccaggagga gcaggacgag 360gagcttgacc acatattatc ccctccaccc atgccgtttc ggaaatgcag caacccagat 420gtggcttctg gccctggaaa atcactgaag tataaaagac agctgagtga ggatggaaga 480cagctaaggc gagggagcct gggaggagcc ctgactggga ggtaccttct tccaaacccg 540gtggcgggac aggcctggcc ggcctctgca gagacgtcca acctcgtgcg catgcgcagc 600caggccctgg gccagtcggc gccctcgctc accgccagcc tgaaggagct gagtctcccc 660agaagaggaa gtttttgccg aacaagcaac cggaaaagct taataggcaa tgggcagtca 720ccagcattgc ctcgaccaca ctcacctctc tctgctcatg caggaaatag ccctcaagat 780agtccaagaa atttctcccc cagtgcctca gcccattttt catttgcacg gaggactgat 840ggacgccgct ggtcgttggc ttctctccct tcctctggct atgggacaaa cacacccagc 900tctacggtct cttcatcctg ttcctcccag gagaagttgc atcagttacc ataccaacca 960acaccagacg agttacactt cttatcaaaa catttctgta ccaccgaaag catcgccact 1020gagaacagat gcaggaacac gccgatgcgc ccccgttccc gaagtctgag ccctggacgt 1080tctcccgcct gctgtgacca tgaaataatt atgatgaacc atgtctacaa agaaaggttc 1140ccaaaggcta cagctcagat ggaagaacgt ctaaaggaaa ttatcaccag ctactctcct 1200gacaacgttc tacccttagc agatggagtg cttagtttca ctcaccacca gattattgaa 1260ctggctcgag attgcttgga taaatcccac cagggcctca tcacctcacg atacttcctt 1320gaattacagc acaaattaga taagttgcta caggaggctc atgatcgttc agaaagtgga 1380gaattggcat ttattaaaca actagttcga aagatcctaa ttgttattgc ccgccctgct 1440cggttattag agtgcctgga atttgatccg gaagaatttt actacctatt ggaagcagca 1500gaaggccatg ccaaagaagg acagggtatt aaaaccgaca ttcccaggta catcattagc 1560caactgggac tcaataagga tcccttggaa gaaatggctc atttgggaaa ctacgatagt 1620gggacagcag aaacaccaga aacagatgaa tcagtgagta gctctaatgc ctccctgaaa 1680cttcgaagga aacctcggga aagtgatttt gaaacgatta aattgattag caatggagcc 1740tatggggcag tctactttgt tcggcataaa gaatcccggc agaggtttgc catgaagaag 1800attaataaac agaacctcat ccttcgaaac cagatccagc aggcctttgt ggagcgggat 1860atcctgactt ttgcagaaaa cccctttgtt gtcagcatgt attgctcctt tgaaacaagg 1920cgccacttgt gcatggtcat ggaatatgtg gaagggggag actgtgctac tttaatgaaa 1980aacatgggtc ctctccctgt tgatatggcc agaatgtact ttgctgagac ggtcttggcc 2040ttggaatatt tacataatta tggaattgta cacagggatt tgaaaccaga caacttgttg 2100gttacctcca tggggcacat aaagctgaca gattttggat tatctaaggt gggactaatg 2160agcatgacta ccaaccttta cgagggtcat attgagaagg atgctagaga gttcctggat 2220aaacaggtct gtggcacacc tgaatacatt gcaccagaag tgattctgag gcagggttat 2280ggaaagccgg tggactggtg ggccatgggg attatcctct atgaatttct ggttggatgc 2340gtgccattct ttggggatac tccagaggag ctatttggac aagtcatcag tgatgagatc 2400aactggcctg agaaggatga ggcaccccca cctgatgccc aggatctgat taccttactc 2460ctcaggcaga atcccctgga gaggctggga acaggtggtg catatgaagt caaacagcat 2520cgattcttcc gttctttaga ctggaacagt ttgctgagac agaaggcaga atttattccc 2580caactggaat ctgaggatga cacaagttat tttgatactc ggtctgagaa gtatcatcat 2640atggaaacgg aggaagaaga tgacacaaat gatgaagact ttaatgtgga aataaggcag 2700ttttcttcat gttcacacag gttttcaaaa gttttcagca gtatagatcg aatcactcag 2760aattcagcag aagagaagga agactctgtg gacaaaacca aaagcaccac cttgccatcc 2820acagaaacac tgagctggag ttcagaatat tctgaaatgc aacagctatc aacatccaac 2880tcttcagata ctgaaagcaa cagacataaa ctcagttctg gcctacttcc caaactggct 2940atttcaacag agggagagca agatgaagct gcctcctgcc ctggagaccc ccatgaggag 3000ccaggaaagc cagcccttcc tcctgaagag tgtgcccagg aggagcctga ggtcaccacc 3060ccagccagca ccatcagcag ctccaccctg tcagttggca gtttttcaga gcacttggat 3120cagataaatg gacgaagcga gtgtgtggac agtacagata attcctcaaa gccatccagt 3180gaacccgctt ctcacatggc tcggcagcga ttagaaagca cagaaaaaaa gaaaatctcg 3240gggaaagtca caaagtccct ctctgccagt gctctttccc tcatgatccc aggagatatg 3300tttgctgttt cccctctggg aagtccaatg tctccccatt ccctgtcctc ggacccttct 3360tcttcacgag attcctctcc cagccgagat tcctcagcag cttctgccag tccacatcag 3420ccgattgtga tccacagttc ggggaagaac tacggcttta ccatccgagc catccgggtg 3480tatgtgggag acagtgacat ctatacagtg caccatatcg tctggaatgt agaagaagga 3540agtccggcat gccaggcagg actgaaggct ggagatctta tcactcacat caatggagaa 3600ccagtgcatg gacttgtcca cacagaagtt atagaactcc tactgaagag tgggaataag 3660gtgtcaatca ctactacccc atttgaaaac acatcaatca aaactggacc agccaggaga 3720aacagctata agagccggat ggtgaggcgg agcaagaaat ccaagaagaa agaaagtctc 3780gaaaggagga gatctctttt caaaaagcta gccaagcagc cttctccttt actccacacc 3840agccgaagtt tctcctgctt gaacagatcc ctgtcatcgg gtgagagcct cccaggttcc 3900cccactcata gcttgtctcc ccggtctcca acaccaagct accgctccac ccctgacttc 3960ccatctggta ctaattcctc ccagagcagc tcccctagtt ctagtgcccc caattcccca 4020gcagggtccg ggcacatccg gcccagcact ctccacggtc ttgcacccaa actcggcggg 4080cagcggtacc ggtccggaag gcgaaagtcc gccggcaaca tcccactgtc cccgctggcc 4140cggacgccct ctccaacccc gcaacccacc tccccgcagc

ggtcaccatc ccctcttctg 4200ggacactcac tgggcaattc caagatcgcg caagcctttc ccagcaagat gcactccccg 4260cccaccatcg tcagacacat cgtgaggccc aagagtgcgg agccccccag gtccccgctg 4320ctcaagcgcg tgcagtccga ggagaagctg tcgccctctt acggcagtga caagaagcac 4380ctgtgctccc gcaagcacag cctggaggtg acccaagagg aggtgcagcg ggagcagtcc 4440cagcgggagg cgccgctgca gagcctggat gagaacgtgt gcgacgtgcc gccgctcagc 4500cgcgcccggc cagtggagca aggctgcctg aaacgcccag tctcccggaa ggtgggccgc 4560caggagtctg tggacgacct ggaccgcgac aagctgaagg ccaaggtggt ggtgaagaaa 4620gcagacggct tcccagagaa acaggaatcc caccagaaat cccatggacc cgggagtgat 4680ttggaaaact ttgctctgtt taagctggaa gagagagaga agaaagtcta tccgaaggct 4740gtggaaaggt caagtacttt tgaaaacaaa gcgtctatgc aggaggcgcc accgctgggc 4800agcctgctga aggatgctct tcacaagcag gccagcgtgc gcgccagcga gggtgcgatg 4860tcggatggcc gggtgcctgc ggagcaccgc cagggtggcg gggacttcag acgggccccc 4920gctcctggca ccctccagga tggtctctgc cactccctcg acaggggcat ctctgggaag 4980ggggaaggca cggagaagtc ctcccaggcc aaggagcttc tccgatgtga aaagttagac 5040agcaagctgg ccaacatcga ttacctccga aagaaaatgt cacttgagga caaagaggac 5100aacctctgcc ctgtgctgaa gcccaagatg acagctggct cccacgaatg cctgccaggg 5160aacccagtcc gacccacggg tgggcagcag gagcccccgc cggcttctga gagccgagct 5220tttgtcagca gcacccatgc agctcagatg agtgccgtct cttttgttcc cctcaaggcc 5280ttaacaggcc gggtggacag tggaacggag aagcctggct tggttgctcc tgagtcccct 5340gttaggaaga gcccctccga gtataagctg gaaggtaggt ctgtctcatg cctgaagccg 5400atcgagggca ctctggacat tgctctcctg tccggacctc aggcctccaa gacagaactg 5460ccttccccag agtctgcaca gagccccagc ccaagtggtg acgtgagggc ctctgtgcca 5520ccagttctcc ccagcagcag tgggaaaaag aacgatacca ccagtgcaag agagctttct 5580ccttccagct taaagatgaa taaatcctac ctgctggagc cttggttcct gccccccagc 5640cgaggtctcc agaattcacc agcagtttcc ctgcctgacc cagagttcaa gagggacagg 5700aaaggtcccc atcctactgc caggagccct ggaacagtca tggaaagcaa tccccaacag 5760agagagggca gctcccctaa acaccaagac cacaccactg accccaagct tctgacctgc 5820ctggggcaga acctccacag ccctgacctg gccaggccac gctgcccgct cccacctgaa 5880gcttccccct caagggagaa gccaggcctg agggaatcgt ctgaaagagg ccctcccaca 5940gccagaagcg agcgctctgc tgcgagggct gacacatgca gagagccctc catggaactg 6000tgctttccag aaactgcgaa aaccagtgac aactccaaaa atctcctctc tgtgggaagg 6060acccacccag atttctatac acagacccag gccatggaga aagcatgggc gccgggtggg 6120aaaacgaacc acaaagatgg cccaggtgag gcgaggcccc cgcccagaga caactcctct 6180ctgcactcag ctggaattcc ctgtgagaag gagctgggca aggtgaggcg tggcgtggaa 6240cccaagcccg aagcgcttct tgccaggcgg tctctgcagc cacctggaat tgagagtgag 6300aagagtgaaa agctctccag tttcccatct ttgcagaaag atggtgccaa ggaacctgaa 6360aggaaggagc agcctctaca aaggcatccc agcagcatcc ctccgccccc tctgacggcc 6420aaagacctgt ccagcccggc tgccaggcag cattgcagtt ccccaagcca cgcttctggc 6480agagagccgg gggccaagcc cagcactgca gagcccagct cgagccccca ggaccctccc 6540aagcctgttg ctgcgcacag tgaaagcagc agccacaagc cccggcctgg ccctgacccg 6600ggccctccaa agactaagca ccccgaccgg tccctctcct ctcagaaacc aagtgtcggg 6660gccacaaagg gcaaagagcc tgccactcag tccctcggtg gctctagcag agaggggaag 6720ggccacagta agagtgggcc ggatgtgttt cctgctaccc caggctccca gaacaaagcc 6780agcgatggga ttggccaggg agaaggtggg ccctctgtcc cactgcacac tgacagggct 6840cctctagacg ccaagccaca acccaccagt ggtgggcggc ccctggaggt gctggagaag 6900cctgtgcatt tgccaaggcc gggacaccca gggcctagtg agccagcgga ccagaaactg 6960tccgctgttg gtgaaaagca aaccctgtct ccaaagcacc ccaaaccatc cactgtgaaa 7020gattgcccca ccctgtgcaa acagacagac aacagacaga cagacaaaag cccgagtcag 7080ccggccgcca acaccgacag aagggcggaa gggaagaaat gcactgaagc actttatgct 7140ccagcagagg gcgacaagct cgaggccggc ctttcctttg tgcatagcga gaaccggttg 7200aaaggcgcgg agcggccagc cgcgggggtg gggaagggct tccctgaggc cagagggaaa 7260gggcccggtc cccagaagcc accgacggag gcagacaagc ccaatggcat gaaacggtcc 7320ccctcagcca ctgggcagag ttctttccga tccacggccc tcccggaaaa gtctctgagc 7380tgctcctcca gcttccctga aaccagggcc ggagttagag aggcctctgc agccagcagc 7440gacacctctt ctgccaaggc cgccgggggc atgctggagc ttccagcccc cagcaacagg 7500gaccatagga aggctcagcc tgccggggag ggccgaaccc acatgacaaa gagtgactcc 7560ctgccctcct tccgggtctc caccctgcct ctggagtcac accaccccga cccaaacacc 7620atgggcgggg ccagccaccg ggacagggct ctctcggtga ctgccaccgt aggggaaacc 7680aaagggaagg accctgcccc agcccagcct cccccagcta ggaaacagaa cgtgggcaga 7740gacgtgacca agccatcccc agccccaaac actgaccgcc ccatctctct ttctaatgag 7800aaggactttg tggtacggca gaggcggggg aaagagagtt tgcgtagcag ccctcacaaa 7860aaggccttgt aa 7872117254DNAHomo sapiens 11atgaaagccc agcgggaaag gctacagatt ccggggctga ccttggattg ccgaacaagc 60aaccggaaaa gcttaatagg caatgggcag tcaccagcat tgcctcgacc acactcacct 120ctctctgctc atgcaggaaa tagccctcaa gatagtccaa gaaatttctc ccccagtgcc 180tcagcccatt tttcatttgc acggagaaat gacaggactg atggacgccg ctggtcgttg 240gcttctctcc cttcctctgg ctatgggaca aacacaccca gctctacggt ctcttcatcc 300tgttcctccc aggagaagtt gcatcagtta ccataccaac caacaccaga cgagttacac 360ttcttatcaa aacatttctg taccaccgaa agcatcgcca ctgagaacag atgcaggaac 420acgccgatgc gcccccgttc ccgaagtctg agccctggac gttctcccgc ctgctgtgac 480catgaaataa ttatgatgaa ccatgtctac aaagaaaggt tcccaaaggc tacagctcag 540atggaagaac gtctaaagga aattatcacc agctactctc ctgacaacgt tctaccctta 600gcagatggag tgcttagttt cactcaccac cagattattg aactggctcg agattgcttg 660gataaatccc accagggcct catcacctca cgatacttcc ttgaattaca gcacaaatta 720gataagttgc tacaggaggc tcatgatcgt tcagaaagtg gagaattggc atttattaaa 780caactagttc gaaagatcct aattgttatt gcccgccctg ctcggttatt agagtgcctg 840gaatttgatc cggaagaatt ttactaccta ttggaagcag cagaaggcca tgccaaagaa 900ggacagggta ttaaaaccga cattcccagg tacatcatta gccaactggg actcaataag 960gatcccttgg aagaaatggc tcatttggga aactacgata gtgggacagc agaaacacca 1020gaaacagatg aatcagtgag tagctctaat gcctccctga aacttcgaag gaaacctcgg 1080gaaagtgatt ttgaaacgat taaattgatt agcaatggag cctatggggc agtctacttt 1140gttcggcata aagaatcccg gcagaggttt gccatgaaga agattaataa acagaacctc 1200atccttcgaa accagatcca gcaggccttt gtggagcggg atatcctgac ttttgcagaa 1260aacccctttg ttgtcagcat gtattgctcc tttgaaacaa ggcgccactt gtgcatggtc 1320atggaatatg tggaaggggg agactgtgct actttaatga aaaacatggg tcctctccct 1380gttgatatgg ccagaatgta ctttgctgag acggtcttgg ccttggaata tttacataat 1440tatggaattg tacacaggga tttgaaacca gacaacttgt tggttacctc catggggcac 1500ataaagctga cagattttgg attatctaag gtgggactaa tgagcatgac taccaacctt 1560tacgagggtc atattgagaa ggatgctaga gagttcctgg ataaacaggt ctgtggcaca 1620cctgaataca ttgcaccaga agtgattctg aggcagggtt atggaaagcc ggtggactgg 1680tgggccatgg ggattatcct ctatgaattt ctggttggat gcgtgccatt ctttggggat 1740actccagagg agctatttgg acaagtcatc agtgatgaga tcaactggcc tgagaaggat 1800gaggcacccc cacctgatgc ccaggatctg attaccttac tcctcaggca gaatcccctg 1860gagaggctgg gaacaggtgg tgcatatgaa gtcaaacagc atcgattctt ccgttcttta 1920gactggaaca gtttgctgag acagaaggca gaatttattc cccaactgga atctgaggat 1980gacacaagtt attttgatac tcggtctgag aagtatcatc atatggaaac ggaggaagaa 2040gatgacacaa atgatgaaga ctttaatgtg gaaataaggc agttttcttc atgttcacac 2100aggttttcaa aagttttcag cagtatagat cgaatcactc agaattcagc agaagagaag 2160gaagactctg tggacaaaac caaaagcacc accttgccat ccacagaaac actgagctgg 2220agttcagaat attctgaaat gcaacagcta tcaacatcca actcttcaga tactgaaagc 2280aacagacata aactcagttc tggcctactt cccaaactgg ctatttcaac agagggagag 2340caagatgaag ctgcctcctg ccctggagac ccccatgagg agccaggaaa gccagccctt 2400cctcctgaag agtgtgccca ggaggagcct gaggtcacca ccccagccag caccatcagc 2460agctccaccc tgtcagttgg cagtttttca gagcacttgg atcagataaa tggacgaagc 2520gagtgtgtgg acagtacaga taattcctca aagccatcca gtgaacccgc ttctcacatg 2580gctcggcagc gattagaaag cacagaaaaa aagaaaatct cggggaaagt cacaaagtcc 2640ctctctgcca gtgctctttc cctcatgatc ccaggagata tgtttgctgt ttcccctctg 2700ggaagtccaa tgtctcccca ttccctgtcc tcggaccctt cttcttcacg agattcctct 2760cccagccgag attcctcagc agcttctgcc agtccacatc agccgattgt gatccacagt 2820tcggggaaga actacggctt taccatccga gccatccggg tgtatgtggg agacagtgac 2880atctatacag tgcaccatat cgtctggaat gtagaagaag gaagtccggc atgccaggca 2940ggactgaagg ctggagatct tatcactcac atcaatggag aaccagtgca tggacttgtc 3000cacacagaag ttatagaact cctactgaag agtgggaata aggtgtcaat cactactacc 3060ccatttgaaa acacatcaat caaaactgga ccagccagga gaaacagcta taagagccgg 3120atggtgaggc ggagcaagaa atccaagaag aaagaaagtc tcgaaaggag gagatctctt 3180ttcaaaaagc tagccaagca gccttctcct ttactccaca ccagccgaag tttctcctgc 3240ttgaacagat ccctgtcatc gggtgagagc ctcccaggtt cccccactca tagcttgtct 3300ccccggtctc caacaccaag ctaccgctcc acccctgact tcccatctgg tactaattcc 3360tcccagagca gctcccctag ttctagtgcc cccaattccc cagcagggtc cgggcacatc 3420cggcccagca ctctccacgg tcttgcaccc aaactcggcg ggcagcggta ccggtccgga 3480aggcgaaagt ccgccggcaa catcccactg tccccgctgg cccggacgcc ctctccaacc 3540ccgcaaccca cctccccgca gcggtcacca tcccctcttc tgggacactc actgggcaat 3600tccaagatcg cgcaagcctt tcccagcaag atgcactccc cgcccaccat cgtcagacac 3660atcgtgaggc ccaagagtgc ggagcccccc aggtccccgc tgctcaagcg cgtgcagtcc 3720gaggagaagc tgtcgccctc ttacggcagt gacaagaagc acctgtgctc ccgcaagcac 3780agcctggagg tgacccaaga ggaggtgcag cgggagcagt cccagcggga ggcgccgctg 3840cagagcctgg atgagaacgt gtgcgacgtg ccgccgctca gccgcgcccg gccagtggag 3900caaggctgcc tgaaacgccc agtctcccgg aaggtgggcc gccaggagtc tgtggacgac 3960ctggaccgcg acaagctgaa ggccaaggtg gtggtgaaga aagcagacgg cttcccagag 4020aaacaggaat cccaccagaa atcccatgga cccgggagtg atttggaaaa ctttgctctg 4080tttaagctgg aagagagaga gaagaaagtc tatccgaagg ctgtggaaag gtcaagtact 4140tttgaaaaca aagcgtctat gcaggaggcg ccaccgctgg gcagcctgct gaaggatgct 4200cttcacaagc aggccagcgt gcgcgccagc gagggtgcga tgtcggatgg ccgggtgcct 4260gcggagcacc gccagggtgg cggggacttc agacgggccc ccgctcctgg caccctccag 4320gatggtctct gccactccct cgacaggggc atctctggga agggggaagg cacggagaag 4380tcctcccagg ccaaggagct tctccgatgt gaaaagttag acagcaagct ggccaacatc 4440gattacctcc gaaagaaaat gtcacttgag gacaaagagg acaacctctg ccctgtgctg 4500aagcccaaga tgacagctgg ctcccacgaa tgcctgccag ggaacccagt ccgacccacg 4560ggtgggcagc aggagccccc gccggcttct gagagccgag cttttgtcag cagcacccat 4620gcagctcaga tgagtgccgt ctcttttgtt cccctcaagg ccttaacagg ccgggtggac 4680agtggaacgg agaagcctgg cttggttgct cctgagtccc ctgttaggaa gagcccctcc 4740gagtataagc tggaaggtag gtctgtctca tgcctgaagc cgatcgaggg cactctggac 4800attgctctcc tgtccggacc tcaggcctcc aagacagaac tgccttcccc agagtctgca 4860cagagcccca gcccaagtgg tgacgtgagg gcctctgtgc caccagttct ccccagcagc 4920agtgggaaaa agaacgatac caccagtgca agagagcttt ctccttccag cttaaagatg 4980aataaatcct acctgctgga gccttggttc ctgcccccca gccgaggtct ccagaattca 5040ccagcagttt ccctgcctga cccagagttc aagagggaca ggaaaggtcc ccatcctact 5100gccaggagcc ctggaacagt catggaaagc aatccccaac agagagaggg cagctcccct 5160aaacaccaag accacaccac tgaccccaag cttctgacct gcctggggca gaacctccac 5220agccctgacc tggccaggcc acgctgcccg ctcccacctg aagcttcccc ctcaagggag 5280aagccaggcc tgagggaatc gtctgaaaga ggccctccca cagccagaag cgagcgctct 5340gctgcgaggg ctgacacatg cagagagccc tccatggaac tgtgctttcc agaaactgcg 5400aaaaccagtg acaactccaa aaatctcctc tctgtgggaa ggacccaccc agatttctat 5460acacagaccc aggccatgga gaaagcatgg gcgccgggtg ggaaaacgaa ccacaaagat 5520ggcccaggtg aggcgaggcc cccgcccaga gacaactcct ctctgcactc agctggaatt 5580ccctgtgaga aggagctggg caaggtgagg cgtggcgtgg aacccaagcc cgaagcgctt 5640cttgccaggc ggtctctgca gccacctgga attgagagtg agaagagtga aaagctctcc 5700agtttcccat ctttgcagaa agatggtgcc aaggaacctg aaaggaagga gcagcctcta 5760caaaggcatc ccagcagcat ccctccgccc cctctgacgg ccaaagacct gtccagcccg 5820gctgccaggc agcattgcag ttccccaagc cacgcttctg gcagagagcc gggggccaag 5880cccagcactg cagagcccag ctcgagcccc caggaccctc ccaagcctgt tgctgcgcac 5940agtgaaagca gcagccacaa gccccggcct ggccctgacc cgggccctcc aaagactaag 6000caccccgacc ggtccctctc ctctcagaaa ccaagtgtcg gggccacaaa gggcaaagag 6060cctgccactc agtccctcgg tggctctagc agagagggga agggccacag taagagtggg 6120ccggatgtgt ttcctgctac cccaggctcc cagaacaaag ccagcgatgg gattggccag 6180ggagaaggtg ggccctctgt cccactgcac actgacaggg ctcctctaga cgccaagcca 6240caacccacca gtggtgggcg gcccctggag gtgctggaga agcctgtgca tttgccaagg 6300ccgggacacc cagggcctag tgagccagcg gaccagaaac tgtccgctgt tggtgaaaag 6360caaaccctgt ctccaaagca ccccaaacca tccactgtga aagattgccc caccctgtgc 6420aaacagacag acaacagaca gacagacaaa agcccgagtc agccggccgc caacaccgac 6480agaagggcgg aagggaagaa atgcactgaa gcactttatg ctccagcaga gggcgacaag 6540ctcgaggccg gcctttcctt tgtgcatagc gagaaccggt tgaaaggcgc ggagcggcca 6600gccgcggggg tggggaaggg cttccctgag gccagaggga aagggcccgg tccccagaag 6660ccaccgacgg aggcagacaa gcccaatggc atgaaacggt ccccctcagc cactgggcag 6720agttctttcc gatccacggc cctcccggaa aagtctctga gctgctcctc cagcttccct 6780gaaaccaggg ccggagttag agaggcctct gcagccagca gcgacacctc ttctgccaag 6840gccgccgggg gcatgctgga gcttccagcc cccagcaaca gggaccatag gaaggctcag 6900cctgccgggg agggccgaac ccacatgaca aagagtgact ccctgccctc cttccgggtc 6960tccaccctgc ctctggagtc acaccacccc gacccaaaca ccatgggcgg ggccagccac 7020cgggacaggg ctctctcggt gactgccacc gtaggggaaa ccaaagggaa ggaccctgcc 7080ccagcccagc ctcccccagc taggaaacag aacgtgggca gagacgtgac caagccatcc 7140ccagccccaa acactgaccg ccccatctct ctttctaatg agaaggactt tgtggtacgg 7200cagaggcggg ggaaagagag tttgcgtagc agccctcaca aaaaggcctt gtaa 7254127089DNAHomo sapiens 12atggatatgt ctgaccccaa tttttggact gtgctctcaa actttacttt gcctcatttg 60aggagtggga acaggcttcg gcgaacacaa agttgccgaa caagcaaccg gaaaagctta 120ataggcaatg ggcagtcacc agcattgcct cgaccacact cacctctctc tgctcatgca 180ggaaatagcc ctcaagatag tccaagaaat ttctccccca gtgcctcagc ccatttttca 240tttgcacgga ggactgatgg acgccgctgg tcgttggctt ctctcccttc ctctggctat 300gggacaaaca cacccagctc tacggtctct tcatcctgtt cctcccagga gaagttgcat 360cagttaccat accaaccaac accagacgag ttacacttct tatcaaaaca tttctgtacc 420accgaaagca tcgccactga gaacagatgc aggaacacgc cgatgcgccc ccgttcccga 480agtctgagcc ctggacgttc tcccgcctgc tgtgaccatg aaataattat gatgaaccat 540gtctacaaag aaaggttccc aaaggctaca gctcagatgg aagaacgtct aaaggaaatt 600atcaccagct actctcctga caacgttcta cccttagcag atggagtgct tagtttcact 660caccaccaga ttattgaact ggctcgagat tgcttggata aatcccacca gggcctcatc 720acctcacgat acttccttga attacagcac aaattagata agttgctaca ggaggctcat 780gatcgttcag aaagtggaga attggcattt attaaacaac tagttcgaaa gatcctaatt 840gttattgccc gccctgctcg gttattagag tgcctggaat ttgatccgga agaattttac 900tacctattgg aagcagcaga aggccatgcc aaagaaggac agggtattaa aaccgacatt 960cccaggtaca tcattagcca actgggactc aataaggatc ccttggaaga aatggctcat 1020ttgggaaact acgatagtgg gacagcagaa acaccagaaa cagatgaatc agtgagtagc 1080tctaatgcct ccctgaaact tcgaaggaaa cctcgggaaa gtgattttga aacgattaaa 1140ttgattagca atggagccta tggggcagtc tactttgttc ggcataaaga atcccggcag 1200aggtttgcca tgaagaagat taataaacag aacctcatcc ttcgaaacca gatccagcag 1260gcctttgtgg agcgggatat cctgactttt gcagaaaacc cctttgttgt cagcatgtat 1320tgctcctttg aaacaaggcg ccacttgtgc atggtcatgg aatatgtgga agggggagac 1380tgtgctactt taatgaaaaa catgggtcct ctccctgttg atatggccag aatgtacttt 1440gctgagacgg tcttggcctt ggaatattta cataattatg gaattgtaca cagggatttg 1500aaaccagaca acttgttggt tacctccatg gggcacataa agctgacaga ttttggatta 1560tctaaggtgg gactaatgag catgactacc aacctttacg agggtcatat tgagaaggat 1620gctagagagt tcctggataa acaggtctgt ggcacacctg aatacattgc accagaagtg 1680attctgaggc agggttatgg aaagccggtg gactggtggg ccatggggat tatcctctat 1740gaatttctgg ttggatgcgt gccattcttt ggggatactc cagaggagct atttggacaa 1800gtcatcagtg atgagatcaa ctggcctgag aaggatgagg cacccccacc tgatgcccag 1860gatctgatta ccttactcct caggcagaat cccctggaga ggctgggaac aggtggtgca 1920tatgaagtca aacagcatcg attcttccgt tctttagact ggaacagttt gctgagacag 1980aaggcagaat ttattcccca actggaatct gaggatgaca caagttattt tgatactcgg 2040tctgagaagt atcatcatat ggaaacggag gaagaagatg acacaaatga tgaagacttt 2100aatgtggaaa taaggcagtt ttcttcatgt tcacacaggt tttcaaaagt tttcagcagt 2160atagatcgaa tcactcagaa ttcagcagaa gagaaggaag actctgtgga caaaaccaaa 2220agcaccacct tgccatccac agaaacactg agctggagtt cagaatattc tgaaatgcaa 2280cagctatcaa catccaactc ttcagatact gaaagcaaca gacataaact cagttctggc 2340ctacttccca aactggctat ttcaacagag ggagagcaag atgaagctgc ctcctgccct 2400ggagaccccc atgaggagcc aggaaagcca gcccttcctc ctgaagagtg tgcccaggag 2460gagcctgagg tcaccacccc agccagcacc atcagcagct ccaccctgtc agatatgttt 2520gctgtttccc ctctgggaag tccaatgtct ccccattccc tgtcctcgga cccttcttct 2580tcacgagatt cctctcccag ccgagattcc tcagcagctt ctgccagtcc acatcagccg 2640attgtgatcc acagttcggg gaagaactac ggctttacca tccgagccat ccgggtgtat 2700gtgggagaca gtgacatcta tacagtgcac catatcgtct ggaatgtaga agaaggaagt 2760ccggcatgcc aggcaggact gaaggctgga gatcttatca ctcacatcaa tggagaacca 2820gtgcatggac ttgtccacac agaagttata gaactcctac tgaagagtgg gaataaggtg 2880tcaatcacta ctaccccatt tgaaaacaca tcaatcaaaa ctggaccagc caggagaaac 2940agctataaga gccggatggt gaggcggagc aagaaatcca agaagaaaga aagtctcgaa 3000aggaggagat ctcttttcaa aaagctagcc aagcagcctt ctcctttact ccacaccagc 3060cgaagtttct cctgcttgaa cagatccctg tcatcgggtg agagcctccc aggttccccc 3120actcatagct tgtctccccg gtctccaaca ccaagctacc gctccacccc tgacttccca 3180tctggtacta attcctccca gagcagctcc cctagttcta gtgcccccaa ttccccagca 3240gggtccgggc acatccggcc cagcactctc cacggtcttg cacccaaact cggcgggcag 3300cggtaccggt ccggaaggcg aaagtccgcc ggcaacatcc cactgtcccc gctggcccgg 3360acgccctctc caaccccgca acccacctcc ccgcagcggt caccatcccc tcttctggga 3420cactcactgg gcaattccaa gatcgcgcaa gcctttccca gcaagatgca ctccccgccc 3480accatcgtca gacacatcgt gaggcccaag agtgcggagc cccccaggtc cccgctgctc 3540aagcgcgtgc agtccgagga gaagctgtcg ccctcttacg gcagtgacaa gaagcacctg 3600tgctcccgca agcacagcct ggaggtgacc caagaggagg tgcagcggga gcagtcccag 3660cgggaggcgc cgctgcagag cctggatgag aacgtgtgcg acgtgccgcc gctcagccgc 3720gcccggccag tggagcaagg ctgcctgaaa cgcccagtct cccggaaggt gggccgccag 3780gagtctgtgg acgacctgga ccgcgacaag ctgaaggcca aggtggtggt gaagaaagca 3840gacggcttcc cagagaaaca ggaatcccac cagaaatccc atggacccgg gagtgatttg 3900gaaaactttg ctctgtttaa gctggaagag agagagaaga aagtctatcc gaaggctgtg 3960gaaaggtcaa gtacttttga aaacaaagcg tctatgcagg aggcgccacc gctgggcagc

4020ctgctgaagg atgctcttca caagcaggcc agcgtgcgcg ccagcgaggg tgcgatgtcg 4080gatggccggg tgcctgcgga gcaccgccag ggtggcgggg acttcagacg ggcccccgct 4140cctggcaccc tccaggatgg tctctgccac tccctcgaca ggggcatctc tgggaagggg 4200gaaggcacgg agaagtcctc ccaggccaag gagcttctcc gatgtgaaaa gttagacagc 4260aagctggcca acatcgatta cctccgaaag aaaatgtcac ttgaggacaa agaggacaac 4320ctctgccctg tgctgaagcc caagatgaca gctggctccc acgaatgcct gccagggaac 4380ccagtccgac ccacgggtgg gcagcaggag cccccgccgg cttctgagag ccgagctttt 4440gtcagcagca cccatgcagc tcagatgagt gccgtctctt ttgttcccct caaggcctta 4500acaggccggg tggacagtgg aacggagaag cctggcttgg ttgctcctga gtcccctgtt 4560aggaagagcc cctccgagta taagctggaa ggtaggtctg tctcatgcct gaagccgatc 4620gagggcactc tggacattgc tctcctgtcc ggacctcagg cctccaagac agaactgcct 4680tccccagagt ctgcacagag ccccagccca agtggtgacg tgagggcctc tgtgccacca 4740gttctcccca gcagcagtgg gaaaaagaac gataccacca gtgcaagaga gctttctcct 4800tccagcttaa agatgaataa atcctacctg ctggagcctt ggttcctgcc ccccagccga 4860ggtctccaga attcaccagc agtttccctg cctgacccag agttcaagag ggacaggaaa 4920ggtccccatc ctactgccag gagccctgga acagtcatgg aaagcaatcc ccaacagaga 4980gagggcagct cccctaaaca ccaagaccac accactgacc ccaagcttct gacctgcctg 5040gggcagaacc tccacagccc tgacctggcc aggccacgct gcccgctccc acctgaagct 5100tccccctcaa gggagaagcc aggcctgagg gaatcgtctg aaagaggccc tcccacagcc 5160agaagcgagc gctctgctgc gagggctgac acatgcagag agccctccat ggaactgtgc 5220tttccagaaa ctgcgaaaac cagtgacaac tccaaaaatc tcctctctgt gggaaggacc 5280cacccagatt tctatacaca gacccaggcc atggagaaag catgggcgcc gggtgggaaa 5340acgaaccaca aagatggccc aggtgaggcg aggcccccgc ccagagacaa ctcctctctg 5400cactcagctg gaattccctg tgagaaggag ctgggcaagg tgaggcgtgg cgtggaaccc 5460aagcccgaag cgcttcttgc caggcggtct ctgcagccac ctggaattga gagtgagaag 5520agtgaaaagc tctccagttt cccatctttg cagaaagatg gtgccaagga acctgaaagg 5580aaggagcagc ctctacaaag gcatcccagc agcatccctc cgccccctct gacggccaaa 5640gacctgtcca gcccggctgc caggcagcat tgcagttccc caagccacgc ttctggcaga 5700gagccggggg ccaagcccag cactgcagag cccagctcga gcccccagga ccctcccaag 5760cctgttgctg cgcacagtga aagcagcagc cacaagcccc ggcctggccc tgacccgggc 5820cctccaaaga ctaagcaccc cgaccggtcc ctctcctctc agaaaccaag tgtcggggcc 5880acaaagggca aagagcctgc cactcagtcc ctcggtggct ctagcagaga ggggaagggc 5940cacagtaaga gtgggccgga tgtgtttcct gctaccccag gctcccagaa caaagccagc 6000gatgggattg gccagggaga aggtgggccc tctgtcccac tgcacactga cagggctcct 6060ctagacgcca agccacaacc caccagtggt gggcggcccc tggaggtgct ggagaagcct 6120gtgcatttgc caaggccggg acacccaggg cctagtgagc cagcggacca gaaactgtcc 6180gctgttggtg aaaagcaaac cctgtctcca aagcacccca aaccatccac tgtgaaagat 6240tgccccaccc tgtgcaaaca gacagacaac agacagacag acaaaagccc gagtcagccg 6300gccgccaaca ccgacagaag ggcggaaggg aagaaatgca ctgaagcact ttatgctcca 6360gcagagggcg acaagctcga ggccggcctt tcctttgtgc atagcgagaa ccggttgaaa 6420ggcgcggagc ggccagccgc gggggtgggg aagggcttcc ctgaggccag agggaaaggg 6480cccggtcccc agaagccacc gacggaggca gacaagccca atggcatgaa acggtccccc 6540tcagccactg ggcagagttc tttccgatcc acggccctcc cggaaaagtc tctgagctgc 6600tcctccagct tccctgaaac cagggccgga gttagagagg cctctgcagc cagcagcgac 6660acctcttctg ccaaggccgc cgggggcatg ctggagcttc cagcccccag caacagggac 6720cataggaagg ctcagcctgc cggggagggc cgaacccaca tgacaaagag tgactccctg 6780ccctccttcc gggtctccac cctgcctctg gagtcacacc accccgaccc aaacaccatg 6840ggcggggcca gccaccggga cagggctctc tcggtgactg ccaccgtagg ggaaaccaaa 6900gggaaggacc ctgccccagc ccagcctccc ccagctagga aacagaacgt gggcagagac 6960gtgaccaagc catccccagc cccaaacact gaccgcccca tctctctttc taatgagaag 7020gactttgtgg tacggcagag gcgggggaaa gagagtttgc gtagcagccc tcacaaaaag 7080gccttgtaa 708913717DNAHomo sapiens 13atgggggaga aagtttcgga ggcgccagag ccggtgcccc gcggctgcag tggccacggc 60agccggactc cagcctctgc gctggtcgcc gcgtcctctc cgggtgcttc ctcggccgag 120tcctcctcgg gctcagaaac tctgtcggag gaaggggagc ccggcggctt ctccagagag 180catcagccgc cgccgccgcc gccgttggga ggcaccctgg gcgcccgggc gcccgccgcg 240tgggctccgg caagcgtgct gctggagcgc ggagtccttg cgctgccgcc gccgcttccc 300ggaggagctg tgccgcccgc gccccggggc agcagcgcgt cccaggagga gcaggacgag 360gagcttgacc acatattatc ccctccaccc atgccgtttc ggaaatgcag caacccagat 420gtggcttctg gccctggaaa atcactgaag tataaaagac agctgagtga ggatggaaga 480cagctaaggc gagggagcct gggaggagcc ctgactggga ggtaccttct tccaaacccg 540gtggcgggac aggcctggcc ggcctctgca gagacgtcca acctcgtgcg catgcgcagc 600caggccctgg gccagtcggc gccctcgctc accgccagcc tgaaggagct gagtctcccc 660agaagaggaa gtttccctgt gtgtccaaat gctgggagaa catcacccct tggatga 717147290DNAHomo sapiens 14atggatatgt ctgaccccaa tttttggact gtgctctcaa actttacttt gcctcatttg 60aggagtggga acaggcttcg gcgaacacaa agttgccgaa caagcaaccg gaaaagctta 120ataggcaatg ggcagtcacc agcattgcct cgaccacact cacctctctc tgctcatgca 180ggaaatagcc ctcaagatag tccaagaaat ttctccccca gtgcctcagc ccatttttca 240tttgcacgga ggactgatgg acgccgctgg tcgttggctt ctctcccttc ctctggctat 300gggacaaaca cacccagctc tacggtctct tcatcctgtt cctcccagga gaagttgcat 360cagttaccat accaaccaac accagacgag ttacacttct tatcaaaaca tttctgtacc 420accgaaagca tcgccactga gaacagatgc aggaacacgc cgatgcgccc ccgttcccga 480agtctgagcc ctggacgttc tcccgcctgc tgtgaccatg aaataattat gatgaaccat 540gtctacaaag aaaggttccc aaaggctaca gctcagatgg aagaacgtct aaaggaaatt 600atcaccagct actctcctga caacgttcta cccttagcag atggagtgct tagtttcact 660caccaccaga ttattgaact ggctcgagat tgcttggata aatcccacca gggcctcatc 720acctcacgat acttccttga attacagcac aaattagata agttgctaca ggaggctcat 780gatcgttcag aaagtggaga attggcattt attaaacaac tagttcgaaa gatcctaatt 840gttattgccc gccctgctcg gttattagag tgcctggaat ttgatccgga agaattttac 900tacctattgg aagcagcaga aggccatgcc aaagaaggac agggtattaa aaccgacatt 960cccaggtaca tcattagcca actgggactc aataaggatc ccttggaaga aatggctcat 1020ttgggaaact acgatagtgg gacagcagaa acaccagaaa cagatgaatc agtgagtagc 1080tctaatgcct ccctgaaact tcgaaggaaa cctcgggaaa gtgattttga aacgattaaa 1140ttgattagca atggagccta tggggcagtc tactttgttc ggcataaaga atcccggcag 1200aggtttgcca tgaagaagat taataaacag aacctcatcc ttcgaaacca gatccagcag 1260gcctttgtgg agcgggatat cctgactttt gcagaaaacc cctttgttgt cagcatgtat 1320tgctcctttg aaacaaggcg ccacttgtgc atggtcatgg aatatgtgga agggggagac 1380tgtgctactt taatgaaaaa catgggtcct ctccctgttg atatggccag aatgtacttt 1440gctgagacgg tcttggcctt ggaatattta cataattatg gaattgtaca cagggatttg 1500aaaccagaca acttgttggt tacctccatg gggcacataa agctgacaga ttttggatta 1560tctaaggtgg gactaatgag catgactacc aacctttacg agggtcatat tgagaaggat 1620gctagagagt tcctggataa acaggtctgt ggcacacctg aatacattgc accagaagtg 1680attctgaggc agggttatgg aaagccggtg gactggtggg ccatggggat tatcctctat 1740gaatttctgg ttggatgcgt gccattcttt ggggatactc cagaggagct atttggacaa 1800gtcatcagtg atgagatcaa ctggcctgag aaggatgagg cacccccacc tgatgcccag 1860gatctgatta ccttactcct caggcagaat cccctggaga ggctgggaac aggtggtgca 1920tatgaagtca aacagcatcg attcttccgt tctttagact ggaacagttt gctgagacag 1980aaggcagaat ttattcccca actggaatct gaggatgaca caagttattt tgatactcgg 2040tctgagaagt atcatcatat ggaaacggag gaagaagatg acacaaatga tgaagacttt 2100aatgtggaaa taaggcagtt ttcttcatgt tcacacaggt tttcaaaagt tttcagcagt 2160atagatcgaa tcactcagaa ttcagcagaa gagaaggaag actctgtgga caaaaccaaa 2220agcaccacct tgccatccac agaaacactg agctggagtt cagaatattc tgaaatgcaa 2280cagctatcaa catccaactc ttcagatact gaaagcaaca gacataaact cagttctggc 2340ctacttccca aactggctat ttcaacagag ggagagcaag atgaagctgc ctcctgccct 2400ggagaccccc atgaggagcc aggaaagcca gcccttcctc ctgaagagtg tgcccaggag 2460gagcctgagg tcaccacccc agccagcacc atcagcagct ccaccctgtc agttggcagt 2520ttttcagagc acttggatca gataaatgga cgaagcgagt gtgtggacag tacagataat 2580tcctcaaagc catccagtga acccgcttct cacatggctc ggcagcgatt agaaagcaca 2640gaaaaaaaga aaatctcggg gaaagtcaca aagtccctct ctgccagtgc tctttccctc 2700atgatcccag gagatatgtt tgctgtttcc cctctgggaa gtccaatgtc tccccattcc 2760ctgtcctcgg acccttcttc ttcacgagat tcctctccca gccgagattc ctcagcagct 2820tctgccagtc cacatcagcc gattgtgatc cacagttcgg ggaagaacta cggctttacc 2880atccgagcca tccgggtgta tgtgggagac agtgacatct atacagtgca ccatatcgtc 2940tggaatgtag aagaaggaag tccggcatgc caggcaggac tgaaggctgg agatcttatc 3000actcacatca atggagaacc agtgcatgga cttgtccaca cagaagttat agaactccta 3060ctgaagagtg ggaataaggt gtcaatcact actaccccat ttgaaaacac atcaatcaaa 3120actggaccag ccaggagaaa cagctataag agccggatgg tgaggcggag caagaaatcc 3180aagaagaaag aaagtctcga aaggaggaga tctcttttca aaaagctagc caagcagcct 3240tctcctttac tccacaccag ccgaagtttc tcctgcttga acagatccct gtcatcgggt 3300gagagcctcc caggttcccc cactcatagc ttgtctcccc ggtctccaac accaagctac 3360cgctccaccc ctgacttccc atctggtact aattcctccc agagcagctc ccctagttct 3420agtgccccca attccccagc agggtccggg cacatccggc ccagcactct ccacggtctt 3480gcacccaaac tcggcgggca gcggtaccgg tccggaaggc gaaagtccgc cggcaacatc 3540ccactgtccc cgctggcccg gacgccctct ccaaccccgc aacccacctc cccgcagcgg 3600tcaccatccc ctcttctggg acactcactg ggcaattcca agatcgcgca agcctttccc 3660agcaagatgc actccccgcc caccatcgtc agacacatcg tgaggcccaa gagtgcggag 3720ccccccaggt ccccgctgct caagcgcgtg cagtccgagg agaagctgtc gccctcttac 3780ggcagtgaca agaagcacct gtgctcccgc aagcacagcc tggaggtgac ccaagaggag 3840gtgcagcggg agcagtccca gcgggaggcg ccgctgcaga gcctggatga gaacgtgtgc 3900gacgtgccgc cgctcagccg cgcccggcca gtggagcaag gctgcctgaa acgcccagtc 3960tcccggaagg tgggccgcca ggagtctgtg gacgacctgg accgcgacaa gctgaaggcc 4020aaggtggtgg tgaagaaagc agacggcttc ccagagaaac aggaatccca ccagaaatcc 4080catggacccg ggagtgattt ggaaaacttt gctctgttta agctggaaga gagagagaag 4140aaagtctatc cgaaggctgt ggaaaggtca agtacttttg aaaacaaagc gtctatgcag 4200gaggcgccac cgctgggcag cctgctgaag gatgctcttc acaagcaggc cagcgtgcgc 4260gccagcgagg gtgcgatgtc ggatggccgg gtgcctgcgg agcaccgcca gggtggcggg 4320gacttcagac gggcccccgc tcctggcacc ctccaggatg gtctctgcca ctccctcgac 4380aggggcatct ctgggaaggg ggaaggcacg gagaagtcct cccaggccaa ggagcttctc 4440cgatgtgaaa agttagacag caagctggcc aacatcgatt acctccgaaa gaaaatgtca 4500cttgaggaca aagaggacaa cctctgccct gtgctgaagc ccaagatgac agctggctcc 4560cacgaatgcc tgccagggaa cccagtccga cccacgggtg ggcagcagga gcccccgccg 4620gcttctgaga gccgagcttt tgtcagcagc acccatgcag ctcagatgag tgccgtctct 4680tttgttcccc tcaaggcctt aacaggccgg gtggacagtg gaacggagaa gcctggcttg 4740gttgctcctg agtcccctgt taggaagagc ccctccgagt ataagctgga aggtaggtct 4800gtctcatgcc tgaagccgat cgagggcact ctggacattg ctctcctgtc cggacctcag 4860gcctccaaga cagaactgcc ttccccagag tctgcacaga gccccagccc aagtggtgac 4920gtgagggcct ctgtgccacc agttctcccc agcagcagtg ggaaaaagaa cgataccacc 4980agtgcaagag agctttctcc ttccagctta aagatgaata aatcctacct gctggagcct 5040tggttcctgc cccccagccg aggtctccag aattcaccag cagtttccct gcctgaccca 5100gagttcaaga gggacaggaa aggtccccat cctactgcca ggagccctgg aacagtcatg 5160gaaagcaatc cccaacagag agagggcagc tcccctaaac accaagacca caccactgac 5220cccaagcttc tgacctgcct ggggcagaac ctccacagcc ctgacctggc caggccacgc 5280tgcccgctcc cacctgaagc ttccccctca agggagaagc caggcctgag ggaatcgtct 5340gaaagaggcc ctcccacagc cagaagcgag cgctctgctg cgagggctga cacatgcaga 5400gagccctcca tggaactgtg ctttccagaa actgcgaaaa ccagtgacaa ctccaaaaat 5460ctcctctctg tgggaaggac ccacccagat ttctatacac agacccaggc catggagaaa 5520gcatgggcgc cgggtgggaa aacgaaccac aaagatggcc caggtgaggc gaggcccccg 5580cccagagaca actcctctct gcactcagct ggaattccct gtgagaagga gctgggcaag 5640gtgaggcgtg gcgtggaacc caagcccgaa gcgcttcttg ccaggcggtc tctgcagcca 5700cctggaattg agagtgagaa gagtgaaaag ctctccagtt tcccatcttt gcagaaagat 5760ggtgccaagg aacctgaaag gaaggagcag cctctacaaa ggcatcccag cagcatccct 5820ccgccccctc tgacggccaa agacctgtcc agcccggctg ccaggcagca ttgcagttcc 5880ccaagccacg cttctggcag agagccgggg gccaagccca gcactgcaga gcccagctcg 5940agcccccagg accctcccaa gcctgttgct gcgcacagtg aaagcagcag ccacaagccc 6000cggcctggcc ctgacccggg ccctccaaag actaagcacc ccgaccggtc cctctcctct 6060cagaaaccaa gtgtcggggc cacaaagggc aaagagcctg ccactcagtc cctcggtggc 6120tctagcagag aggggaaggg ccacagtaag agtgggccgg atgtgtttcc tgctacccca 6180ggctcccaga acaaagccag cgatgggatt ggccagggag aaggtgggcc ctctgtccca 6240ctgcacactg acagggctcc tctagacgcc aagccacaac ccaccagtgg tgggcggccc 6300ctggaggtgc tggagaagcc tgtgcatttg ccaaggccgg gacacccagg gcctagtgag 6360ccagcggacc agaaactgtc cgctgttggt gaaaagcaaa ccctgtctcc aaagcacccc 6420aaaccatcca ctgtgaaaga ttgccccacc ctgtgcaaac agacagacaa cagacagaca 6480gacaaaagcc cgagtcagcc ggccgccaac accgacagaa gggcggaagg gaagaaatgc 6540actgaagcac tttatgctcc agcagagggc gacaagctcg aggccggcct ttcctttgtg 6600catagcgaga accggttgaa aggcgcggag cggccagccg cgggggtggg gaagggcttc 6660cctgaggcca gagggaaagg gcccggtccc cagaagccac cgacggaggc agacaagccc 6720aatggcatga aacggtcccc ctcagccact gggcagagtt ctttccgatc cacggccctc 6780ccggaaaagt ctctgagctg ctcctccagc ttccctgaaa ccagggccgg agttagagag 6840gcctctgcag ccagcagcga cacctcttct gccaaggccg ccgggggcat gctggagctt 6900ccagccccca gcaacaggga ccataggaag gctcagcctg ccggggaggg ccgaacccac 6960atgacaaaga gtgactccct gccctccttc cgggtctcca ccctgcctct ggagtcacac 7020caccccgacc caaacaccat gggcggggcc agccaccggg acagggctct ctcggtgact 7080gccaccgtag gggaaaccaa agggaaggac cctgccccag cccagcctcc cccagctagg 7140aaacagaacg tgggcagaga cgtgaccaag ccatccccag ccccaaacac tgaccgcccc 7200atctctcttt ctaatgagaa ggactttgtg gtacggcaga ggcgggggaa agagagtttg 7260cgtagcagcc ctcacaaaaa ggccttgtaa 7290152618PRTMus musculus 15Met Gly Glu Lys Val Ser Glu Ala Pro Glu Pro Val Pro Arg Gly Cys1 5 10 15Ser Gly His Gly Ala Arg Thr Leu Val Ser Ser Ala Ala Ala Val Ser 20 25 30Ser Glu Gly Ala Ser Ser Ala Glu Ser Ser Ser Gly Ser Glu Thr Leu 35 40 45Ser Glu Glu Gly Glu Pro Ser Arg Phe Ser Cys Arg Ser Gln Pro Pro 50 55 60Arg Pro Pro Gly Gly Ala Leu Gly Thr Arg Leu Pro Ala Ala Trp Ala65 70 75 80Pro Ala Arg Val Ala Leu Glu Arg Gly Val Pro Thr Leu Pro Leu Pro 85 90 95His Pro Gly Gly Ala Val Leu Pro Val Pro Gln Val Ser Ser Ala Ser 100 105 110Gln Glu Glu Gln Asp Glu Glu Leu Asp His Ile Leu Ser Pro Pro Pro 115 120 125Met Pro Phe Arg Lys Cys Ser Asn Pro Asp Val Ala Cys Gly Leu Gly 130 135 140Lys Ser Leu Lys Tyr Lys Arg Gln Leu Ser Glu Asp Gly Lys Gln Leu145 150 155 160Arg Arg Gly Ser Leu Gly Gly Ala Leu Thr Gly Arg Tyr Leu Leu Pro 165 170 175Asn Pro Val Ala Gly Gln Ala Trp Pro Ala Ser Ala Glu Thr Ser Asn 180 185 190Leu Val Arg Met Arg Ser Gln Ala Leu Gly Gln Ser Ala Pro Ser Leu 195 200 205Thr Ala Ser Leu Lys Glu Leu Ser Leu Pro Arg Arg Gly Ser Leu Cys 210 215 220Arg Thr Ser Asn Arg Lys Ser Leu Ile Gly Asn Gly Gln Ser Pro Ala225 230 235 240Leu Pro Arg Pro His Ser Pro Leu Ser Ala His Ala Gly Asn Ser Pro 245 250 255Gln Asp Ser Pro Arg Asn Phe Ser Pro Ser Ala Ser Ala His Phe Ser 260 265 270Phe Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser Leu Ala Ser Leu Pro 275 280 285Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr Val Ser Ser Ser 290 295 300Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro Tyr Gln Pro Thr Pro305 310 315 320Asp Glu Leu His Phe Leu Ser Lys His Phe Cys Thr Thr Glu Ser Ile 325 330 335Ala Thr Glu Asn Arg Cys Arg Asn Thr Pro Met Arg Pro Arg Ser Arg 340 345 350Ser Leu Ser Pro Gly Arg Ser Pro Ala Cys Cys Asp His Glu Ile Ile 355 360 365Met Met Asn His Val Tyr Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln 370 375 380Met Glu Glu Arg Leu Lys Glu Ile Ile Thr Ser Tyr Ser Pro Asp His385 390 395 400Val Leu Pro Leu Ala Asp Gly Val Leu Ser Phe Thr His His Gln Ile 405 410 415Ile Glu Leu Ala Arg Asp Cys Leu Asp Lys Ser His Gln Gly Leu Ile 420 425 430Thr Ser Arg Tyr Phe Phe Glu Leu Gln His Lys Leu Asp Lys Leu Leu 435 440 445Gln Glu Ala His Asp Arg Ser Glu Ser Gly Glu Leu Ala Phe Ile Lys 450 455 460Gln Leu Val Arg Lys Ile Leu Ile Val Ile Ala Arg Pro Ala Arg Leu465 470 475 480Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr Tyr Leu Leu Glu 485 490 495Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly Ile Lys Thr Asp Ile 500 505 510Pro Arg Tyr Ile Ile Ser Gln Leu Gly Leu Asn Lys Asp Pro Leu Glu 515 520 525Glu Met Ala Gln Leu Gly Asn Tyr Asp Ser Arg Thr Ala Glu Thr Pro 530 535 540Glu Met Asp Glu Ser Val Ser Ser Ser Asn Thr Ser Leu Arg Leu Arg545 550 555 560Arg Lys Pro Arg Glu Ser Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn 565 570 575Gly Ala Tyr Gly Ala Val Tyr Phe Val Arg His Lys Glu Ser Arg Gln 580 585 590Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn 595 600 605Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu 610 615 620Asn Pro Phe Val Val Ser Met Tyr Cys Ser Phe Glu Thr Arg Arg

His625 630 635 640Leu Cys Met Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu 645 650 655Met Lys Asn Met Gly Pro Leu Pro Val Asp Met Ala Arg Met Tyr Phe 660 665 670Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val 675 680 685His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr Ser Met Gly His 690 695 700Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly Leu Met Ser Met705 710 715 720Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe 725 730 735Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro Glu Val 740 745 750Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp Trp Ala Met Gly 755 760 765Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp 770 775 780Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Ile Asn Trp785 790 795 800Pro Glu Lys Asp Glu Ala Pro Pro Pro Asp Ala Gln Glu Leu Ile Thr 805 810 815Leu Leu Leu Arg Gln Asn Pro Leu Glu Arg Leu Gly Thr Gly Gly Ala 820 825 830Tyr Glu Val Lys Gln His Arg Phe Phe Arg Ser Leu Asp Trp Asn Ser 835 840 845Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp 850 855 860Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Lys Tyr His His Met Glu865 870 875 880Thr Glu Glu Glu Asp Asp Thr Asn Asp Glu Asp Phe Thr Val Glu Ile 885 890 895Arg Gln Phe Ser Ser Cys Ser His Arg Phe Ser Lys Val Phe Ser Ser 900 905 910Ile Asp Arg Ile Thr Gln Asn Ser Gly Glu Asp Lys Asp Asp Ser Glu 915 920 925Asp Lys Thr Lys Ser Thr Thr Leu Pro Ser Thr Glu Thr Leu Ser Trp 930 935 940Ser Ser Glu Tyr Ser Glu Met Gln Gln Leu Ser Thr Ser Asn Ser Ser945 950 955 960Asp Thr Glu Ser Asn Arg Cys Lys Leu Ser Ser Gly Leu Leu Pro Lys 965 970 975Leu Ala Ile Ser Thr Asp Gly Glu Gln Asp Glu Ala Val Pro Cys Ser 980 985 990Gly Asp Pro Arg Glu Glu Pro Glu Lys Pro Val Pro Pro Ser Glu Glu 995 1000 1005Cys Thr Gln Glu Glu Pro Glu Val Thr Thr Pro Ala Ser Thr Ile Ser 1010 1015 1020Ser Ser Thr Leu Ser Val Gly Ser Phe Ser Glu His Leu Asp Gln Ile1025 1030 1035 1040Asn Gly Arg Ser Glu Cys Val Asp Ser Thr Asp Asn Ser Ser Lys Pro 1045 1050 1055Ser Ser Glu Pro Thr Ser His Val Ala Arg Gln Arg Leu Glu Ser Thr 1060 1065 1070Glu Lys Lys Lys Ile Ser Gly Lys Val Thr Lys Ser Leu Ser Ala Ser 1075 1080 1085Ala Leu Ser Leu Met Ile Pro Gly Asp Met Phe Ala Val Ser Pro Leu 1090 1095 1100Gly Ser Pro Met Ser Pro His Ser Leu Ser Ser Asp Pro Ser Ser Ser1105 1110 1115 1120Arg Asp Ser Ser Pro Ser Arg Asp Ser Ser Ala Ala Ser Ala Ser Pro 1125 1130 1135His Gln Pro Ile Val Ile His Ser Ser Gly Lys Asn Tyr Gly Phe Thr 1140 1145 1150Ile Arg Ala Ile Arg Val Tyr Val Gly Asp Ser Asp Ile Tyr Thr Val 1155 1160 1165His His Ile Val Trp Asn Val Glu Glu Gly Ser Pro Ala Tyr Gln Ala 1170 1175 1180Gly Leu Lys Ala Gly Asp Leu Ile Thr His Ile Asn Gly Glu Pro Val1185 1190 1195 1200His Gly Leu Val His Thr Glu Val Ile Glu Leu Leu Leu Lys Ser Gly 1205 1210 1215Asn Lys Val Ser Ile Thr Thr Thr Pro Phe Glu Asn Thr Ser Ile Lys 1220 1225 1230Thr Gly Pro Ala Arg Arg Asn Ser Tyr Lys Gly Arg Met Val Arg Arg 1235 1240 1245Ser Lys Lys Ser Lys Lys Lys Glu Ser Leu Glu Arg Arg Arg Ser Leu 1250 1255 1260Phe Lys Lys Leu Ala Lys Gln Pro Ser Pro Leu Leu His Thr Ser Arg1265 1270 1275 1280Ser Phe Ser Cys Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser Leu Pro 1285 1290 1295Gly Ser Pro Thr His Ser Leu Ser Pro Arg Ser Pro Thr Pro Ser Tyr 1300 1305 1310Arg Ser Thr Pro Asp Phe Pro Ser Gly Thr Asn Ser Ser Gln Ser Ser 1315 1320 1325Ser Pro Ser Ser Ser Ala Pro Asn Ser Pro Ala Gly Ser Gly His Ile 1330 1335 1340Arg Pro Ser Thr Leu His Gly Leu Ala Pro Lys Leu Ser Gly Gln Arg1345 1350 1355 1360Tyr Arg Ser Gly Arg Arg Lys Ser Ala Gly Ser Ile Pro Leu Ser Pro 1365 1370 1375Leu Ala Arg Thr Pro Ser Pro Thr Pro Gln Pro Thr Ser Pro Gln Arg 1380 1385 1390Ser Pro Ser Pro Leu Leu Gly His Ser Leu Gly Asn Ala Lys Ile Thr 1395 1400 1405Gln Ala Phe Pro Ser Lys Met His Ser Pro Pro Thr Ile Val Arg His 1410 1415 1420Ile Val Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu Leu Lys1425 1430 1435 1440Arg Val Gln Ser Glu Glu Lys Leu Ser Pro Ser Tyr Gly Ser Asp Lys 1445 1450 1455Lys Leu Leu Cys Ser Arg Lys His Ser Leu Glu Val Thr Gln Glu Glu 1460 1465 1470Val Gln Arg Glu Gln Cys Gln Arg Glu Val Thr Leu Gln Ser Leu Glu 1475 1480 1485Glu Asn Val Cys Asp Ala Pro Ser Leu Ser Arg Ala Arg Pro Val Glu 1490 1495 1500Gln Gly Cys Leu Lys Arg Pro Val Ser Arg Lys Val Gly Arg Gln Glu1505 1510 1515 1520Ser Val Asp Asp Leu Asp Arg Asp Lys Leu Lys Ala Lys Val Val Val 1525 1530 1535Lys Lys Pro Glu Glu Lys His Glu Ser His Gln Lys Pro His Ser Leu 1540 1545 1550Gly Gly Asp Ser Glu Ser Tyr Ala Leu Phe Arg Leu Glu Glu Arg Glu 1555 1560 1565Lys Lys Val Tyr Ser Lys Gly Leu Glu Arg Ser Gly His Phe Glu Asn 1570 1575 1580Thr Ser Ala Glu Leu Pro Ser Val Gly Ser Leu Leu Lys Asp Thr Leu1585 1590 1595 1600His Lys Gln Ala Ser Val Arg Ala Ser Glu Gly Val Thr Ser Asp Gly 1605 1610 1615Ala Ala Cys Ser Leu Thr Pro Gly Glu His Ser Gln Ser Leu Gly Asp 1620 1625 1630Phe Lys Arg Ala Ser Ala Ser Gly Ile Leu His Asp Ser Val Cys Pro 1635 1640 1645Ile Ser Asp Arg Pro Ala Pro Gly Lys Val Glu Tyr Ser Glu Lys Ala 1650 1655 1660Ser Gln Ala Lys Glu Leu Leu Arg Ser Glu Lys Leu Asp Ser Lys Leu1665 1670 1675 1680Ala Asn Ile Asp Tyr Leu Arg Lys Lys Met Ser Leu Asp Asp Lys Asp 1685 1690 1695Asp Ser His Cys Ala Ile Leu Lys Pro Lys Ile Thr Ser Ser Ala His 1700 1705 1710Glu Cys Leu Pro Gly Asn Pro Ile Arg Pro Met Ala Gly Gln Gln Glu 1715 1720 1725Thr Pro Pro Ala Ser Glu Asn Arg Ala Phe Ile Asn Ser Thr His Thr 1730 1735 1740Pro Gln Met Ser Ala Val Ser Phe Val Pro Leu Lys Ala Leu Ala Gly1745 1750 1755 1760Arg Val Glu Asn Gly Gly Glu Lys Ala Gly Leu Ala Ala Pro Glu Ser 1765 1770 1775Pro Val Arg Lys Ser Pro Ser Glu Tyr Lys Leu Glu Gly Arg Ser Val 1780 1785 1790Ser Cys Leu Lys Pro Ile Glu Gly Thr Leu Asp Ile Ala Leu Leu Ser 1795 1800 1805Gly Pro His Ala Ser Lys Thr Glu Leu Leu Ser Pro Glu Pro Ala Gln 1810 1815 1820Ser Pro Ser Pro Gly Ile Asn Val Gly Pro Cys Val Pro Leu Ala Leu1825 1830 1835 1840Pro Gly Ser Ser Gly Lys Lys Gly Asp Ser Thr Ser Leu Arg Glu Pro 1845 1850 1855Ser Ser Ala Asn Leu Lys Val Asn Lys Ser Tyr Leu Leu Glu Pro Arg 1860 1865 1870Phe Leu Pro Pro Ser Arg Ala Leu Gln Asp Ser Leu Ala Ala Ser Gly 1875 1880 1885Pro Glu Pro Lys Ser Lys Pro Glu Arg Lys Leu Ile His Pro Ser Ala 1890 1895 1900Arg Ser Pro Ala Thr Val Thr Glu Ser Asn Leu Gln Gln Lys Glu Gly1905 1910 1915 1920Gly Pro Ala Thr His Gln Asp Arg Ser Thr Asp Thr Arg Asn Leu Pro 1925 1930 1935Gly Pro Gly Gln Thr Leu His Asn Val Asp Leu Pro Arg Leu Cys Thr 1940 1945 1950Arg Ala Pro Leu Pro Pro Glu Gly Thr Pro Ala Lys Glu Lys Pro Cys 1955 1960 1965Leu Lys Glu Pro Ser Ala Lys Val Lys Ser Glu Trp Ser Ala Val Arg 1970 1975 1980Asp Asp Gly His Arg Asp Pro Cys Ala Lys Leu Cys Pro Ala Glu Thr1985 1990 1995 2000Gly Lys Ala Ser Asp Ser Ser Lys Pro Leu Pro Ser Gly Gly Arg Thr 2005 2010 2015Gln Pro Asp Phe Tyr Lys Gln Thr Gln Thr Ser Glu Lys Ala Trp Ala 2020 2025 2030His Ala Lys Thr Asn His Lys Asp Ser Gln Asp Glu Val Lys Ser Leu 2035 2040 2045Ala Arg Glu Asp Ser Ala Ser Leu Leu Tyr Glu Lys Glu Ile Gly Arg 2050 2055 2060Ala Arg Lys Gly Pro Glu Pro Lys Pro Glu Val Pro Ala Thr Arg Cys2065 2070 2075 2080Pro Pro Gln Pro Pro Gly Ile Glu Gly Glu Lys Arg Glu Lys Leu Ser 2085 2090 2095Ala Ala Pro Ser Leu Gln Lys Gln Ala Pro Lys Glu Pro Asp Arg Lys 2100 2105 2110Glu Gln Thr Ser Gln Arg Pro Gly Gly Ser Gly Pro Gln Gln Pro Pro 2115 2120 2125Pro Thr Lys Glu Leu Ser Asn Ser Ala Ser Trp Gln His Gly Ser Ser 2130 2135 2140Pro Ser His Thr Leu Lys Lys Glu Pro Gly Thr Lys Ala Ala Ala Ala2145 2150 2155 2160Glu Pro Ser Thr Ser Leu His Asp Thr Pro Arg Ser Ala Thr Ala Thr 2165 2170 2175Thr Thr Ala Ile Ala Thr Thr Thr Thr Thr Thr Ser Ala Gly His Ser 2180 2185 2190Asp Cys Ser Ser His Lys Ala Arg Pro Gly Pro Asp Pro Ser Pro Ser 2195 2200 2205Lys Ser Lys His Gln Asp Arg Ser Leu Ser Ser Gln Lys Leu Ser Ala 2210 2215 2220Gly Ser Ala Lys Gly Lys Glu Pro Val Thr Gln Pro Leu Gly Gly Ser2225 2230 2235 2240Ile Arg Glu Gly Lys Gly Gly Ser Lys Gly Pro Val Asp Thr Phe Ser 2245 2250 2255Ala Val Leu Thr Thr Gln Gly Lys Ala Ser Asp Val Leu Val Gln Gly 2260 2265 2270Glu Gly Arg Val Ser Ile Ile Val His Thr Glu Glu Cys Pro Leu Asp 2275 2280 2285Ala Lys Leu Lys Asn Thr Asn Gly Gly Cys Pro Pro Glu Met Gln Ala 2290 2295 2300Lys His Pro Pro Arg Gln Gly His Leu Ser Glu Ala Ala Asp Gln Lys2305 2310 2315 2320Pro Leu Ile Ala Gly Glu Lys Gln Ser Pro Ser Pro Lys His Pro Lys 2325 2330 2335Pro Ser Thr Val Lys Asp Tyr Pro Ser Leu Cys Arg Gln Thr Asp Arg 2340 2345 2350Ser Pro Ser His Gln Ala Thr Thr Gly Asp Arg Lys Ala Glu Gly Lys 2355 2360 2365Lys Cys Thr Asp Ala Leu Tyr Val Ala Ala Pro Glu Gly Tyr Lys Pro 2370 2375 2380Glu Ala Ser Pro Ser Leu His His Gly Glu Thr Gly Leu Arg Gly Ser2385 2390 2395 2400Glu Arg Pro Pro Met Gly Met Gly Lys Gly Phe Ser Glu Pro Lys Gly 2405 2410 2415Lys Gly Pro Gly Pro Gln Lys Ser Leu Ala Glu Thr Gly Lys Pro Ser 2420 2425 2430Gly Met Lys Arg Ser Pro Ser Ala Thr Val Gln Ser Ser Leu Arg Ser 2435 2440 2445Ala Ala Pro Pro Glu Lys Ser Leu Ser Tyr Ser Ala Ser Phe Pro Glu 2450 2455 2460Ala Gln Pro Gly Val Arg Glu Val Pro Ala Ala Asn Ser Ser Pro Ser2465 2470 2475 2480Ser Ala Lys Ala Thr Gly Gly Thr Ser Glu Phe Pro Ala Pro Ser Ser 2485 2490 2495Arg Asp His Arg Lys Leu Gln Ser Gly Gly Asp Gly Arg Ser Gln Met 2500 2505 2510Ile Lys Ser Asp Ser Leu Pro Ser Phe Arg Leu Ser Thr Ser Ala Leu 2515 2520 2525Glu Ser His Phe Gln Asp Pro Gln Val Pro Ile Ala Ser Gly His Arg 2530 2535 2540Gly Arg Ala Leu Ser Val Thr Ala Ala Thr Gly Glu Pro Lys Gly Arg2545 2550 2555 2560Glu Leu Ala Gln Pro Pro Pro Val Arg Lys Gln Asn Ala Cys Arg Glu 2565 2570 2575Ala Thr Arg Ala Pro Pro Ala Pro Ser Thr Asp Arg Ser Leu Pro Leu 2580 2585 2590Ser Ser Glu Lys Asp Phe Val Val Arg Gln Arg Arg Gly Lys Glu Thr 2595 2600 2605Leu Arg Ser Ser Pro His Lys Lys Ala Ser 2610 2615167857DNAMus musculus 16atgggggaga aagtttccga ggcgcctgag cccgtgcccc ggggctgcag cggacacggc 60gcccggaccc tagtctcttc ggcggcagcc gtgtcctcgg agggcgcttc ctcagcggag 120tcatcctctg gctcggaaac tctgtcggag gaaggggagc ccagccgctt ctcctgcagg 180tcgcagccgc cgcggccgcc gggcggcgcc ctgggaaccc ggctacccgc cgcgtgggct 240cccgcgcgcg tggctctgga gcgtggagtc cctaccctgc cgctgccgca cccgggagga 300gcggtgctgc cggtgcccca ggtcagcagc gcatcccaag aggagcagga tgaagagctt 360gaccacatac tgtctccgcc acccatgccg tttcggaaat gcagcaaccc agatgtggcc 420tgcggcctcg gaaaatcact gaagtacaag agacagctta gtgaggatgg gaagcagctg 480cggcggggga gcctgggagg agccctcaca gggaggtacc tccttccaaa cccggtagca 540ggacaggcct ggcctgcttc ggcggagacg tccaacctcg tgcgcatgcg cagccaggcc 600cttggccaat cggctccctc gctcacagcc agcttgaagg agctgagcct cccccgaaga 660ggaagtcttt gccgaacaag caaccggaag agtttgatag gcaatggcca gtctccagca 720ctgcctcgac cacactcacc tctctctgct catgcaggaa atagccctca agacagtcca 780aggaatttct cccccagtgc ctcagcccat ttctcatttg cgaggagaac ggatgggcgc 840cgctggtctc tggcttctct cccttcctca ggctatggga caaatacccc aagctccacc 900gtctcctcat cctgttcttc ccaggagaag ttgcaccagc taccatacca gccaacccca 960gatgaattac acttcttatc caaacacttc tgcacaacag aaagtatcgc cactgagaac 1020cggtgcagaa acacacccat gcgtccacgt tcccggagtc tcagccctgg acggtccccc 1080gcctgctgtg accatgaaat aattatgatg aaccatgtct acaaagaaag gttcccaaag 1140gccacagctc agatggaaga gcgtctgaag gagatcatca ccagctactc tccagaccat 1200gttctcccct tggcagatgg ggtacttagt ttcactcacc atcagatcat tgagctggct 1260cgggactgtt tggataaatc tcaccagggt ctcatcacgt cgagatactt ttttgagttg 1320cagcacaaac tggacaagtt gctccaggag gctcacgatc gctctgaaag tggagaactg 1380gcatttatca agcaactagt ccgaaagatc ctaattgtca ttgcccgccc cgctcggtta 1440ttggagtgtt tggaatttga tcctgaagaa ttttattacc tattggaagc tgcagaaggc 1500catgccaaag aaggccaagg aatcaaaact gacatcccta ggtatatcat cagccagctg 1560ggactcaata aggacccttt agaagaaatg gctcagttgg ggaattacga cagtaggaca 1620gcagagacac cagagatgga tgagtcagtg agtagctcaa atacttccct gagacttcga 1680aggaaacccc gagagagtga ttttgaaaca attaaattga tcagcaatgg agcctacggg 1740gcagtctact ttgttcggca caaagagtcc cgccagaggt ttgccatgaa gaagatcaac 1800aagcagaacc tcatccttcg gaaccagatc cagcaggcct tcgtggagcg agacatcctg 1860actttcgcag agaacccctt tgtggtcagc atgtattgct cctttgaaac gaggcgtcac 1920ttatgcatgg tcatggagta tgtagaaggg ggagactgtg cgaccctaat gaaaaacatg 1980ggacctctcc cagttgatat ggccagaatg tatttcgccg agaccgtctt ggccttggag 2040tacctgcata attacggaat cgtacacagg gacttgaagc cagacaacct gttggtcacc 2100tccatggggc acataaaact gactgacttc ggcttgtcta aggtgggatt aatgagcatg 2160accaccaatc tctatgaagg ccacatagag aaggacgctc gagagttctt agataaacag 2220gtctgtggta cacctgagta cattgccccc gaggtgattc tgagacaggg ctacgggaaa 2280cccgtggact ggtgggccat gggcattatc ctctatgaat ttctggtcgg atgtgtgcct 2340ttctttgggg acactccaga agagctattt ggacaagtca tcagtgatga aatcaactgg 2400cctgaaaagg acgaggcccc tcctccagac gctcaggagc tgattacctt gctcctcagg 2460cagaatccgc tggagaggct gggaacaggt ggagcctatg aagtgaagca gcatcgtttc 2520ttccgctcct tagactggaa cagtttgctg agacagaagg cggaatttat tccccaactg 2580gaatcggagg atgacacaag ttattttgat actcggtcag agaagtatca tcacatggag 2640acggaggagg aggacgatac aaacgatgag gacttcaccg tggagataag gcagttttct 2700tcctgttcac acaggttttc aaaagttttc agcagtatag atcgcataac tcaaaattca 2760ggagaagaca aagatgactc tgaggacaag accaaaagca caacgttgcc atccacagag 2820acactcagct ggagttccga atactctgaa atgcaacagt tatcgacctc caactcttca 2880gatactgaaa

gcaacaggtg caaactcagc tctggcttgc tccccaagct ggctatttcg 2940acagatgggg aacaagatga ggctgtccct tgctctggag accccagaga ggagccagag 3000aaacctgtcc ctccctctga ggagtgtact caggaggagc ccgaggtcac caccccagcc 3060agcaccatca gcagttccac actgtcagtt ggcagttttt cagagcactt ggatcagata 3120aatgggcgaa gcgagtgtgt ggacagtaca gataattcct caaagccatc cagtgaaccc 3180acttctcacg tggctcgaca gcgcttagaa agcacagaga aaaagaaaat ttctgggaaa 3240gtcacaaagt ccctctcggc cagtgctctg tccctcatga tcccaggaga tatgttcgct 3300gtatctccat tgggaagccc aatgtcccca cactccctgt cttcagaccc ttcttcttca 3360cgggattcct ctcccagccg agactcttct gcagcatctg ccagtccgca tcagcccatt 3420gtcatccaca gctcaggcaa gaactatggg ttcaccatcc gtgctatccg cgtgtacgtg 3480ggggacagtg acatctacac agtgcaccat atcgtctgga acgtagaaga aggaagtccc 3540gcataccagg caggactgaa ggccggggat ctgatcacac acatcaacgg agagccggtg 3600cacggcctcg tccacacgga agttatcgag ctcctgctga agagtgggaa taaggtgtct 3660atcaccacta ctccatttga aaacacatca atcaaaacgg gaccagccag gagaaacagt 3720tacaagggcc ggatggtgag acgaagcaag aagtccaaga agaaggagag tctagaaagg 3780aggagatctc tcttcaagaa gctggccaag cagccttctc ctttgctcca caccagccga 3840agtttctcct gcttaaaccg gtccctgtca tctggagaga gcctcccggg ttccccaact 3900cacagcttgt ccccgaggtc tccaacaccc agttatcgtt ctactcccga ttttccgtca 3960ggtacaaatt cctcccagag cagctcccca agttcaagtg cccccaattc tccagcaggt 4020tcagggcaca tccggcccag caccctccat ggcctggctc ccaaactcag cgggcagcga 4080taccgctctg gaagacggaa gtcggctggc agcatccctc tctccccgct ggccaggaca 4140ccctctccca ctccacagcc tacctctcct cagcgttcac catccccact gttgggacac 4200tcactgggca atgccaagat cactcaggcc tttcctagca agatgcactc tccccccaca 4260atcgtcagac acatcgtgag gcccaagagt gcagagccgc cccgctcccc actgctgaaa 4320cgggtgcagt cggaggaaaa gttgtcaccc tcctatggca gtgacaagaa gcttctgtgc 4380tcccgcaagc atagcctaga ggtgacacaa gaggaggtac agagggagca gtgtcagcgg 4440gaagtgacac tgcagagcct ggaagagaat gtgtgtgacg ctccttccct cagtcgggcc 4500aggccagtgg agcaaggctg tctgaaacgc cccgtgtccc ggaaggtggg caggcaagag 4560tctgtggatg acctggaccg ggacaagctg aaagccaagg ttgtcgtaaa gaaaccagaa 4620gagaaacatg aatcgcacca gaaacctcac agccttggtg gtgattcgga aagctatgct 4680ctcttcaggc tagaggagag agagaaaaaa gtgtactcca aggggttgga aaggtcaggc 4740cattttgaaa acacatcagc agagttgcct tctgtgggca gcctgctgaa ggacactctt 4800cacaagcagg ccagcgtgag ggccagcgag ggggtgacct cagacggggc agcttgcagc 4860ctgacaccag gggagcacag ccagtctcta ggtgacttta agcgggcctc agcttctggc 4920attctccatg atagtgtgtg ccccatctct gataggcctg ctcctggaaa ggttgaatac 4980tcggagaagg cctctcaggc caaagagctc cttcgaagtg aaaaactaga cagcaagctg 5040gccaatattg attacctcag aaagaaaatg tcattggatg acaaagatga cagccactgt 5100gccatcctga aacccaagat aacatctagc gcccatgaat gtctgccagg gaaccccata 5160cggcccatgg cagggcaaca agagaccccg ccagcctctg aaaaccgggc attcatcaac 5220agtacccaca cacctcagat gagtgcagtt tcctttgttc ctctcaaagc cttagctggc 5280cgggtagaga acggagggga gaaagcaggc ttagctgctc ccgagtcccc tgtcaggaag 5340agcccctccg agtataagct agagggcagg tcagtttcat gtctcaagcc gatcgagggc 5400acactggaca ttgctctcct gtctggacct cacgcctcca aaacagagtt gctttcccca 5460gagcctgcac agagtcccag cccaggcatc aacgtgggac catgtgtgcc actagctctt 5520cctgggagca gtgggaaaaa gggagactcc accagcctga gagagccttc ctcagccaac 5580ttaaaagtaa ataaatctta tctgctggag cctcggttcc tacccccgag ccgggctctc 5640caggactctc tcgcagcctc tgggccagaa ccgaagtcaa agccggaaag gaagctcatt 5700catccttctg ccaggagccc agcaactgtc acagagagca atcttcagca gaaagagggt 5760ggtcccgcca cacaccaaga ccgctccact gacaccagga acctccctgg cccagggcag 5820accctacaca atgtggacct acccaggctg tgtacacgtg ccccactccc accggaaggg 5880acgcccgcaa aggagaagcc atgtctgaag gaaccctctg ccaaggtgaa aagcgagtgg 5940tctgccgtga gggatgacgg acacagagat ccctgtgcga agctgtgccc ggcagagact 6000ggtaaagcca gcgacagttc caaacccctg ccttccgggg ggaggaccca acccgatttc 6060tacaagcaga cccagacttc ggagaaagca tgggcgcatg caaaaacaaa ccacaaagat 6120agccaagatg aggtgaagtc cctggccagg gaggactcag cttcactttt atatgaaaag 6180gagataggcc gggcacgaaa aggtcctgaa cccaaaccgg aagttcctgc tacccggtgc 6240cctcctcagc caccaggaat tgagggtgag aagcgagaaa agctctccgc tgccccctct 6300ttgcagaaac aggctcccaa agagccagac aggaaggaac agacttcgca aaggcctgga 6360ggtagtggcc ctcaacaacc cccacccacc aaagagctgt ctaactcagc atcctggcag 6420cacggcagtt ctccgagtca cactttaaag aaggagcccg ggaccaaagc tgccgctgca 6480gaaccaagca ccagccttca tgacactccc cgatctgcta cagccaccac cactgccatt 6540gccaccacca ccactaccac cagtgccggg cacagtgact gcagtagcca taaggcccgg 6600cctggccctg accccagccc ttcaaagtct aagcaccaag acaggtccct ctcctcacag 6660aagctgagtg ctggctctgc aaaaggcaaa gagcctgtca ctcaacccct gggtggttcc 6720atcagagaag gcaagggtgg cagcaagggt ccagtggaca cattttctgc tgtcctgacc 6780acccagggca aagcaagtga tgtgcttgtg cagggagaag gtcgggtctc aatcattgtc 6840cacactgaag agtgtcctct cgatgccaaa ctgaaaaaca ccaatggagg gtgtccccca 6900gagatgcagg cgaagcatcc acccagacaa ggacatctca gtgaagcagc agaccagaag 6960ccactcattg ctggtgagaa gcaaagcccg tctccaaagc atcccaaacc atccactgtg 7020aaagattacc ccagtctgtg cagacagaca gacagaagcc caagccatca ggctaccact 7080ggggacagga aggcagaagg aaagaaatgc acagacgcac tttatgtcgc agccccagag 7140ggctacaagc cagaggccag cccttctctc caccacggcg agaccggact cagaggctca 7200gagaggccac ccatgggcat ggggaagggc ttctctgagc ccaaggggaa agggccaggt 7260ccccagaagt cactggctga aacaggcaag cccagcggta tgaaaaggtc accctctgcc 7320accgtgcaga gctctctccg ctcagctgcc cccccagaaa agtctctgag ttactcagcc 7380agctttcccg aggcccagcc tggagtgcga gaggtccctg cagccaacag cagcccctca 7440tctgccaagg ctacaggggg gacctcagag ttcccagccc ccagcagcag ggaccacagg 7500aagcttcagt ctggaggaga cggccgaagc caaatgataa agagtgactc tctgccctcc 7560ttccgcctct ccacctctgc tctggagtca catttccagg atccacaggt gcccatcgca 7620tcaggccacc gaggcagggc actgtcagta actgctgcca caggagaacc caaagggaga 7680gagctcgccc agcctccccc agtcaggaaa cagaatgcgt gcagagaggc gaccagagca 7740cccccagccc caagcacaga tcgctccctc cctctttcct cagagaaaga cttcgtggtt 7800cggcagagaa ggggcaagga gaccttaagg agcagtcctc acaaaaaggc ctcctaa 78571720DNAMus musculus 17taccctgccg ctgccgcacc 201824DNAArtificial SequenceMAST4 exon 1 CRISPR F 18caccggaaac tctgtcggag gaag 241924DNAArtificial SequenceMAST4 exon 1 CRISPR R 19aaaccttcct ccgacagagt ttcc 242024DNAArtificial SequenceMAST4 exon 15 CRISPR F 20caccggcaca aagagtcccg ccag 242124DNAArtificial SequenceMAST4 exon 15 CRISPR R 21aaacctggcg ggactctttg tgcc 2422357DNAMus musculus 22atgggggaga aagtttccga ggcgcctgag cccgtgcccc ggggctgcag cggacacggc 60gcccggaccc tagtctcttc ggcggcagcc gtgtcctcgg agggcgcttc ctcagcggag 120tcatcctctg gctcggaaac tctgtcggag gaaggggagc ccagccgctt ctcctgcagg 180tcgcagccgc cgcggccgcc gggcggcgcc ctgggaaccc ggctacccgc cgcgtgggct 240cccgcgcgcg tggctctgga gcgtggagtc cctaccctgc cgctgccgca cccgggagga 300gcggtgctgc cggtgcccca ggtcagcagc gcatcccaag aggagcagga tgaagag 35723357DNAMus musculus 23atgggggaga aagtttccga ggcgcctgag cccgtgcccc ggggctgcag cggacacggc 60gcccggaccc tagtctcttc ggcggcagcc gtgtcctcgg agggcgcttc ctcagcggag 120tcatcctctg gctcggaaac tctgtcggag gaaggggagc ccagccgctt ctcctgcagg 180tcgcagccgc cgcggccgcc gggcggcgcc ctgggaaccc ggctacccgc cgcgtgggct 240cccgcgcgcg tggctctgga gcgtggagtc cctaccctgc cgctgccgca cccgggagga 300gcggtgctgc cggtgcccca ggtcagcagc gcatcccaag aggagcagga tgaagag 35724209DNAMus musculus 24ggcagtctac tttgttcggc acaaagagtc ccgccagagg tttgccatga agaagatcaa 60caagcagaac ctcatccttc ggaaccagat ccagcaggcc ttcgtggagc gagacatcct 120gactttcgca gagaacccct ttgtggtcag catgtattgc tcctttgaaa cgaggcgtca 180cttatgcatg gtcatggagt atgtagaag 20925209DNAMus musculus 25ggcagtctac tttgttcggc acaaagagtc ccgccagagg tttgccatga agaagatcaa 60caagcagaac ctcatccttc ggaaccagat ccagcaggcc ttcgtggagc gagacatcct 120gactttcgca gagaacccct ttgtggtcag catgtattgc tcctttgaaa cgaggcgtca 180cttatgcatg gtcatggagt atgtagaag 2092620DNAArtificial SequenceAcan Forward 26ggtcactgtt accgccactt 202720DNAArtificial SequenceAcan Reverse 27ccagggagct gatctcgtag 202820DNAArtificial SequenceChad Forward 28gccaaggacc tgcgctggct 202920DNAArtificial SequenceChad Reverse 29gctttcttgg acctcttggt 203020DNAArtificial SequenceCol2a1 Forward 30gccaagacct gaaactctgc 203120DNAArtificial SequenceCol2a1 Reverse 31cttgccccac ttaccagtgt 203220DNAArtificial SequenceCol9a1 Forward 32cgtggatttc caggccgtgg 203320DNAArtificial SequenceCol9a1 Reverse 33tcgctgtcct tgatcaccag 203420DNAArtificial SequenceCol11a1 Forward 34gctaggtgtt cctggtctgc 203520DNAArtificial SequenceCol11a1 Reverse 35ccactttctc cagctgttcc 203620DNAArtificial SequenceComp Forward 36aacggctcgc actgcaccga 203720DNAArtificial SequenceComp Reverse 37cccgttgccg gcccagccaa 203820DNAArtificial SequenceFmod Forward 38ccagcagtcc acctactacg 203920DNAArtificial SequenceFmod Reverse 39tgcctcagct tggagaagac 204020DNAArtificial SequenceLect1 Forward 40gttttgctgg aggagagaag 204120DNAArtificial SequenceLect1 Reverse 41cagtgggtgt agctccgcct 204220DNAArtificial SequenceMatn1 Forward 42ggcaagacct gcaatgtctg 204320DNAArtificial SequenceMatn1 Reverse 43tagtcctggc tccggccatc 204420DNAArtificial SequenceMatn3 Forward 44caggaccagg tgaatgaggt 204520DNAArtificial SequenceMatn3 Reverse 45atctgcattc agagtgtagc 204620DNAArtificial SequenceMatn4 Forward 46agctcccgca gcgtgcgccc 204720DNAArtificial SequenceMatn4 Reverse 47atgccgcggg cgcgcgcctg 204820DNAArtificial SequenceSusd5 Forward 48tctcagaatg gctctcaggg 204920DNAArtificial SequenceSusd5 Reverse 49taccactccc cacagctgtt 205020DNAArtificial SequenceUcma Forward 50ggtcaacagc tccaggaaag 205120DNAArtificial SequenceUcma Reverse 51tttctggtgg ctaagcaagg 205220DNAArtificial SequenceMmp8 Forward 52tgatggaccc aatggaatcc 205320DNAArtificial SequenceMmp8 Reverse 53ggggtcacag gctttgggtg 205420DNAArtificial SequenceMmp9 Forward 54gacgggtatc ccttcgacgg 205520DNAArtificial SequenceMmp9 Reverse 55gtggtggcgc accagcggta 205622DNAArtificial SequenceGapdh Forward 56tggcaaagtg gagattgttg cc 225721DNAArtificial SequenceGapdh Reverse 57aagatggtga tgggcttccc g 215820DNAArtificial SequenceHapln1 Forward 58gggctggact ggtgcaatgc 205920DNAArtificial SequenceHapln1 Reverse 59gcaaatatct ggcccacttt 206020DNAArtificial SequenceHapln3 Forward 60tcctttgggg actaccaagg 206120DNAArtificial SequenceHapln3 Reverse 61cacccgcccc ttgagggcag 206220DNAArtificial SequencePrelp Forward 62gcccacaaca tcctgagaaa 206320DNAArtificial SequencePrelp Reverse 63aagcacatca tgaggtccag 206420DNAArtificial SequenceFbln7 Forward 64actgggaacc gctgtcagca 206520DNAArtificial SequenceFbln7 Reverse 65acatcctcac agctcttccc 206620DNAArtificial SequenceSdc4 Forward 66aggtcatcga cccccaggac 206720DNAArtificial SequenceSdc4 Reverse 67aactcattgg tgggggcttt 206820DNAArtificial SequenceBgn Forward 68aagatctcca agatccatga 206920DNAArtificial SequenceBgn Reverse 69gcctctgaga tgcgcaggta 207025DNAArtificial SequencemMAST4 CRISPR exon 1 sgRNA F 70caccgtaccc tgccgctgcc gcacc 257125DNAArtificial SequencemMAST4 CRISPR exon 1 sgRNA R 71aaacggtgcg gcagcggcag ggtac 2572357DNAMus musculus 72atgggggaga aagtttccga ggcgcctgag cccgtgcccc ggggctgcag cggacacggc 60gcccggaccc tagtctcttc ggcggcagcc gtgtcctcgg agggcgcttc ctcagcggag 120tcatcctctg gctcggaaac tctgtcggag gaaggggagc ccagccgctt ctcctgcagg 180tcgcagccgc cgcggccgcc gggcggcgcc ctgggaaccc ggctacccgc cgcgtgggct 240cccgcgcgcg tggctctgga gcgtggagtc cctaccctgc cgctgccgca cccgggagga 300gcggtgctgc cggtgcccca ggtcagcagc gcatcccaag aggagcagga tgaagag 3577338DNAArtificial SequencehMAST4 CR#1 R 73taatacgact cactatagga gtgtggtcga ggcaatgc 387435DNAArtificial SequencehMAST4 CR#1 R 74ttctagctct aaaacgcatt gcctcgacca cactc 357538DNAArtificial SequencehMAST4 CR#2 F 75taatacgact cactataggt aactcgtctg gtgttggt 387635DNAArtificial SequencehMAST4 CR#2 R 76ttctagctct aaaacaccaa caccagacga gttac 357738DNAArtificial SequencehMAST4 CR#3 F 77taatacgact cactatagag caaccggaaa agcttaat 387835DNAArtificial SequencehMAST4 CR#3 R 78ttctagctct aaaacattaa gcttttccgg ttgct 3579629DNAHomo sapiens 79ttatcacttg tgtgtatggc atgttacata tttgcactca agcgctggaa gaaggcattt 60gattattgct ccactggtgg tgaggaatat tgatggtgtt gtgctatatg aatacattat 120attttctaat attcaagagg tagccacccc tcaaatatta gtgaatgcat aattgtaata 180attttaacaa taacatgagc agataggttg ctcaacctgg tccatgtcta ccgggaacat 240ggttgaacat tattgatgct atattctttt taaactttgt tttttctttc tttttgatag 300ttgccgaaca agcaaccgga aaagcttaat aggcaatggg cagtcaccag cattgcctcg 360accacactca cctctctctg ctcatgcagg taattggtta ccatttcttg agttttgttt 420tatttcttta tttgttggtt ttttaaaata attaatgcat tttgatattt ggtatgtctt 480cacatgttat ctttgttttc ctgctgtttt atccctaagt tgttctttgc gatatgttag 540cccagatctt atcctctctg tttcagtgtt tggactctaa aatacagaat tcctttttat 600atggggtctc tttttaatta tttctttct 62980638DNAHomo sapiens 80tccagagaga aaactatctt ttgggaaatt ataaacaaat gaggcaaaat atggaaagca 60ttttgaactc tgagagagaa catcaagtta tacatttagg cagtcgttct tataacttta 120acatgaaaaa gaaacaataa aaatggtggt attgtccaag tttaactcat cgatctctcc 180tgttcatttg aagagtttct ttctgaggta gttatgtgac ctcactttgg tttttttcag 240tcatcctgtt cctcccagga gaagttgcat cagttaccat accaaccaac accagacgag 300ttacacttct tatcaaaaca tttctgtacc accgaaagca tcgccactga gaacagatgc 360aggaacacgc cgatgcgccc ccgttcccga agtctgaggt gtgtgggcct ggctgaaaac 420cattacttag ttggattctc tattttcaaa cattttgagt gaacacttcg gtcctttagg 480tcatatgtgt gttaactgac ttgcaaacta ttacaaatat agtgtgatgt ttccatgtac 540acataatatt gttaattacc attgaaaggc atcttataag tttccttttc agttctcaca 600atttgctgat tgcagcagta gtaatcacga tggtcttg 63881629DNAHomo sapiens 81ttatcacttg tgtgtatggc atgttacata tttgcactca agcgctggaa gaaggcattt 60gattattgct ccactggtgg tgaggaatat tgatggtgtt gtgctatatg aatacattat 120attttctaat attcaagagg tagccacccc tcaaatatta gtgaatgcat aattgtaata 180attttaacaa taacatgagc agataggttg ctcaacctgg tccatgtcta ccgggaacat 240ggttgaacat tattgatgct atattctttt taaactttgt tttttctttc tttttgatag 300ttgccgaaca agcaaccgga aaagcttaat aggcaatggg cagtcaccag cattgcctcg 360accacactca cctctctctg ctcatgcagg taattggtta ccatttcttg agttttgttt 420tatttcttta tttgttggtt ttttaaaata attaatgcat tttgatattt ggtatgtctt 480cacatgttat ctttgttttc ctgctgtttt atccctaagt tgttctttgc gatatgttag 540cccagatctt atcctctctg tttcagtgtt tggactctaa aatacagaat tcctttttat 600atggggtctc tttttaatta tttctttct 6298220DNAArtificial SequenceHumanAcan RT Forward 82gaatcaactg ctgcagacca 208320DNAArtificial SequenceHumanAcan RT Reverse 83gtgccagatc atcaccacac 208420DNAArtificial SequenceHumanCol9a1 RT Forward 84cgtggatttc caggccgtgg 208520DNAArtificial SequenceHumanCol9a1 RT Reverse 85tcgctgtcct tgatcaccag 208622DNAArtificial SequenceHumanGapdh RT Forward 86tggcaaagtg gagattgttg cc 228721DNAArtificial SequenceHumanGapdh RT Reverse 87aagatggtga tgggcttccc g 218823DNAArtificial SequenceMAST4 Exon 1 targeting sequence 88ggaaactctg tcggaggaag ggg 238923DNAArtificial SequenceMAST4 Exon 15 targetting sequence 89ggcacaaaga gtcccgccag agg

239020DNAArtificial SequencePrimer amplifying Exon 1 (F) 90ctgtggtcca acctctgtca 209120DNAArtificial SequencePrimer amplifying Exon 1 (R) 91atcggctcag tgacacttcc 209229DNAMus musculusMAST4 (w/t) 92gccgcacccg ggaggagcgg tgctgccgg 299327DNAMus musculusMAST4 (k/o) 93gccgcccggg aggagcggtg ctgccgg 27

Claims

1. A composition for promoting production of an extracellular matrix from eukaryotic cells, the composition comprising a compound capable of specifically binding to Microtubule Associated Serine/Threonine Kinase Family Member 4 (MAST4) protein or a fragment thereof, or a compound capable of specifically binding to a nucleic acid encoding the MAST4 protein or the fragment thereof.

2. The composition of claim 1, wherein the MAST4 protein comprises any one amino acid sequence of SEQ ID NOS: 1 to 7 and 15, and the nucleic acid encoding the MAST4 protein comprises any one polynucleotide sequence of SEQ ID NOS: 8 to 14 and 16.

3. The composition of claim 1, wherein the compound capable of specifically binding to the MAST4 protein or the fragment thereof, or the compound capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof is a chemically synthesized compound, polypeptide, or polynucleotide that inhibits activity or expression of the MAST4 protein, or a combination thereof.

4. The composition of claim 3, wherein the polypeptide is an antibody or an antigen-binding site thereof.

5. The composition of claim 1, wherein the compound capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof is microRNA (miRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), Piwi-interacting RNA (piRNA), small nuclear RNA (snRNA), or antisense oligonucleotide, each specific to the nucleic acid encoding the MAST4 protein or the fragment thereof, or a combination thereof.

6. The composition of claim 1, wherein the compound capable of specifically binding to the nucleic acid encoding the MAST4 protein or the fragment thereof is CRISPR-Cas comprising guide RNA specific to the nucleic acid encoding the MAST4 protein or the fragment thereof.

7. The composition of claim 6, wherein the guide RNA is a dual RNA comprising CRISPR RNA (crRNA) and transactivating crRNA (tracrRNA) specific to the nucleic acid encoding the MAST4 protein or the fragment thereof, or a single strand guide RNA comprising parts of the crRNA and the tracrRNA and hybridizing with the nucleic acid encoding the MAST4 protein or the fragment thereof.

8. The composition of claim 1, wherein the eukaryotic cells are fibroblast cells or chondrocytes.

9. The composition of claim 1, wherein the composition is to promote chondrogenesis of the eukaryotic cells.

10. The composition of claim 1, wherein the composition is to prevent or treat a joint disease or to improve symptoms thereof.

11. The composition of claim 9, wherein to promote chondrogenesis is to induce chondrogenesis.

12. The composition of claim 1, wherein the composition is used for tissue regeneration or anti-aging.

13. The composition of claim 1, further comprising TGF-.beta.1.

14. A method of preventing, treating, or improving a joint disease, the method comprising administering the composition of claim 1 to a subject.

15. A method of producing an extracellular matrix from eukaryotic cells, the method comprising contacting the eukaryotic cells with the composition for promoting production of extracellular matrix from eukaryotic cells of claim 1.

16. The method of claim 15, wherein the eukaryotic cells are isolated from a subject.

17. The method of claim 15, wherein the contacting with the eukaryotic cells comprises culturing the eukaryotic cells in the presence of the composition.

18. The method of claim 17, wherein the culturing is to culture in the presence of a chondrogenic inducer.

19. The method of claim 15, further comprising isolating the extracellular matrix from the contacting product.

20. The method of claim 15, wherein the eukaryotic cells are chondrocytes.