HLA Class II Deficient Cells, HLA Class I Deficient Cells Capable of Expressing HLA Class II Proteins, and Uses Thereof

Abstract

The invention provides isolated primate cells preferably human cells that comprise a genetically engineered disruption in a human leukocyte antigen (HLA) class II-related gene, which results in deficiency in MHC class II expression and function. This invention also provides isolated cells further comprising a genetically engineered disruption in a beta-2 microglobulin (B2M) gene, which results in HLA class I/class II deficiency. Also provided are the method of using the cells for transplantation and treating a disease condition.

Description

CROSS REFERENCE

[0001] This application claims priority to U.S. provisional patent application Ser. No. 61/625,314 filed Apr. 17, 2012, incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

[0003] Human pluripotent stem cells have the potential to treat diseases affecting almost every organ system. However, the clinical use of human pluripotent stem cells and their derivatives has a major limitation--rejection of transplanted cells by the recipient due to differences in the major histocompatibility complex.

[0004] The major histocompatibility complex (MHC) is a cell surface multi-component molecule found in all vertebrates that mediates interactions of leukocytes with other leukocytes or other cells. The MHC gene family is divided into three groups: class I, class II and class III. In humans, MHC is referred to as human leukocyte antigen (HLA). HLA class II molecules (HLA-II) are transmembrane protein found only on professional antigen-presenting cells (APCs) including macrophages, dendritic cells and B cells. In addition, solid organ may sometimes express HLA class II genes that participate in immune rejection. The HLA class I (HLA-I) protein is expressed on all nucleated cells and consists of an HLA class I heavy chain (or α chain) and β-2 microglobulin (B2M). HLA class I protein presents peptides on the cell surface to CD8+ cytotoxic T cells. Six HLA class I α chains have been identified to date, including three classical (HLA-A, HLA-B and HLA-C) and three non-classical (HLA-E, HLA-F and HLA-G) α chains. The specificity for peptide binding on the HLA class I molecule peptide binding cleft is determined by the α chain. Recognition by CD8+ T cells of the peptides presented by the HLA class I molecule mediates cellular immunity. HLA class II molecules and class I molecules are both heterodimers. Class I molecules consist of an alpha chain (or heavy chain) and β-2 microglobulin (B2M), whereas the class II molecules consist of two homologous subunits: the alpha subunit and beta subunit.

[0005] HLA class II (HLA-II) molecules or proteins present on the cell surface peptide antigens from extracellular proteins including proteins of an extracellular pathogen, while HLA class I proteins present peptides from intracellular proteins or pathogens. Loaded HLA class II proteins on the cell surface interact with CD4+ helper T cells. The interaction leads to recruitment of phagocytes, local inflammation, and/or humoral responses through the activation of B cells. Several HLA class II gene loci have been identified to date, including HLA-DM (HLA-DMA and HLA-DMB that encode HLA-DM a chain and HLA-DM β chain, respectively), HLA-DO (HLA-DOA and HLA-DOB that encode HLA-DO α chain and HLA-DO β chain, respectively), HLA-DP (HLA-DPA and HLA-DPB that encode HLA-DP α chain and HLA-DP β chain, respectively), HLA-DQ (HLA-DQA and HLA-DQB that encode HLA-DQ α chain and HLA-DQ β chain, respectively), and HLA-DR (HLA-DRA and HLA-DRB that encode HLA-DR α chain and HLA-DR β chain, respectively).

[0006] The HLA class I and/or class II proteins from an allogeneic source constitutes a foreign antigen in the context of transplantation. The recognition of non-self HLA class I and/or class II proteins is a major hurdle in using pluripotent cells for transplantation or replacement therapies.

[0007] Thus, although individualized stem cell preparations or HLA-diverse stem cell banks may address the current problem of transplantation, they require that multiple cell lines be characterized, differentiated into therapeutic cell products, and approved for human administration. This time-consuming, technically difficult, and expensive process is a major factor preventing stem cell-based therapies from entering clinical trials. Thus, there exists a need for a more effective and less expensive cell-based therapies that are not impeded by rejection.

SUMMARY OF THE INVENTION

[0008] In a first aspect, the present invention provides isolated cells comprising a genetically engineered disruption in a human leukocyte antigen (HLA) class II-related gene, wherein the cell is a primate cell. In one embodiment, the HLA class II-related gene is selected from the group consisting of regulatory factor X-associated ankyrin-containing protein (RFXANK), regulatory factor 5 (RFX5), regulatory factor X-associated protein (RFXAP), class II transactivator (CIITA), HLA-DPA (α chain), HLA-DPB (β chain), HLA-DQA, HLA-DQB, HLA-DRA, HLA-DRB, HLA-DMA, HLA-DMB, HLA-DOA and HLA-DOB. In another embodiment, the cell comprises genetically engineered disruptions in at least two, at least three, or in all four of the HLA class II-related genes. In a further embodiment, the HLA class II-related gene is regulatory factor X-associated ankyrin-containing protein (RFXANK). In a still further embodiment, the cell comprises genetically engineered disruptions in all copies of the HLA class II-related gene. In another embodiment the cell further comprises one or more recombinant immunomodulatory genes, each capable of expressing an immunomodulatory polypeptide in the human cell. In a further embodiment, the one or more immunomodulatory genes comprise a polynucleotide capable of encoding an HLA II protein. In another embodiment, the one or more immunomodulatory genes comprise a polynucleotide capable of encoding a single chain fusion HLA class II protein. In a further embodiment, the cell further comprises a genetically engineered disruption in the β2-microglobulin (B2M) gene.

[0009] In another aspect, the present invention provides isolated cells comprising (a) a genetically engineered disruption in a beta-2 microglobulin (B2M) gene; and (b) one or more polynucleotides capable of encoding an HLA class II protein, or a single chain fusion HLA class II protein; wherein the cell is a primate cell.

[0010] In one embodiment of either of these aspects, the cell comprises genetically engineered disruptions of all copies of the B2M gene. In a further embodiment, the HLA II gene encodes an HLA protein selected from the group consisting of an HLA-DM α chain, an HLA-DM β chain, an HLA-DO α chain, an HLA-DO β chain, an HLA-DP α chain, an HLA-DP β chain, an HLA-DQ α chain, an HLA-DQ β chain, an HLA-DR α chain and an HLA-DR β chain.

[0011] In another embodiment, the single chain fusion HLA class II protein comprises at least a portion of an HLA class II gene α chain covalently linked to at least a portion of an HLA class II gene β chain, wherein the HLA class II gene is selected from the group consisting of HLA-DP, HLA-DQ, HLA-DR, HLA-DM, and HLA-DO. In a further embodiment, the single chain fusion HLA class II protein comprises a plurality of different single chain fusion HLA class II proteins. In another embodiment, the single chain fusion HLA class II protein comprises at least a portion of HLA-DQ α chain and at least a portion of HLA-DQ β chain. In a still further embodiment, the single chain fusion HLA class II protein comprises at least a portion of HLA-DQ α chain allele HLA-DQA1*01 and at least a portion of HLA-DQ β chain allele HLA-DQB1*02.

[0012] In a further embodiment of either aspect of the cells of the invention, the HLA protein or the single chain fusion HLA class II protein presents a first target peptide antigen on the cell surface. In one such embodiment, the first target peptide antigen is covalently linked to the single chain fusion HLA class II protein.

[0013] In another embodiment the cell further comprises a polynucleotide capable of encoding a single chain fusion HLA class I protein. In one such embodiment, the single chain fusion HLA class I protein comprises at least a portion of B2M covalently linked to at least a portion of an HLA class I α chain selected from the group consisting of HLA-A, HLA-B, HLA-C, HLA-E, HLA-F and HLA-G. In another such embodiment, the single chain fusion HLA class I protein comprises at least a portion of B2M covalently linked to at least a portion of HLA-A. In a further embodiment the single chain fusion HLA class I protein comprises at least a portion of B2M covalently linked to at least a portion of HLA-A0201. In another embodiment the cell further expresses a second target peptide antigen that is presented by the single chain fusion HLA class I protein on the cell surface. For example, the second target peptide antigen may be covalently linked to the single chain fusion HLA class I protein.

[0014] In another embodiment of either aspect of the cells of the invention, the cell further comprises one or more recombinant genes capable of encoding a suicide gene product. For example, the suicide gene product may comprise a protein selected from the group consisting of thymidine kinase and an apoptotic signaling protein.

[0015] The cells of either aspect of the may have a normal karyotype and may be non-transformed cells. The cells may be stem cells, such as hematopoietic stem cells, embryonic stem cells, pluripotent stem cells, induced pluripotent stem cells, liver stem cells, neural stem cells, pancreatic stem cells or mesenchymal stem cells. The stem cell may be differentiated, such as dendritic cells, pancreatic islet cells, liver cells, muscle cells, keratinocytes, neuronal cells, hematopoietic cells, lymphocytes, red blood cells, platelets, skeletal muscle cells, ocular cells, mesenchymal cells, fibroblasts, lung cells, gastrointestinal (GI) tract cells, vascular cells, endocrine cells, adipocytes or cardiomyocytes. The cells may be human cells.

[0016] In another aspect, the present invention provides vaccines comprising the cell of any one embodiment or combinations of embodiments of the cells of the present invention that include at least one target peptide antigen on the cell surface, wherein the vaccine is capable of eliciting in a primate an immune response specific for the target peptide antigen(s).

[0017] In a further aspect, the invention provides methods of transplantation in a patient in need thereof comprising the step of administering to the patient an effective amount of the cell or vaccine of any embodiment or combination of embodiments of the cells of the invention. In one such embodiment, the patient may be immune competent. In another embodiment, the cell or vaccine may comprise a differentiated cell.

DESCRIPTION OF THE FIGURES

[0018] FIG. 1 shows the structure of exemplary two adeno-associated virus (AAV) gene targeting vectors, designed to insert either a TKNeo (AAV-RFXANK-ETKNpA) or HyTK (AAV-RFXANK-HyTK) gene controlled by an EF1alpha promoter (EF) into exon 3 of the RFXANK gene, which is also shown below the vectors. Selection of vector-infected cells with G418 or hygromycin (Hygro) allows one to isolate cells targeted by the TKNeo or HyTK vectors respectively. Subsequent expression of Cre recombinase and selection with gancyclovir (GCV) then allows one to isolate clones that have removed the TKNeo or HyTK genes, leaving behind two inactivated RFXANK alleles with stop codons in all 3 reading frames, a loxP site, and a polyadenylation site (StopX3-loxP-pA). LoxP is the recombination site for Cre recombinase. ITR is a vector inverted terminal repeat. Similar vectors could be designed to target other genes.

[0019] FIG. 2 (A) Schematic depiction of targeting strategy for infection of human embryonic stem cells with construct AAV-RFXANK-ETKNpA. (B) Photograph of stained gel showing polymerase chain reaction (PCR) products obtained after infection of human embryonic stem cells with AAV-RFXANK-ETKNpA and PCR using a forward primer homologous to the neomycin sequence of the selection cassette and a reverse primer homologous to the RFXANK gene which was outside the targeting homology arm, as indicated by the arrows above.

DETAILED DESCRIPTION OF THE INVENTION

[0020] All references cited are herein incorporated by reference in their entirety. Within this application, unless otherwise stated, the techniques utilized may be found in any of several well-known references such as: Molecular Cloning: A Laboratory Manual (Sambrook, et al., 1989, Cold Spring Harbor Laboratory Press), Gene Expression Technology (Methods in Enzymology, Vol. 185, edited by D. Goeddel, 1991. Academic Press, San Diego, Calif.), "Guide to Protein Purification" in Methods in Enzymology (M. P. Deutshcer, ed., (1990) Academic Press, Inc.); PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, Calif.), Culture of Animal Cells: A Manual of Basic Technique, 2nd Ed. (R. I. Freshney. 1987. Liss, Inc. New York, N.Y.), Gene Transfer and Expression Protocols, pp. 109-128, ed. E. J. Murray, The Humana Press Inc., Clifton, N.J.), and the Ambion 1998 Catalog (Ambion, Austin, Tex.).

[0021] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. "And" as used herein is interchangeably used with "or" unless expressly stated otherwise.

[0022] All embodiments of any aspect of the invention can be used in combination, unless the context clearly dictates otherwise.

[0023] In a first aspect, the present invention provides isolated cells comprising a genetically engineered disruption in a human leukocyte antigen (HLA) class II-related gene, wherein the cell is a primate cell. The HLA class II related genes as used in the instant application broadly refer to genes that encode proteins involved in the HLA class II mediated immune responses. Thus, HLA class II related genes encompass genes that encode the HLA class II molecules such as HLA-DM (SEQ ID NO: 48, 50), HLA-DO (SEQ ID NO: 52, 54), HLA-DP (SEQ ID NO: 36, 38), HLA-DQ (SEQ ID NO: 40, 42), and HLA-DR (SEQ ID NO: 44, 46). The sequences of exemplary HLA class II genes/proteins can be found in publicly available database under GenBank or IMGT/HLA database numbers NM_--033554.3 (SEQ ID NOs:36, 37) for HLA-DPA, HLA00514 (SEQ ID NOs:38, 39) for HLA-DPB, HLA00601 (SEQ ID NOs:40, 41) for HLA-DQA, HLA00622 (SEQ ID NOs:42, 43) for HLA-DQB, NM_--019111 (SEQ ID NOs:44, 45) for HLA-DRA, HLA00664 (SEQ ID NOs:46, 47) for HLA-DRB, NM_--006120 (SEQ ID NOs:48, 49) for HLA-DMA, NM_--002118 (SEQ ID NOs:50, 51) for HLA-DMB, NM_--002119 (SEQ ID NOs:52, 53) for HLA-DOA, and NM_--002120 (SEQ ID NOs:54, 55) for HLA-DOB.

[0024] In addition, HLA class II related genes also include genes that encode HLA class II regulatory proteins that regulate the expression of HLA class II molecules, including without limitation regulatory factor X-associated ankyrin-containing protein (RFXANK), regulatory factor 5 (RFX5), regulatory factor X-associated protein (RFXAP), and class II transactivator (CIITA). For example, regulatory factor X-associated ankyrin-containing protein (RFXANK) together with regulatory factor X-associated protein and regulatory factor-5 form a complex that binds to the X box motif of HLA class II gene promoters and activates transcription of the HLA class II genes. The sequences of exemplary HLA class II-related genes that regulate the expression of HLA class II molecules can be found in publicly available database under GenBank Accession Numbers NM_--134440.1 (SEQ ID NOs:24, 25) and NM_--003721.2 (SEQ ID NOs:26, 27) for RFXANK, NM_--000449.3 (SEQ ID NOs:28, 29) and NM_--001025603.1 (SEQ ID NOs:30, 31) for RFX5, NM_--000538.3 (SEQ ID NOs:32, 33) for RFXAP and NM_--000246.3 (SEQ ID NOs:34, 35) for CIITA. All the sequences disclosed under these GenBank Accession Numbers are herein incorporated by reference.

[0025] In certain embodiments, the invention provides an isolated primate preferably human cell that comprises a genetically engineered disruption in at least one HLA class II-related gene as defined herein. In certain particular embodiments, the cell comprises genetically engineered disruptions of all copies of the at least one HLA class II-related gene. In certain other embodiments, the cell comprises a plurality of genetically engineered disruptions in a plurality of HLA class II-related genes.

[0026] In certain embodiments, the HLA class II-related gene is selected from the group consisting of regulatory factor X-associated ankyrin-containing protein (RFXANK), regulatory factor 5 (RFX5), regulatory factor X-associated protein (RFXAP), and class II transactivator (CIITA). In certain particular embodiments, the cell comprises at least one genetically engineered disruption in at least one, at least two, at least three, or all of the HLA class II-related genes selected from the group consisting of regulatory factor X-associated ankyrin-containing protein (RFXANK), regulatory factor 5 (RFX5), regulatory factor X-associated protein (RFXAP), and class II transactivator (CIITA). Any combinations of these four HLA class II-related genes as target for genetic disruption to create HLA class II deficient cell are within the scope of the invention.

[0027] In certain other embodiments, the cell comprises at least one genetically engineered disruption of an HLA class II-related genes selected from the group consisting of regulatory factor X-associated ankyrin-containing protein (RFXANK) (SEQ ID NO: 24-27), regulatory factor 5 (RFX5) (SEQ ID NO: 28-31), regulatory factor X-associated protein (RFXAP) (SEQ ID NO: 32, 33), class II transactivator (CIITA) (SEQ ID NO: 34, 35), HLA-DPA (a chain) (SEQ ID NO: 36, 37), HLA-DPB (β chain) (SEQ ID NO: 38, 39), HLA-DQA (SEQ ID NO: 40, 41), HLA-DQB (SEQ ID NO: 42, 43), HLA-DRA (SEQ ID NO: 44, 45), HLA-DRB (SEQ ID NO: 46-47), HLA-DMA (SEQ ID NO: 48, 49), HLA-DMB (SEQ ID NO: 50, 51), HLA-DOA (SEQ ID NO: 52, 53) and HLA-DOB (SEQ ID NO: 54, 55).

[0028] The genetically engineered disruptions include without limitation deletions, insertions, substitutions and truncations of a target HLA class II-related gene that result in no expression of the target gene or expression of a truncated or mutated protein with no function or much reduced function as compared to the wild type protein. In certain embodiments, the genetically engineered disruption of a HLA class II-related gene leads to the expression of a truncated HLA class II-related protein. In certain particular embodiments, the HLA class II-related gene is RFXANK (SEQ ID NO: 24-27). In certain other particular embodiments, the HLA-related gene is selected from the group consisting of HLA-DPA (α chain) (SEQ ID NO: 36, 37), HLA-DPB (β chain) (SEQ ID NO: 38, 39), HLA-DQA (SEQ ID NO: 40, 41), HLA-DQB (SEQ ID NO: 42, 43), HLA-DRA (SEQ ID NO: 44, 45), HLA-DRB (SEQ ID NO: 46-47), HLA-DMA (SEQ ID NO: 48, 49), HLA-DMB (SEQ ID NO: 50, 51), HLA-DOA (SEQ ID NO: 52, 53) and HLA-DOB (SEQ ID NO: 54, 55). In certain further embodiments the cell comprises genetically engineered disruptions in all copies of the HLA class II-related gene.

[0029] In another aspect, the invention provides HLA class I and HLA class II deficient cells. In certain embodiments, the invention provides a primate cell, preferably a human cell that comprises a genetically engineered disruption in an HLA class II-related gene and further comprises a genetically engineered disruption in the β2-microglobulin (B2M) gene (SEQ ID NO: 1). In other particular embodiments, the cell further comprises genetically engineered disruptions of all copies of the B2M gene (SEQ ID NO: 1). In certain embodiments, the genetic disruptions in the B2M (SEQ ID NO: 1) gene result in defective or no expression of the B2M protein (SEQ ID NO: 2). In other particular embodiments, the cell further comprises genetically engineered disruptions of all copies of the B2M gene. In certain embodiments, the genetic disruptions in the B2M gene result in defective or no expression of the B2M protein. Since B2M is a common component of all HLA class I proteins, the disruptions preclude the expression of all natural HLA class I proteins on the cell surface. Thus, in this aspect of the invention an HLA class I/class II deficient cell is provided. The B2M coding sequence is shown in SEQ ID NO:1 (GenBank Accession Number NM_--004048) and the B2M protein sequence is shown in SEQ ID NO:2. There may be many single nucleotide polymorphisms (SNPs) in the gene; as will be understood by those of skill in the art, the human cells and methods of the invention are applicable to any such B2M gene and SNPs.

[0030] Any suitable technique for introducing a genetically engineered disruption (in an HLA class II-related gene, in B2M gene or any other suitable gene) can be used; exemplary techniques for gene disruptions are disclosed throughout the application and are within the level of skill in the art based on the teachings herein and the teachings known in the art. Other exemplary techniques can be found, for example, in U.S. Patent Application Publication Number US2008/0219956, published Sep. 11, 2008, and incorporated by reference herein in its entirety. These techniques may optionally include steps to remove non-human DNA sequences from the cells after disruption of an HLA class II-related gene and optionally disruption of B2M gene.

[0031] One such techniques employs an adeno-associated virus gene targeting vector, optionally including removing the transgene used for targeting via techniques such as those described below, or by removing the transgene used for targeting by Cre-mediated loxP recombination, or other suitable recombination techniques. See Khan et al. 2011, Protocol, 6:482-501, which is incorporated by reference in its entirety. Exemplary targeting vectors and exemplary vector diagrams are also disclosed herein. It is within the level of those of skill in the art, based on the teachings herein and known in the art, to utilize a variety of techniques for making the HLA class II, preferably human cells, of the invention.

[0032] In certain embodiments, the cell genome of HLA class II deficient cells may comprise no more than 100, no more than 50 or no more than 30 nucleotides of non-human DNA sequences. In certain other embodiments, the cell genome may comprise 6, 5, 4, 3, 2, 1, or 0 nucleotides of non-human DNA sequences. Exemplary strategy for genetically disrupting the RFXANK gene is shown in FIG. 1. The non-human DNA sequences can be removed by a second round of targeting to delete the HyTK or TKNeo transgenes in the first vectors or by the Cre-mediated loxP recombination.

[0033] In certain other embodiments, the HLA class II or HLA class I/class II deficient cells further comprise one or more recombinant immunomodulatory genes. Suitable immunomodulatory genes include without limitation a gene encoding a viral protein that inhibits antigen presentation, a microRNA gene, a gene that encodes an HLA class II protein, or a gene that encodes a single chain (SC) fusion HLA class II protein. The term "single chain fusion HLA class II protein," "single chain fusion HLA class II molecule" or "single chain fusion HLA class II antigen" refers to a fusion protein comprising at least a portion of the HLA class II α chain covalently linked, either directly or via a linker sequence, to at least a portion of an HLA class II β chain or a class II α or β chain linked to a peptide antigen, or linked class II α and β chains also linked to a peptide antigen. On the other hand, the term "HLA class II protein," "HLA class II molecule" or "HLA class II antigen" refers to a non-covalently associated heterodimer of an HLA class II α chain and an HLA β chain expressed on the surface of a wild type cell. In embodiments wherein the gene encodes an HLA class II protein (as opposed to a single chain fusion HLA class II protein), the gene is under control of a promoter not involved in normal class II expression in the cell. In one embodiment, the gene is episomally expressed; in another embodiment, the gene is integrated into the cell's genome. In either embodiment, the gene is operatively linked (i.e.: under transcriptional control) to a promoter not involved in normal class II expression in the cell. Any suitable promoter may be used, as may be determined by one of skill in the art based on the specific intended design and use of the constructs and cells.

[0034] In another aspect, the present invention provides isolated cells comprising (a) a genetically engineered disruption in a beta-2 microglobulin (B2M) gene; and (b) one or more polynucleotides capable of encoding an HLA II protein (alpha or beta chains) or a single chain fusion HLA class II protein; wherein the cell is a primate cell. Cells according to this aspect of the invention are HLA class I deficient cells.

[0035] HLA class II deficient cells, HLA class I deficient cells, or HLA class I/class II deficient cells can be used as universal donor cells. In certain particular embodiments, the HLA class II deficient cells, HLA class I deficient cells, or HLA class I/class II deficient cells are hematopoietic cells or dendritic cells for use in transplantation. In addition, solid organ cells may sometimes express HLA class II genes that participate in immune rejection. Thus, in certain advantageous embodiments, the invention provides HLA class II, HLA class I deficient cells, or HLA class I/class II deficient cells for transplantation for treatment of diseases or injuries associated with solid organs.

[0036] In certain particular embodiments of any of the cells of the present invention, the HLA α and β chains are selected from the group consisting of α and β chains of HLA-DM, HLA-DR, HLA-DP, HLA-DQ, and HLA-DO. The α and β chains can be but do not have to be from the same HLA class II gene. For example, an HLA class II protein or a single chain fusion HLA class II protein may comprise at least a portion of an HLA-DQ α chain and at least a portion of an HLA-DQ β chain (also referred to as a dimeric construct). HLA class II proteins and single chain fusion HLA class II proteins comprising mismatching HLA class II alleles are also contemplated. In certain particular embodiments, an HLA class II protein or a single chain fusion HLA class II protein may comprise at least a portion of the HLA-DQ α chain allele HLA-DQA1*01 (SEQ ID NO:41) and at least a portion of the HLA-DQ β chain allele HLA-DQB1*02 (SEQ ID NO:43). In certain preferred embodiments, the leader sequence (or signal peptide) of the second portion of the fusion protein is removed in the fusion construct. For example, in a single chain fusion HLA class II protein that comprises at least a portion of HLA-DQA1*01 (SEQ ID NO: 41) at the N-terminus covalently linked to at least a portion of HLA-DQB1*02 (SEQ ID NO: 43) at the C-terminus, the HLA-DQA1*01 (SEQ ID NO: 41) leader sequence is left in, and the HLA-DQB1*02 (SEQ ID NO: 43) leader sequence is removed from the construct. In certain other embodiments, the cell further expresses at least two, at least three, or at least four or more different single chain fusion HLA class II proteins. In certain particular embodiments, the HLA class II protein or single chain fusion HLA class II protein also comprises a first target peptide antigen that occupies the peptide binding site of the HLA class II protein or single chain fusion HLA class II protein, wherein the peptide antigen is covalently linked to the HLA class II protein or single chain fusion HLA class II protein (also referred to as a trimeric construct). In certain other embodiments, the covalently linked peptide antigen is cleaved via a built-in protease cleavage site, and the cleaved peptide antigen can bind to the peptide binding site of the single chain fusion HLA-II protein for presentation.

[0037] Thus, HLA class II, HLA class I deficient cells, or HLA class I/class II deficient cells also encompass cells having genetically engineered disruptions in all copies of an HLA class II gene (e.g., disruptions in all copies of HLA-DQ a and/or β chain), wherein one HLA class II allele is genetically engineered to express, instead of the wild type HLA class II protein, an HLA class II protein of interest or a single chain fusion HLA class II protein (i.e., genetically targeted knockin in one HLA-II allele). Take HLA-DQ as an example, in certain embodiments, HLA-DQ.sup.-/- cells express HLA-DQ protein only in the context of a single chain fusion HLA-DQ protein from an HLA-DQ genetic locus. In certain advantageous embodiments, the expression of the single chain fusion HLA class II protein is regulated by the endogenous HLA-DQ regulatory sequence located at the HLA-DQ locus.

[0038] In related embodiments, HLA class II, HLA class I deficient cells, or HLA class I/class II deficient cells further encompass cells having genetically engineered disruptions in all copies of a certain HLA-II gene, wherein all alleles of the specific HLA-II gene are genetically engineered to express, instead of the wild type HLA-II protein, single chain fusion HLA class II proteins (i.e., genetically targeted knockin in all HLA-II alleles). HLA class II, HLA class I deficient cells, or HLA class I/class II deficient cells with such genetic disruptions express a particular HLA-II protein only in the context of single chain fusion HLA class II proteins from the genetic loci of all the alleles of the particular HLA-II gene.

[0039] HLA class II proteins and single chain fusion HLA class II proteins comprising sequence variants and fragments of HLA class II α chains and β chains are contemplated by the instant invention, wherein such HLA class II proteins or single chain fusion constructs nevertheless possess normal HLA class II functions, e.g., forming proper secondary structure of the heterodimer on the cell surface, presenting peptides in the peptide binding site, interacting with CD4+ helper T cells and triggering HLA class II-mediated immune responses. In certain embodiments, the variants share at least 75%, 78%, 80%, 81%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or complete sequence homology with the naturally occurring HLA class II α or β chain sequences, wherein the variants possess normal HLA class II functions. In certain other embodiments, the variants share at least 75%, 80%, 81%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or complete sequence homology with the sequences of HLA class II α or β chains as shown in SEQ ID NOs:37, 39, 41, 43, 45, 47, 49, 51, 53 and 55.

[0040] Further, the HLA class II, HLA class I deficient cells, or HLA class I/class II deficient cells can be engineered to recombinantly express a single chain fusion HLA class I protein in a B2M-/- genetic background. The HLA class I deficient cells or HLA class I/class II deficient cells recombinantly expressing a single chain fusion HLA class I protein are nevertheless deficient in normal B2M function in that the cells do not express wild type B2M protein (SEQ ID NO:2) that can form a non-covalently associated heterodimer with any HLA class I α chain on the cell surface.

[0041] The term "single chain fusion HLA class I protein," "single chain fusion HLA class I molecule" or "single chain fusion HLA class I antigen" refers to a fusion protein comprising at least a portion of the B2M protein covalently linked, either directly or via a linker sequence, to at least a portion of an HLA-I α chain. On the other hand, the term "HLA class I protein," "HLA class I molecule" or "HLA class I antigen" refers to a non-covalently associated heterodimer of B2M and an HLA α chain expressed on the surface of a wild type cell.

[0042] As used herein, the term "HLA class I α chain" or "HLA-I heavy chain" refers to the α chain of the HLA class I heterodimer. HLA class I heavy chain includes without limitation HLA class I α chains HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G. Representative DNA and protein sequences are provided for HLA-A (GenBank No. K02883.1, SEQ ID NO:3; UniProt No. P01892, SEQ ID NO:4), HLA-B (NM_--005514, SEQ ID NO:5; NP_--005505; SEQ ID NO:6), HLA-C (NM_--002117, SEQ ID NO:7; NP_--002108, SEQ ID NO:8), HLA-E (NM_--005516, SEQ ID NO:9; NP_--005507, SEQ ID NO:10), HLA-F (NM_--018950, SEQ ID NO:11; NP_--061823, SEQ ID NO:12), and HLA-G (NM_--002127, SEQ ID NO:13; NP_--002118, SEQ ID NO:14).

[0043] In addition, although the term "HLA class I or II protein/molecule" is known to refer to the MHC class I or II protein/molecule in human, the terms HLA and MHC are sometimes used interchangeably throughout this application: for example, the term HLA class I or HLA class II protein can also be used to refer to the primate equivalent to the HLA class I protein or HLA class II protein, respectively, in a primate. One of skill in the art will be able to discern the meaning of the term based on the content.

[0044] Thus, HLA class I deficient cells or HLA class I/class II deficient cells also encompass cells having genetically engineered disruptions in all copies of the B2M gene, wherein one B2M allele is genetically engineered to express, instead of the wild type B2M protein, a single chain fusion HLA class I protein (i.e., genetically targeted knockin in one B2M allele). B2M-/- cells with such genetic background express B2M only in the context of the single chain fusion HLA class I protein from a B2M genetic locus. In certain advantageous embodiments, the expression of the single chain fusion HLA class I protein is regulated by the endogenous B2M regulatory sequence located at the B2M locus.

[0045] In related embodiments, HLA class I deficient cells or HLA class I/class II deficient cells further encompass cells having genetically engineered disruptions in all copies of the B2M gene, wherein all B2M alleles are genetically engineered to express, instead of the wild type B2M protein, single chain fusion HLA class I proteins (i.e., genetically targeted knockin in all B2M alleles). HLA class I deficient cells or HLA class I/class II deficient cells with such genetic disruptions express B2M only in the context of single chain fusion HLA class I proteins from the genetic loci of all the alleles of the B2M gene. In certain embodiments, the cells are genetically engineered to express the same type of single chain fusion HLA class I protein from the genetic loci of all alleles of the B2M gene; while in other embodiments, the cells are genetically engineered to express different types of single chain fusion HLA class I proteins from different genetic loci of the B2M gene.

[0046] In certain embodiments, the single chain fusion HLA class I protein comprises at least a portion of B2M (SEQ ID NO: 2) and at least a portion of HLA-A (SEQ ID NO: 4), HLA-B (SEQ ID NO: 6), HLA-C (SEQ ID NO: 8), HLA-E (SEQ I D NO: 10), HLA-F (SEQ ID NO: 12) or HLA-G (SEQ ID NO: 14) (also referred to as a dimeric construct). In certain preferred embodiments, the HLA α chain contained in the single chain fusion HLA class I protein does not contain the leader sequence (or signal sequence) of the HLA class I α chain (leaderless HLA α chain). In certain other embodiments, the single chain fusion HLA class I protein comprises at least a portion of B2M (SEQ ID NO: 2) and at least a portion of HLA-C (SEQ ID NO: 8), HLA-E (SEQ ID NO: 10) or HLA-G (SEQ ID NO: 14). In certain further embodiments, the single chain fusion HLA class I protein comprises at least a portion of B2M (SEQ ID NO: 2) and at least a portion of HLA-A (SEQ ID NO: 4), HLA-E (SEQ ID NO: 10) or HLA-G (SEQ ID NO: 14). In certain preferred embodiments, the single chain fusion HLA class I protein comprises a leader sequence (or signal peptide) covalently linked to at least a portion of B2M and at least a portion of an HLA α chain to ensure proper folding of the single chain fusion on the cell surface. The leader sequence can be the leader sequence of the B2M protein, the leader sequence of an HLA α chain protein or the leader sequence of other secretary proteins. In certain particular embodiments, the single chain fusion HLA class I protein comprises a B2M protein with its leader sequence removed. In certain other particular embodiments, the single chain fusion HLA class I protein comprises an HLA α chain protein with its leader sequence removed. Certain HLA class I α chains are highly polymorphic. As will be understood by those of skill in the art, the human cells and methods of the invention are applicable to any such HLA α chains and polymorphism thereof.

[0047] Single chain fusion HLA class I proteins comprising sequence variants and fragments of B2M and/or HLA α chains are contemplated by the instant invention, wherein such single chain fusion constructs nevertheless possess normal HLA class I functions, e.g., forming proper secondary structure of the heterodimer on the cell surface, presenting peptides in the peptide binding cleft and engaging the inhibitory receptors on the surface of NK cells. In certain embodiments, the variants share at least 75%, 80%, 81%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or complete sequence homology with the naturally occurring HLA heavy chains and B2M sequences, wherein the variants possess normal HLA class I functions. In certain other embodiments, the variants share at least 75%, 80%, 81%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or complete sequence homology with the sequences of B2M or HLA heavy chains as shown in SEQ ID NOs:2, 4, 6, 8, 10, 12 or 14.

[0048] In certain particular embodiments, the HLA-A variants share at least 85%, 88,%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or complete sequence homology with SEQ ID NO:4. In certain other particular embodiments, the HLA-B variants share at least 81%, 83%, 85%, 88,%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or complete sequence homology with SEQ ID NO:6. In certain further embodiments, the HLA-C variants share at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or complete sequence homology with SEQ ID NO:8. In yet other embodiments, the HLA-E variants share at least 97%, 98%, 99%, or complete sequence homology with SEQ ID NO:10. In certain particular embodiments, the HLA-F variants share at least 99%, or complete sequence homology with SEQ ID NO:12. In certain other embodiments, the HLA-G variants share at least 98%, 99%, or complete sequence homology with SEQ ID NO:14.

[0049] In certain other embodiments, the single chain fusion HLA class I protein comprises full-length B2M (SEQ ID NO: 2) (including its leader sequence) and an HLA α chain without the leader sequence (leaderless HLA α chain); while in certain other embodiments, the single chain fusion HLA class I protein comprises B2M (SEQ ID NO: 2) protein without the leader sequence. It is understood that B2M-/- cells expressing two, three or more different types of single chain fusion HLA class I protein in any combination, for example, expressing SC fusion comprising HLA-A (SEQ ID NO: 4) (or a leaderless HLA-A) and SC fusion comprising HLA-C (SEQ ID NO: 8) (or a leaderless HLA-C), expressing SC fusion comprising HLA-A (SEQ ID NO: 4) (or a leaderless HLA-A) and SC fusion comprising HLA-E (SEQ ID NO: 10) (or a leaderless HLA-E), or expressing SC fusion comprising HLA-B (SEQ ID NO: 6) (or a leaderless HLA-B), SC fusion comprising HLA-E (SEQ ID NO: 10) (or a leaderless HLA-E) and SC fusion comprising HLA-G (SEQ ID NO: 14) (or a leaderless HLA-G), etc., are all contemplated by the invention and fall within the scope of the invention.

[0050] Natural killer (NK) cells are part of the innate immune response. Several pathogens can down regulate HLA class I protein expression in infected cells. The NK cells monitor infection by recognizing and inducing apoptosis in cells that do not express HLA class I proteins. The inhibitory receptors on the NK cell surface recognize HLA class I α chain alleles thereby preventing NK-medicated apoptosis in uninfected normal cells. Thus, in certain particular embodiments, the single chain fusion HLA-I protein inhibits NK cell-mediated killing of cells that do not express endogenous HLA class I proteins by binding to the inhibitory receptors on the NK cells. For example, HLA-E is a ligand for the CD94/NKG2 receptor of NK cells that inhibits NK cell-mediated apoptosis. Thus, in certain particular embodiments, the B2M-/- cell expresses the single chain fusion HLA class I protein comprising at least a portion of B2M and at least a portion of HLA-E. In addition, HLA-G is normally expressed on the surface of placental cytotrophoblasts that do not express HLA-A, B or C, and it protects these cells from NK cell-mediated lysis by interacting with the inhibitory ILT2(LIR1) receptor on NK cells (Pazmany et al., 1996, Science 274, 792-795). Thus, in certain other preferred embodiments, the B2M-/- cell expresses the single chain fusion HLA class I protein comprising at least a portion of B2M and at least a portion of HLA-G.

[0051] In certain particular embodiments, the single chain fusion HLA class I protein comprises at least a portion of B2M and at least a portion of HLA-A0201. HLA-A0201 (SEQ ID NO:4) is a common HLA class I allele found in a large percentage of the population in the United States. Thus, in certain advantageous embodiments, the isolated cell expresses the single chain fusion HLA class I protein comprising at least a portion of B2M and at least a portion of HLA-A0201 in a B2M-/- genetic background, wherein the isolated cell is immune compatible with a large percentage of the human population in the United States. Other suitable common alleles that can be used include without limitation HLA-A0101, HLA-A0301, HLA-B0702, HLA-B0801, HLA-00401, HLA-00701, and HLA-00702. In certain preferred embodiments, the HLA allele comprises at least a portion of HLA-A0201 (SEQ ID NO:4), HLA-B0702 (SEQ ID NO:6) or HLA-00401 (SEQ ID NO:8).

[0052] In certain further embodiments, the single chain fusion HLA class I protein also comprises a second target peptide antigen that occupies the peptide binding cleft of the single chain fusion HLA class I protein, wherein the peptide antigen is covalently linked to the single chain fusion HLA class I protein (also referred to as a trimeric construct). An example of the trimeric construct is shown in FIG. 2. The HLA-bGBE construct of FIG. 2 comprises B2M and HLA-E covalently linked to a peptide antigen (such as, but not limited to, the HLA-G signal peptide as illustrated in the figure) (SEQ ID NO:23) designed to occupy the peptide binding cleft of the single chain fusion HLA class I protein. In certain other embodiments, the covalently linked peptide antigen is cleaved via a built-in protease cleavage site, and the cleaved peptide antigen can bind to the peptide binding cleft of the single chain fusion HLA-I protein for presentation.

[0053] In certain alternative embodiments, the peptide antigen occupying the peptide binding cleft of the single chain fusion HLA class I protein is produced by the intracellular antigen processing pathway, in which the peptide antigen is produced by proteasome, transported to and loaded onto the single chain fusion HLA class I protein in the endoplasmic reticulum. In certain particular embodiments, the peptide antigen comprises a peptide of a tumor antigen. In certain other embodiments, the peptide antigen comprises a peptide of a protein from a pathogen including without limitation a bacterium, a virus, a fungus and a parasite. In further embodiments, the peptide antigen comprises a peptide of a tumor antigen. In certain particular embodiments, the HLA class I deficient cell or HLA class I/class II deficient cell expresses a single chain fusion HLA class I protein that is covalently linked to a peptide that does not comprise an auto-antigen or neo-antigen to the patient. It is within the ability of a skilled person to design the single chain fusion HLA class I protein and the peptide antigen presented thereon to modulate the immune response that may be elicited in a recipient.

[0054] The isolated HLA class II deficient cells, HLA class I deficient cells, or HLA class I/class II deficient cells expressing an HLA class II protein or a single chain fusion HLA class II protein optionally a single chain fusion HLA class I protein comprising a specific peptide antigen either covalently or non-covalently bound to the single chain fusion proteins can be used, for example, for administration to a recipient to elicit an immune response. Accordingly, in a related aspect, the invention provides a vaccine comprising the isolated cell of the invention, wherein the vaccine is capable of eliciting in a recipient an immune response specific for the target peptide antigen. The immune response includes without limitation a cellular immune response and/or a humoral immune response. The vaccine may comprise a stem cell or a differentiated cell; in certain particular embodiments, the cell is a differentiated dendritic cell. In certain other embodiments, the cell further expresses a cytokine. Any suitable cytokine can be used; in certain particular embodiments, the cytokine is IL2 or IFN-γ. In certain preferred embodiments, the cell is a human cell and the recipient is a human. Thus, in a further aspect, the invention provides kits comprising the vaccines of the invention and optionally an immune adjuvant.

[0055] The single chain fusion HLA class I protein, HLA class II protein, or single chain fusion HLA class II protein can be expressed from an expression vector that allows either transient or more preferably, stable expression of the protein in a cell. Exemplary suitable expression vectors are known in the art. One such example is a retroviral vector, which is capable of integrating into the cellular genome to provide long-term, stable expression of an exogenous gene. In certain particular embodiments, the viral vector is derived from human foamy virus, a type of retrovirus. Other suitable viral vectors include without limitation vectors derived from retrovirus, adenoviral virus, adeno-associated virus, lentivirus, herpes simplex virus, vaccinia virus, and pox virus.

[0056] In certain preferred embodiments, the polynucleotide capable of encoding a single chain fusion HLA class I or class II protein or an HLA class II protein is integrated into the chromosome of the cells, preferably into the B2M or the HLA class II loci, for stable expression. Thus, in certain preferred embodiments, the B2M loci are disrupted by inserting in the B2M loci the polynucleotide capable of encoding a single chain fusion HLA class I protein to replace the expression of the endogenous wild type B2M protein. Thus, in certain other preferred embodiments, certain HLA-II loci are disrupted by inserting in the HLA-II loci the polynucleotide capable of encoding an HLA class II protein or a single chain fusion HLA class II protein to replace the expression of the endogenous wild type HLA-II protein. The result of such gene targeting precludes formation of wild type HLA class I proteins and specific HLA class II proteins but permits expression of a predetermined HLA class II protein or single chain fusion HLA class I or class II protein of choice on the surface of the otherwise HLA class II deficient cells. Other expression vectors are also contemplated and the selection of suitable expression vector is within the ability of one ordinary skill in the art.

[0057] The "isolated cell" can be any suitable cell type for a given purpose. For example, the cell can be a pluripotent stem cell or a differentiated cell. "A stem cell" broadly encompasses any cells that are capable of further differentiation. "A pluripotent stem cell" refers to a stem cell that has the potential to differentiate into any of the three germ layers: endoderm, mesoderm or ectoderm. "An adult stem cell," on the other hand, is multipotent in that it can produce only a limited number of cell types. "An embryonic stem (ES) cell" refers to a pluripotent stem cell derived from the inner cell mass of the blastocyst, an early-stage embryo. "Induced pluripotent stem cells (iPS cells)" are pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by artificially inducing expression of certain genes.

[0058] In another aspect, the invention provides a method of transplantation in a patient in need thereof comprising the step of administering to the patient an effective amount of the cells of the invention for transplantation. Because the HLA class II deficient cells and/or HLA class I deficient cells do not express wild type HLA class II protein (and optionally also HLA class I protein) on the cell surface, the cells when administered to a patient elicit minimal or no immune responses in the patient. Thus, transplantation using the HLA class II deficient cells and/or HLA class I deficient cells limits the need for taking immune suppressant therapies. Thus, in certain preferred embodiments, the patient is immune competent. In certain other embodiments, the cell is an isogeneic cell; while in other embodiments, the cell is an allogeneic cell.

[0059] In certain further embodiments, the cells of the invention are pluripotent stem cells; while in other embodiments, the cells of the invention are differentiated cells. In certain preferred embodiments, the cell is a human cell and the patient is a human patient. In certain particular embodiments, the method of transplantation comprises administering to a human an effective amount of the pluripotent stem cells or differentiated cells. In certain preferred embodiments, the cells of the invention further express one or more engineered single chain fusion HLA class II proteins and optionally also a single chain fusion HLA class I protein. In certain other embodiments, the cells are able to escape NK cell-mediated killing and elicit minimal or no immune response in the recipient after transplantation.

[0060] Transplantation therapy, replacement therapy or regenerative therapy refers to therapies for a disease condition by administering to a patient cells or tissues to replenish or replace defective cellular functions in a target organ. In certain particular embodiments, the need for transplantation arises as a result of physical or pathological injuries to a tissue or organ. In certain other particular embodiments, the need for transplantation arises as a result of one or more genetic defect or mutation in the patient and the transplantation of the cells of the invention replenishes or replaces defective cellular functions in the patient without the need for gene therapy to correct the underlying genetic mutation of the patient. In certain further embodiments, the transplantation includes without limitation hematopoietic stem cell transplantation, or transplantation of cells that are incorporated into an organ such as liver, kidney, pancreas, lung, brain, muscle, heart, gastrointestinal tract, nervous system, skin, bones, bone marrow, fat, connective tissue, immune system, or blood vessels. In certain particular embodiments, the target organ is a solid organ.

[0061] In certain particular embodiments, the cells administered to the recipient may or may not be incorporated into an organ in need of such therapy. In certain embodiments, the cells of the invention are differentiated into the desired cell type, either before or after transplantation, and provide the necessary cellular function without itself being incorporated into the tissue at the site of transplantation. For example, in certain embodiments for treating diabetes, the cells of the invention either as pluripotent stem cells or differentiated pancreatic beta islet cells are transplanted to a diabetic patient. The transplanted cells need not reconstitute a functioning pancreas: they just need to secrete insulin in response to glucose levels. In certain particular embodiments, the cells are transplanted into an ectopic location and are not fully incorporated into the pancreas. Transplantation of pluripotent cells of the invention, differentiated cells of the invention, or a tissue differentiated and developed ex vivo from the cells of the invention are all contemplated by the invention. In certain preferred embodiments, the cell is a human cell and the patient is a human patient. In certain other preferred embodiments, the cells of the invention express one or more single chain fusion HLA class II proteins and optionally also single chain fusion HLA class I proteins.

[0062] In a further aspect, the invention provides a method of treating a disease condition in a patient in need thereof comprising the step of administering to the patient an effective amount of the cell of the invention to treat the disease condition, wherein the disease condition is diabetes, an autoimmune disease, cancer, infection, anemia, cytopenia, myocardial infarction, heart failure, skeletal or joint condition, osteogenesis imperfecta or burns. In certain particular embodiments, the disease condition results from pathological or physical injuries to a tissue or organ. In certain embodiments, the cells of the invention are stem cells; while in other embodiments, the cells of the invention are differentiated cells. In certain preferred embodiments, the cell is a human cell and the patient is a human patient. In certain particular embodiments, the human cell is a differentiated cell. Transplantation of a tissue developed ex vivo from the cells of the invention is also contemplated by the invention. In certain preferred embodiments, the cells of the invention further express one or more single chain fusion HLA class II proteins and optionally also one or more single chain fusion HLA class I proteins. In certain embodiments, the cell is an isogeneic cell; while in other embodiments, the cell is an allogeneic cell.

[0063] In certain particular embodiments, the cell is a differentiated cell including without limitation a dendritic cell, lymphocyte, red blood cell, platelet, hematopoietic cell, pancreatic islet cell, liver cell, muscle cell, keratinocyte, cardiomyocyte, neuronal cell, skeletal muscle cell, ocular cell, mesenchymal cell, fibroblast, lung cell, GI tract cell, vascular cell, endocrine cell and adipocyte. In certain other particular embodiments, the invention provides a method of treating a disease condition in a solid organ. In certain embodiments, the cells of the invention used in treating a disease condition express one or more single chain fusion HLA class I proteins and optionally also one or more single chain fusion HLA class I proteins.

[0064] "Treating" a patient having a disease or disorder means accomplishing one or more of the following: (a) reducing the severity of the disease; (b) arresting the development of the disease or disorder; (c) inhibiting worsening of the disease or disorder; (d) limiting or preventing recurrence of the disease or disorder in patients that have previously had the disease or disorder; (e) causing regression of the disease or disorder; (f) improving or eliminating the symptoms of the disease or disorder; and (f) improving survival. In certain preferred embodiments, the disease or disorder is a disease or disorder that can be treated by transplantation of tissues or cells.

[0065] The effective amount of the isolated cells of the invention for transplantation or for treating a disease condition depends on a number of factors, such as the type of tissue, the severity of the disease condition, the transplantation reaction, the reason for transplantation, and the age and general health of the patient. The effective amount can be determined by a skilled researcher or clinician by routine practice. Due to the reduced immunogenicity of the transplanted cells, relative large amount of cells can be tolerated by a patient to achieve the desired therapeutic effects. Alternatively, the cells can be repeatedly transplanted at intervals until a desired therapeutic effect is achieved.

[0066] The route for administration of the cells of the invention is not limited in any particular way. Exemplary delivery routes include without limitation intravenous, intramuscular, subdermal, intraperitoneal, transcutaneous, intracutaneous, and subcutaneous route. The cells of the present invention can also be administered topically by injection. For example, the cells can be injected into an injured joint, a fractured bone, an infarct site, an ischemic site or their periphery.

[0067] In certain particular embodiments, the cells are administered via a delivery device including without limitation a syringe. For example, the cells can be suspended in a solution or a pharmaceutical composition contained in such a delivery device. The "solution" or "pharmaceutical composition" comprises a physiological compatible buffer and optionally a pharmaceutically acceptable carrier or diluent in which the cells of the invention remain viable. The use of such carriers and diluents is well known in the art. The solution includes without limitation physiologically compatible buffers such as Hank's solution, Ringer' solution, or physiologically buffered saline. The cells can be kept in the solution or pharmaceutical composition for short term storage without losing viability. In certain particular embodiments, the cells are frozen for long term storage without losing viability according to cryopreservation methods well-known in the art.

[0068] Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran, but still fluid to the extent that can be easily delivered by syringe injection. The solution is preferably sterile, stable under the conditions of manufacture and storage and is free of microorganism contamination through the use of, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. The cells contained in the solution can be stem cells or differentiated cells as described herein, in a pharmaceutically acceptable carrier or diluent and, as required, other ingredients indicated above.

[0069] The cells may be administered systemically (e.g., intravenously) or locally (e.g., directly into a myocardial defect under the guidance of echocardiogram, or by direct application to damaged tissues or organs accessible during open surgery). For injections, the cells may be in an injectable liquid suspension preparation or in a biocompatible medium which is injectable in liquid form and becomes semi-solid at the site of damaged tissue. A syringe, a controllable endoscopic delivery device or other similar devises can be used so long as the needle lumen is of sufficient diameter (e.g. at least 30 gauge or larger) to avoid physical damages to the cells during delivery.

[0070] In certain other embodiments, the cells can be transplanted via a solid support, e.g., a planar surface or three-dimensional matrix. The matrix or planar surface is surgically implanted into the appropriate site in a patient. For example, a patient needing a pancreatic graft can have differentiated cells on a solid support surgically implanted in the pancreas tissue. Exemplary solid support includes without limitation a patch, a gel matrix (such as GELFOAM® from Pharmacia-Upjohn), polyvinyl alcohol sponge (PVA)-collagen gel implants (such as IVALON, Unipoint Industries, High Point, N.C.) and other similar or equivalent devices. A variety of other encapsulation technologies can be used with the cells of the invention, for example, WO 91/10470; WO 91/10425; U.S. Pat. No. 5,837,234; U.S. Pat. No. 5,011,472; U.S. Pat. No. 4,892,538).

[0071] The cells of the invention can be differentiated into various cell types of all three lineages, including without limitation hematopoietic, mesenchymal, pancreatic endoderm, cardiac and keratinocytes cells. In certain embodiments, the differentiated cell further expresses an HLA class II protein or a single chain fusion HLA class II protein and optionally also a single chain fusion HLA class I protein. In general, each cell type can be analyzed for HLA class II and optionally also class I protein expression, reactivity with human T cells and NK cells, appropriate differentiation markers, and xenotransplantation in immunodeficient mice to examine in vivo developmental potential. A brief discussion of each differentiated cell type follows.

[0072] In certain embodiments, the cells of the invention can be differentiated to hematopoietic cells for treating various hematopoietic diseases currently treated by bone marrow transplantation. Patients receiving transfusion can become refractory to platelet transfusions due to HLA mismatches. Anemic or cytopenic patients can be treated by delivering the cells of the invention-derived erythrocytes, platelets or neutrophils to treat bleeding or infection.

[0073] Further, stem cells of the invention-derived dendritic cells are antigen-presenting cells that can be used as cellular vaccines when properly engineered. In certain embodiments, the cells of the invention engineered to express an HLA class II protein or a single chain fusion HLA class II protein and optionally also a single chain fusion HLA class I protein and a unique peptide antigen are used to vaccinate against specific pathogen or tumor antigens. In certain other embodiments, differentiated HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient cytotoxic lymphocytes with HLA-restricted reactivity against specific antigens are used to eliminate infected cells or tumor cells.

[0074] To obtain hematopoietic cells, the pluripotent cells are first allowed to form embryoid bodies, thereafter non-adherent cells were cultured in the presence of hematopoietic cytokines to develop into specific cell lineages. The differentiation of hematopoietic cells from the cells of the invention that express an HLA class II protein or a single chain fusion HLA class II protein and optionally also a single chain fusion HLA class I protein can be analyzed by flow cytometry and colony assays. The different cell populations are sorted based on their surface markers, and used to monitor the expression of HLA genes and reactivity with human NK cells and T cells as measured by Elispot, mixed lymphocyte reactions, and cytotoxicity assays. The effectiveness of the single chain fusion HLA constructs on suppression of NK cell-mediated killing can be examined at different stages of differentiation and transplantation. See Bix et al., 1991, Nature 349, 329-331. The hematopoietic stem cells can also be assayed using xenotransplantation models in, for example, immunodeficient mice (SCID-repopulating cells or SRCs).

[0075] The cells of the invention can be differentiated into hematopoietic cell either before or after the cells are administered to a patient. In certain preferred embodiments, the cell is a human cell and the patient is a human. In vitro hematopoietic differentiation can be performed according to established protocols. See for example, Slukvin et al., 2006, J Immunol 176:2924-32, and Chang et al., 2006, Blood 108:1515-23.

[0076] In certain other embodiments, the cells of the invention can be differentiated into mesenchymal stem cells. In certain embodiments, the cells of the invention express one or more HLA class II protein or single chain fusion HLA class II proteins and optionally also one or more single chain fusion HLA class I proteins. MSCs have the potential to form several differentiated cell types, including marrow stromal cells, adipocytes, osteoblasts, and chondrocytes. Thus, inducing pluripotent stem cells to form MSCs (iMSCs) is useful in treating skeletal and joint conditions. The iMSCs can be further differentiated into osteoblasts and formed bone in vivo. Deyle et al., 2012, Mol. Ther. 20(1):204-13. Cellular responses of T cells and NK cells to ESCs, iMSCs, and their more terminally differentiated derivatives such as osteoblasts can be examined.

[0077] In certain particular embodiments, the mesenchymal stem cells are capable of differentiating into non-limiting examples of cell types such as marrow stromal cells, adipocytes, osteoblasts, osteocytes and chondrocytes. The cells of the invention are differentiated into mesenchymal stem cells either before or after the cells are administered to a patient. In certain preferred embodiments, the cell is a human cell and the patient is a human. In vitro mesenchymal differentiation can be performed according to established protocols. See for example, Deyle et al., supra.

[0078] In yet other particular embodiments, the cells of the invention can be differentiated into insulin-producing pancreatic islet cells. In certain embodiments, the cells of the invention express one or more HLA class II proteins or single chain fusion HLA class II proteins and optionally also one or more single chain fusion HLA class I proteins. The cells of the invention can be used to treat insulin-dependent diabetes mellitus. Advantageously, the transplanted cells do not need to reconstitute a functioning pancreas: they just need to secrete insulin in response to glucose levels. Therefore the treatment can succeed with different cell doses, with cells that are not perfectly differentiated into adult cell types, and when cells are transplanted into an ectopic location. Specific auto-antigens such as those derived from GAD65 or Insulin can cause autoimmune destruction of β cells in diabetes (Di Lorenzo et al., 2007, Clin Exp Immunol 148, 1-16). Thus, HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient cells expressing single chain fusion HLA protein presenting a predetermined peptide antigen provide additional advantages in that they do not present these auto-antigens and can avoid autoimmune rejection and prevent a relapse of diabetes after transplantation.

[0079] The cells of the invention can be differentiated into pancreatic cells as described previously, which employs exposure of cells to different cytokines and drugs to promote sequential formation of mesendoderm, definitive endoderm, and pancreatic progenitors (Kroon et al., 2008, Nat Biotechnol 26, 443-452). These cells can be further cultured in implants in immunodeficient mice. The wild-type cells and cells of the invention with or without expressing one or more single chain fusion HLA class II proteins or both one or more single chain fusion HLA class II proteins and optionally also one or more single chain HLA class I proteins can be analyzed at different developmental stages for their reactivity with T cells and NK cells.

[0080] The cells of the invention are differentiated into pancreatic islet cell either before or after patient administration. In certain preferred embodiments, the cell is a human cell and the patient is a human. In vitro hematopoietic differentiation can be performed according to established protocols. See for example, Kroon et al., 2008, Nat Biotechnol 26, 443-452.

[0081] In certain other particular embodiments, the cells of the invention can be differentiated into cardiomyocytes. In certain embodiments, the cells of the invention further express one or more HLA class II proteins or single chain fusion HLA class II proteins and optionally also one or more single chain fusion HLA class I proteins. The common clinical problems of myocardial infarction and congestive heart failure can be treated by transplanting healthy stem cell-derived cardiomyocytes that engraft and re-establish functional myocardium. The cells of the invention-derived cardiomyocytes allow these treatments to proceed with pre-packaged cells and avoid the immunosuppression currently required for allogeneic heart transplants. Physiologically relevant tests can be performed on the cardiomyocytes derived from the cells of the invention, such as electrical conduction and contraction studies. HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient stem cells or differentiated cardiomyocytes with or without expressing a single chain fusion HLA class I protein can be tested to determine their immunological reactivity when expressing cardiomyocyte genes, and to establish which HLA modifications minimize these immune responses.

[0082] The cells of the invention can be differentiated into cardiomyocytes either before or after the cells are administered to a patient. In certain preferred embodiments, the cell is a human cell and the patient is a human. In certain embodiments, the cells of the invention are differentiated into cardiomyocytes for treating diseases including without limitation myocardial infarction and congestive heart failure. In vitro cardiomyocyte differentiation can be performed according to established protocols. See for example, Laflamme et al., 2007, Nat Biotechnol 25, 1015-1024.

[0083] In yet other particular embodiments, the cells of the invention can be differentiated into keratinocytes. In certain embodiments, the cells of the invention used for differentiation into keratinocytes express one or more single chain fusion HLA class II proteins and optionally also one or more HLA class II proteins or single chain fusion HLA class I proteins. Severe burns and genetic skin conditions require treatment with skin grafts, and this is currently done with a variety of cell sources such as porcine skin grafts and cultured autologous human keratinocytes. Keratinocytes derived from the cells of the invention can provide a major clinical advance, since burns could be treated as an emergency with pre-packaged cells, and genetic diseases such as epidermolysis bullosum can be treated with otherwise normal HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient cells that do not require correction of the responsible genetic mutations. In many cases the cells only need to engraft long enough for neighboring host cells to repopulate the affected area. For in vivo differentiation, the cells of the invention can be embedded in polyvinyl alcohol sponge (PVA)-collagen gel implants for transplantation into a recipient. The cells of the invention can be differentiated into keratinocytes either before or after transplantation. In certain preferred embodiments, the cell is a human cell and the patient is a human.

[0084] In yet another aspect, the invention provides a use of the cells of the invention for the preparation for a medicament for transplantation. In a related aspect, the invention provides a use of the cells of the invention for the preparation for a medicament for treating a disease condition.

[0085] Further, the cells of the invention can serve as a research tool to provide a system for studying the functions of immunoregulatory proteins in a HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient genetic background. In certain embodiments, the cells of the invention further express one or more HLA class II proteins or single chain fusion HLA class II proteins and optionally also one or more single chain fusion HLA class I proteins. Accordingly, in a related aspect, the invention provides a method of determining the function of an immunoregulatory protein comprising the steps of introducing one or more immunoregulatory genes into the cells of the invention of the invention and assaying for the activities of the immunoregulatory genes. In certain preferred embodiments, the cell is a human cell. For example, the cells of the invention can be used to study the function of an immune regulatory gene, or to study an immune response, in the absence of unwanted HLA class II antigens or HLA class I/class II antigens. In a further related aspect, the invention provides a method of identifying a compound or molecule that modulates the function of the immunoregulatory protein comprising the steps of contacting the HLA class II deficient cells, HLA class I deficient cells, or HLA class I/class II deficient cells comprising the one or more immunoregulatory genes with a compound or molecule of interest and assaying for the activities of the immunoregulatory genes. In certain preferred embodiments, the cell is a human cell.

[0086] In a related aspect, the invention provides kits that comprise the HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient cells of the invention and an implant, wherein the implant comprises the cells of the invention.

[0087] In yet another aspect, the invention provides an in vivo research tool in a mammal, particular in a non-human primate, that are administered the cells of the invention, for studying the functions of immunoregulatory genes, or identifying a compound that modulates the function of an immunoregulatory gene in the administered cells in an HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient genetic background. In certain embodiments, the cells of the invention further express one or more HLA class II proteins or single chain fusion HLA class II proteins and optionally also one or more single chain fusion HLA class I proteins.

[0088] Mice, especially immune deficient mice, have been used as a model system for studying human cells in vivo. Human stem cells can behave differently in mice. In addition, the mouse and human immune systems have different HLA class II genes, NK cell receptors and non-classical MHC class I genes (e.g. HLA-E, F and G). Therefore, a Macaca nemestrina (Mn, pigtailed macaque) model can be developed to study the cells of the invention. The Macaca mulatta genome has been sequenced, which is highly homologous to the nemestrina genome. Further, the organization of macaque MHC loci is similar to human HLA, including the non-classical genes. Homologs of the human HLA-E and HLA-G genes have been identified in macaques. The macaque MHC loci also contain homologs of many human NK cell receptors. Human and Mn HLA class II deficient, HLA class I deficient, or HLA class I/class II deficient ESCs can be used for transplantation in macaques.

[0089] MHC class II-deficient of MHC class I/class II-deficient macaque ESCs can be developed using the same AAV-mediated gene targeting strategy described for human cells. Mn versions of the single chain fusion HLA class II proteins and optionally single chain fusion HLA class I proteins are expressed in the HLA class II or HLA class II/class I deficient macaques ESCs using the analogous viral vectors as described above.

[0090] Cells can be expanded in vitro and labeled with a vector expressing GFP for subsequent identification of transplanted cells. The cells can be embedded in polyvinyl alcohol sponge (PVA)-collagen gel implants, and placed subdermally into macaques. The implants can be harvested, sectioned and stained to determine the cell types that are present. Specific antibodies can be used to identify the differentiated cell types formed by the transplanted cells.

[0091] Any and every embodiment described above applies to any and every aspect of the invention, unless the context clearly indicates otherwise. All embodiments within and between different aspects can be combined unless the context clearly dictates otherwise.

EXAMPLES

Example 1

Construction of Human Embryonic Stem Cells with Knockout Mutation in RFXANK Gene

[0092] FIG. 1 shows the structure of exemplary two adeno-associated virus (AAV) gene targeting vectors, designed to insert either a TKNeo (AAV-RFXANK-ETKNpA) or HyTK (AAV-RFXANK-HyTK) gene controlled by an EF1alpha promoter (EF) into exon 3 of the RFXANK gene, which is also shown below the vectors. Selection of vector-infected cells with G418 or hygromycin (Hygro) allows one to isolate cells targeted by the TKNeo or HyTK vectors respectively. Subsequent expression of Cre recombinase and selection with gancyclovir (GCV) then allows one to isolate clones that have removed the TKNeo or HyTK genes, leaving behind two inactivated RFXANK alleles with stop codons in all 3 reading frames, a loxP site, and a polyadenylation site (StopX3-loxP-pA). LoxP is the recombination site for Cre recombinase. ITR is a vector inverted terminal repeat. Similar vectors could be designed to target other genes.

[0093] The AAV-RFXANK-ETKNpA vector (SEQ ID NO: 56) was used to create a knockout mutation in a first allele of the RFXANK gene. Human embryonic stem cells were infected with AAV-RFXANK-ETKNpA and screened for targeting by PCR using a forward primer homologous to the neomycin sequence of the selection cassette and a reverse primer homologous to the RFXANK gene which was outside the targeting homology arm, as indicated by the arrows above. As shown in FIG. 2, 5 positive clones of the correct size are shown above out of 40 clones screened yielding a targeting frequency of 12.5%.

Sequence CWU 1

1

561987DNAHomo sapiensCDS(61)..(420) 1aatataagtg gaggcgtcgc gctggcgggc attcctgaag ctgacagcat tcgggccgag 60atg tct cgc tcc gtg gcc tta gct gtg ctc gcg cta ctc tct ctt tct 108Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser 1 5 10 15 ggc ctg gag gct atc cag cgt act cca aag att cag gtt tac tca cgt 156Gly Leu Glu Ala Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg 20 25 30 cat cca gca gag aat gga aag tca aat ttc ctg aat tgc tat gtg tct 204His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser 35 40 45 ggg ttt cat cca tcc gac att gaa gtt gac tta ctg aag aat gga gag 252Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu 50 55 60 aga att gaa aaa gtg gag cat tca gac ttg tct ttc agc aag gac tgg 300Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp 65 70 75 80 tct ttc tat ctc ttg tac tac act gaa ttc acc ccc act gaa aaa gat 348Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp 85 90 95 gag tat gcc tgc cgt gtg aac cat gtg act ttg tca cag ccc aag ata 396Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile 100 105 110 gtt aag tgg gat cga gac atg taa gcagcatcat ggaggtttga agatgccgca 450Val Lys Trp Asp Arg Asp Met 115 tttggattgg atgaattcca aattctgctt gcttgctttt taatattgat atgcttatac 510acttacactt tatgcacaaa atgtagggtt ataataatgt taacatggac atgatcttct 570ttataattct actttgagtg ctgtctccat gtttgatgta tctgagcagg ttgctccaca 630ggtagctcta ggagggctgg caacttagag gtggggagca gagaattctc ttatccaaca 690tcaacatctt ggtcagattt gaactcttca atctcttgca ctcaaagctt gttaagatag 750ttaagcgtgc ataagttaac ttccaattta catactctgc ttagaatttg ggggaaaatt 810tagaaatata attgacagga ttattggaaa tttgttataa tgaatgaaac attttgtcat 870ataagattca tatttacttc ttatacattt gataaagtaa ggcatggttg tggttaatct 930ggtttatttt tgttccacaa gttaaataaa tcataaaact tgatgtgtta tctctta 9872119PRTHomo sapiens 2Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser 1 5 10 15 Gly Leu Glu Ala Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg 20 25 30 His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser 35 40 45 Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu 50 55 60 Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp 65 70 75 80 Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp 85 90 95 Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile 100 105 110 Val Lys Trp Asp Arg Asp Met 115 31611DNAHomo sapiensCDS(85)..(1182) 3gagaagccaa tcagtgtcgt cgcggtcgct gttctaaagt ccgcacgcac ccaccgggac 60tcagattctc cccagacgcc gagg atg gcc gtc atg gcg ccc cga acc ctc 111 Met Ala Val Met Ala Pro Arg Thr Leu 1 5 ctc ctg cta ctc tcg ggg gcc ctg gcc ctg acc cag acc tgg gcg ggc 159Leu Leu Leu Leu Ser Gly Ala Leu Ala Leu Thr Gln Thr Trp Ala Gly 10 15 20 25 tcc cac tcc atg agg tat ttc ttc aca tcc gtg tcc cgg ccc ggc cgc 207Ser His Ser Met Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly Arg 30 35 40 ggg gag ccc cgc ttc atc gcc gtg ggc tac gtg gac gac acg cag ttc 255Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe 45 50 55 gtg cgg ttc gac agc gac gcc gcg agc cag aag atg gag ccg cgg gcg 303Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Lys Met Glu Pro Arg Ala 60 65 70 ccg tgg ata gag cag gag ggg ccg gag tat tgg gac cag gag aca cgg 351Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu Thr Arg 75 80 85 aat atg aag gcc cac tca cag act gac cga gcg aac ctg ggg acc ctg 399Asn Met Lys Ala His Ser Gln Thr Asp Arg Ala Asn Leu Gly Thr Leu 90 95 100 105 cgc ggc tac tac aac cag agc gag gac ggt tct cac acc atc cag ata 447Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile Gln Ile 110 115 120 atg tat ggc tgc gac gtg ggg ccg gac ggg cgc ttc ctc cgc ggg tac 495Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg Gly Tyr 125 130 135 cgg cag gac gcc tac gac ggc aag gat tac atc gcc ctg aac gag gac 543Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn Glu Asp 140 145 150 ctg cgc tct tgg acc gcg gcg gac atg gca gct cag atc acc aag cgc 591Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr Lys Arg 155 160 165 aag tgg gag gcg gtc cat gcg gcg gag cag cgg aga gtc tac ctg gag 639Lys Trp Glu Ala Val His Ala Ala Glu Gln Arg Arg Val Tyr Leu Glu 170 175 180 185 ggc cgg tgc gtg gac ggg ctc cgc aga tac ctg gag aac ggg aag gag 687Gly Arg Cys Val Asp Gly Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu 190 195 200 acg ctg cag cgc acg gac ccc ccc aag aca cat atg acc cac cac ccc 735Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His His Pro 205 210 215 atc tct gac cat gag gcc acc ctg agg tgc tgg gcc ctg ggc ttc tac 783Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr 220 225 230 cct gcg gag atc aca ctg acc tgg cag cgg gat ggg gag gac cag acc 831Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr 235 240 245 cag gac acg gag ctc gtg gag acc agg cct gca ggg gat gga acc ttc 879Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr Phe 250 255 260 265 cag aag tgg gcg gct gtg gtg gtg cct tct gga gag gag cag aga tac 927Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg Tyr 270 275 280 acc tgc cat gtg cag cat gag ggt ctg ccc aag ccc ctc acc ctg aga 975Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg 285 290 295 tgg gag ctg tct tcc cag ccc acc atc ccc atc gtg ggc atc att gct 1023Trp Glu Leu Ser Ser Gln Pro Thr Ile Pro Ile Val Gly Ile Ile Ala 300 305 310 ggc ctg gtt ctc ctt gga gct gtg atc act gga gct gtg gtc gct gcc 1071Gly Leu Val Leu Leu Gly Ala Val Ile Thr Gly Ala Val Val Ala Ala 315 320 325 gtg atg tgg agg agg aag agc tca gat aga aaa gga ggg agt tac act 1119Val Met Trp Arg Arg Lys Ser Ser Asp Arg Lys Gly Gly Ser Tyr Thr 330 335 340 345 cag gct gca agc agt gac agt gcc cag ggc tct gat gtg tct ctc aca 1167Gln Ala Ala Ser Ser Asp Ser Ala Gln Gly Ser Asp Val Ser Leu Thr 350 355 360 gct tgt aaa gtg tga gacagctgcc ttgtgtggga ctgagaggca agagttgttc 1222Ala Cys Lys Val 365 ctgcccttcc ctttgtgact tgaagaaccc tgactttgtt tctgcaaagg cacctgcatg 1282tgtctgtgtt cgtgtaggca taatgtgagg aggtggggag agcaccccac ccccatgtcc 1342accatgaccc tcttcccacg ctgacctgtg ctccctctcc aatcatcttt cctgttccag 1402agaggtgggg ctgaggtgtc tccatctctg tctcaacttc atggtgcact gagctgtaac 1462ttcttccttc cctattaaaa ttagaacctg agtataaatt tactttctca aattcttgcc 1522atgagaggtt gatgagttaa ttaaaggaga agattcctaa aatttgagag acaaaattaa 1582tggaacgcat gagaaccttc cagagtcca 16114365PRTHomo sapiens 4Met Ala Val Met Ala Pro Arg Thr Leu Leu Leu Leu Leu Ser Gly Ala 1 5 10 15 Leu Ala Leu Thr Gln Thr Trp Ala Gly Ser His Ser Met Arg Tyr Phe 20 25 30 Phe Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala 35 40 45 Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala 50 55 60 Ala Ser Gln Lys Met Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly 65 70 75 80 Pro Glu Tyr Trp Asp Gln Glu Thr Arg Asn Met Lys Ala His Ser Gln 85 90 95 Thr Asp Arg Ala Asn Leu Gly Thr Leu Arg Gly Tyr Tyr Asn Gln Ser 100 105 110 Glu Asp Gly Ser His Thr Ile Gln Ile Met Tyr Gly Cys Asp Val Gly 115 120 125 Pro Asp Gly Arg Phe Leu Arg Gly Tyr Arg Gln Asp Ala Tyr Asp Gly 130 135 140 Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala 145 150 155 160 Asp Met Ala Ala Gln Ile Thr Lys Arg Lys Trp Glu Ala Val His Ala 165 170 175 Ala Glu Gln Arg Arg Val Tyr Leu Glu Gly Arg Cys Val Asp Gly Leu 180 185 190 Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Thr Asp Pro 195 200 205 Pro Lys Thr His Met Thr His His Pro Ile Ser Asp His Glu Ala Thr 210 215 220 Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr 225 230 235 240 Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu 245 250 255 Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val 260 265 270 Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu 275 280 285 Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Leu Ser Ser Gln Pro 290 295 300 Thr Ile Pro Ile Val Gly Ile Ile Ala Gly Leu Val Leu Leu Gly Ala 305 310 315 320 Val Ile Thr Gly Ala Val Val Ala Ala Val Met Trp Arg Arg Lys Ser 325 330 335 Ser Asp Arg Lys Gly Gly Ser Tyr Thr Gln Ala Ala Ser Ser Asp Ser 340 345 350 Ala Gln Gly Ser Asp Val Ser Leu Thr Ala Cys Lys Val 355 360 365 51578DNAHomo sapiensCDS(55)..(1143) 5agttctaaag tccccacgca cccacccgga ctcagagtct cctcagacgc cgag atg 57 Met 1 ctg gtc atg gcg ccc cga acc gtc ctc ctg ctg ctc tcg gcg gcc ctg 105Leu Val Met Ala Pro Arg Thr Val Leu Leu Leu Leu Ser Ala Ala Leu 5 10 15 gcc ctg acc gag acc tgg gcc ggc tcc cac tcc atg agg tat ttc tac 153Ala Leu Thr Glu Thr Trp Ala Gly Ser His Ser Met Arg Tyr Phe Tyr 20 25 30 acc tcc gtg tcc cgg ccc ggc cgc ggg gag ccc cgc ttc atc tca gtg 201Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser Val 35 40 45 ggc tac gtg gac gac acc cag ttc gtg agg ttc gac agc gac gcc gcg 249Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala Ala 50 55 60 65 agt ccg aga gag gag ccg cgg gcg ccg tgg ata gag cag gag ggg ccg 297Ser Pro Arg Glu Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro 70 75 80 gag tat tgg gac cgg aac aca cag atc tac aag gcc cag gca cag act 345Glu Tyr Trp Asp Arg Asn Thr Gln Ile Tyr Lys Ala Gln Ala Gln Thr 85 90 95 gac cga gag agc ctg cgg aac ctg cgc ggc tac tac aac cag agc gag 393Asp Arg Glu Ser Leu Arg Asn Leu Arg Gly Tyr Tyr Asn Gln Ser Glu 100 105 110 gcc ggg tct cac acc ctc cag agc atg tac ggc tgc gac gtg ggg ccg 441Ala Gly Ser His Thr Leu Gln Ser Met Tyr Gly Cys Asp Val Gly Pro 115 120 125 gac ggg cgc ctc ctc cgc ggg cat gac cag tac gcc tac gac ggc aag 489Asp Gly Arg Leu Leu Arg Gly His Asp Gln Tyr Ala Tyr Asp Gly Lys 130 135 140 145 gat tac atc gcc ctg aac gag gac ctg cgc tcc tgg acc gcc gcg gac 537Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp 150 155 160 acg gcg gct cag atc acc cag cgc aag tgg gag gcg gcc cgt gag gcg 585Thr Ala Ala Gln Ile Thr Gln Arg Lys Trp Glu Ala Ala Arg Glu Ala 165 170 175 gag cag cgg aga gcc tac ctg gag ggc gag tgc gtg gag tgg ctc cgc 633Glu Gln Arg Arg Ala Tyr Leu Glu Gly Glu Cys Val Glu Trp Leu Arg 180 185 190 aga tac ctg gag aac ggg aag gac aag ctg gag cgc gct gac ccc cca 681Arg Tyr Leu Glu Asn Gly Lys Asp Lys Leu Glu Arg Ala Asp Pro Pro 195 200 205 aag aca cac gtg acc cac cac ccc atc tct gac cat gag gcc acc ctg 729Lys Thr His Val Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu 210 215 220 225 agg tgc tgg gcc ctg ggt ttc tac cct gcg gag atc aca ctg acc tgg 777Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp 230 235 240 cag cgg gat ggc gag gac caa act cag gac act gag ctt gtg gag acc 825Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu Thr 245 250 255 aga cca gca gga gat aga acc ttc cag aag tgg gca gct gtg gtg gtg 873Arg Pro Ala Gly Asp Arg Thr Phe Gln Lys Trp Ala Ala Val Val Val 260 265 270 cct tct gga gaa gag cag aga tac aca tgc cat gta cag cat gag ggg 921Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly 275 280 285 ctg ccg aag ccc ctc acc ctg aga tgg gag ccg tct tcc cag tcc acc 969Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Pro Ser Ser Gln Ser Thr 290 295 300 305 gtc ccc atc gtg ggc att gtt gct ggc ctg gct gtc cta gca gtt gtg 1017Val Pro Ile Val Gly Ile Val Ala Gly Leu Ala Val Leu Ala Val Val 310 315 320 gtc atc gga gct gtg gtc gct gct gtg atg tgt agg agg aag agt tca 1065Val Ile Gly Ala Val Val Ala Ala Val Met Cys Arg Arg Lys Ser Ser 325 330 335 ggt gga aaa gga ggg agc tac tct cag gct gcg tgc agc gac agt gcc 1113Gly Gly Lys Gly Gly Ser Tyr Ser Gln Ala Ala Cys Ser Asp Ser Ala 340 345 350 cag ggc tct gat gtg tct ctc aca gct tga aaagcctgag acagctgtct 1163Gln Gly Ser Asp Val Ser Leu Thr Ala 355 360 tgtgagggac tgagatgcag gatttcttca cgcctcccct ttgtgacttc aagagcctct 1223ggcatctctt tctgcaaagg cacctgaatg tgtctgcgtc cctgttagca taatgtgagg 1283aggtggagag acagcccacc cttgtgtcca ctgtgacccc tgttcccatg ctgacctgtg 1343tttcctcccc agtcatcttt cttgttccag agaggtgggg ctggatgtct ccatctctgt 1403ctcaacttta cgtgcactga gctgcaactt cttacttccc tactgaaaat aagaatctga 1463atataaattt gttttctcaa atatttgcta tgagaggttg atggattaat taaataagtc 1523aattcctgga atttgagaga gcaaataaag acctgagaac cttccagaaa aaaaa 15786362PRTHomo sapiens 6Met Leu Val Met Ala Pro Arg Thr Val Leu Leu Leu Leu Ser Ala Ala 1 5 10 15 Leu Ala Leu Thr Glu Thr Trp Ala Gly Ser His Ser Met Arg Tyr Phe 20 25 30 Tyr Thr Ser

Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser 35 40 45 Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala 50 55 60 Ala Ser Pro Arg Glu Glu Pro Arg Ala Pro Trp Ile Glu Gln Glu Gly 65 70 75 80 Pro Glu Tyr Trp Asp Arg Asn Thr Gln Ile Tyr Lys Ala Gln Ala Gln 85 90 95 Thr Asp Arg Glu Ser Leu Arg Asn Leu Arg Gly Tyr Tyr Asn Gln Ser 100 105 110 Glu Ala Gly Ser His Thr Leu Gln Ser Met Tyr Gly Cys Asp Val Gly 115 120 125 Pro Asp Gly Arg Leu Leu Arg Gly His Asp Gln Tyr Ala Tyr Asp Gly 130 135 140 Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala 145 150 155 160 Asp Thr Ala Ala Gln Ile Thr Gln Arg Lys Trp Glu Ala Ala Arg Glu 165 170 175 Ala Glu Gln Arg Arg Ala Tyr Leu Glu Gly Glu Cys Val Glu Trp Leu 180 185 190 Arg Arg Tyr Leu Glu Asn Gly Lys Asp Lys Leu Glu Arg Ala Asp Pro 195 200 205 Pro Lys Thr His Val Thr His His Pro Ile Ser Asp His Glu Ala Thr 210 215 220 Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr 225 230 235 240 Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu 245 250 255 Thr Arg Pro Ala Gly Asp Arg Thr Phe Gln Lys Trp Ala Ala Val Val 260 265 270 Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu 275 280 285 Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Pro Ser Ser Gln Ser 290 295 300 Thr Val Pro Ile Val Gly Ile Val Ala Gly Leu Ala Val Leu Ala Val 305 310 315 320 Val Val Ile Gly Ala Val Val Ala Ala Val Met Cys Arg Arg Lys Ser 325 330 335 Ser Gly Gly Lys Gly Gly Ser Tyr Ser Gln Ala Ala Cys Ser Asp Ser 340 345 350 Ala Gln Gly Ser Asp Val Ser Leu Thr Ala 355 360 71586DNAHomo sapiensCDS(66)..(1166) 7tccgcagtcc cggttctaaa gtccccagtc acccacccgg actcacattc tccccagagg 60ccgag atg cgg gtc atg gcg ccc cga gcc ctc ctc ctg ctg ctc tcg gga 110 Met Arg Val Met Ala Pro Arg Ala Leu Leu Leu Leu Leu Ser Gly 1 5 10 15 ggc ctg gcc ctg acc gag acc tgg gcc tgc tcc cac tcc atg agg tat 158Gly Leu Ala Leu Thr Glu Thr Trp Ala Cys Ser His Ser Met Arg Tyr 20 25 30 ttc gac acc gcc gtg tcc cgg ccc ggc cgc gga gag ccc cgc ttc atc 206Phe Asp Thr Ala Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile 35 40 45 tca gtg ggc tac gtg gac gac acg cag ttc gtg cgg ttc gac agc gac 254Ser Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp 50 55 60 gcc gcg agt ccg aga ggg gag ccg cgg gcg ccg tgg gtg gag cag gag 302Ala Ala Ser Pro Arg Gly Glu Pro Arg Ala Pro Trp Val Glu Gln Glu 65 70 75 ggg ccg gag tat tgg gac cgg gag aca cag aag tac aag cgc cag gca 350Gly Pro Glu Tyr Trp Asp Arg Glu Thr Gln Lys Tyr Lys Arg Gln Ala 80 85 90 95 cag gct gac cga gtg agc ctg cgg aac ctg cgc ggc tac tac aac cag 398Gln Ala Asp Arg Val Ser Leu Arg Asn Leu Arg Gly Tyr Tyr Asn Gln 100 105 110 agc gag gac ggg tct cac acc ctc cag agg atg tct ggc tgc gac ctg 446Ser Glu Asp Gly Ser His Thr Leu Gln Arg Met Ser Gly Cys Asp Leu 115 120 125 ggg ccc gac ggg cgc ctc ctc cgc ggg tat gac cag tcc gcc tac gac 494Gly Pro Asp Gly Arg Leu Leu Arg Gly Tyr Asp Gln Ser Ala Tyr Asp 130 135 140 ggc aag gat tac atc gcc ctg aac gag gac ctg cgc tcc tgg acc gcc 542Gly Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala 145 150 155 gcg gac acc gcg gct cag atc acc cag cgc aag ttg gag gcg gcc cgt 590Ala Asp Thr Ala Ala Gln Ile Thr Gln Arg Lys Leu Glu Ala Ala Arg 160 165 170 175 gcg gcg gag cag ctg aga gcc tac ctg gag ggc acg tgc gtg gag tgg 638Ala Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp 180 185 190 ctc cgc aga tac ctg gag aac ggg aag gag acg ctg cag cgc gca gaa 686Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Ala Glu 195 200 205 ccc cca aag aca cac gtg acc cac cac ccc ctc tct gac cat gag gcc 734Pro Pro Lys Thr His Val Thr His His Pro Leu Ser Asp His Glu Ala 210 215 220 acc ctg agg tgc tgg gcc ctg ggc ttc tac cct gcg gag atc aca ctg 782Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu 225 230 235 acc tgg cag cgg gat ggg gag gac cag acc cag gac acc gag ctt gtg 830Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val 240 245 250 255 gag acc agg cca gca gga gat gga acc ttc cag aag tgg gca gct gtg 878Glu Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val 260 265 270 gtg gtg cct tct gga caa gag cag aga tac acg tgc cat atg cag cac 926Val Val Pro Ser Gly Gln Glu Gln Arg Tyr Thr Cys His Met Gln His 275 280 285 gag ggg ctg caa gag ccc ctc acc ctg agc tgg gag cca tct tcc cag 974Glu Gly Leu Gln Glu Pro Leu Thr Leu Ser Trp Glu Pro Ser Ser Gln 290 295 300 ccc acc atc ccc atc atg ggc atc gtt gct ggc ctg gct gtc ctg gtt 1022Pro Thr Ile Pro Ile Met Gly Ile Val Ala Gly Leu Ala Val Leu Val 305 310 315 gtc cta gct gtc ctt gga gct gtg gtc acc gct atg atg tgt agg agg 1070Val Leu Ala Val Leu Gly Ala Val Val Thr Ala Met Met Cys Arg Arg 320 325 330 335 aag agc tca ggt gga aaa gga ggg agc tgc tct cag gct gcg tgc agc 1118Lys Ser Ser Gly Gly Lys Gly Gly Ser Cys Ser Gln Ala Ala Cys Ser 340 345 350 aac agt gcc cag ggc tct gat gag tct ctc atc act tgt aaa gcc tga 1166Asn Ser Ala Gln Gly Ser Asp Glu Ser Leu Ile Thr Cys Lys Ala 355 360 365 gacagctgcc tgtgtgggac tgagatgcag gatttcttca cacctctcct ttgtgacttc 1226aagagcctct ggcatctctt tctgcaaagg cacctgaatg tgtctgcgtt cctgttagca 1286taatgtgagg aggtggagag acagcccacc cccgtgtcca ccgtgacccc tgtccccaca 1346ctgacctgtg ttccctcccc gatcatcttt cctgttccag agaggtgggg ctggatgtct 1406ccatctctgt ctcaaattca tggtgcactg agctgcaact tcttacttcc ctaatgaagt 1466taagaacctg aatataaatt tgtgttctca aatatttgct atgaagcgtt gatggattaa 1526ttaaataagt caattcctag aagttgagag agcaaataaa gacctgagaa ccttccagaa 15868366PRTHomo sapiens 8Met Arg Val Met Ala Pro Arg Ala Leu Leu Leu Leu Leu Ser Gly Gly 1 5 10 15 Leu Ala Leu Thr Glu Thr Trp Ala Cys Ser His Ser Met Arg Tyr Phe 20 25 30 Asp Thr Ala Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser 35 40 45 Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ala 50 55 60 Ala Ser Pro Arg Gly Glu Pro Arg Ala Pro Trp Val Glu Gln Glu Gly 65 70 75 80 Pro Glu Tyr Trp Asp Arg Glu Thr Gln Lys Tyr Lys Arg Gln Ala Gln 85 90 95 Ala Asp Arg Val Ser Leu Arg Asn Leu Arg Gly Tyr Tyr Asn Gln Ser 100 105 110 Glu Asp Gly Ser His Thr Leu Gln Arg Met Ser Gly Cys Asp Leu Gly 115 120 125 Pro Asp Gly Arg Leu Leu Arg Gly Tyr Asp Gln Ser Ala Tyr Asp Gly 130 135 140 Lys Asp Tyr Ile Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala 145 150 155 160 Asp Thr Ala Ala Gln Ile Thr Gln Arg Lys Leu Glu Ala Ala Arg Ala 165 170 175 Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu 180 185 190 Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Ala Glu Pro 195 200 205 Pro Lys Thr His Val Thr His His Pro Leu Ser Asp His Glu Ala Thr 210 215 220 Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr 225 230 235 240 Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu Leu Val Glu 245 250 255 Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val 260 265 270 Val Pro Ser Gly Gln Glu Gln Arg Tyr Thr Cys His Met Gln His Glu 275 280 285 Gly Leu Gln Glu Pro Leu Thr Leu Ser Trp Glu Pro Ser Ser Gln Pro 290 295 300 Thr Ile Pro Ile Met Gly Ile Val Ala Gly Leu Ala Val Leu Val Val 305 310 315 320 Leu Ala Val Leu Gly Ala Val Val Thr Ala Met Met Cys Arg Arg Lys 325 330 335 Ser Ser Gly Gly Lys Gly Gly Ser Cys Ser Gln Ala Ala Cys Ser Asn 340 345 350 Ser Ala Gln Gly Ser Asp Glu Ser Leu Ile Thr Cys Lys Ala 355 360 365 92679DNAHomo sapiensCDS(127)..(1203) 9gcagactcag ttctcattcc caatgggtgt cgggtttcta gagaagccaa tcagcgtcgc 60cacgactccc gactataaag tccccatccg gactcaagaa gttctcagga ctcagaggct 120gggatc atg gta gat gga acc ctc ctt tta ctc ctc tcg gag gcc ctg 168 Met Val Asp Gly Thr Leu Leu Leu Leu Leu Ser Glu Ala Leu 1 5 10 gcc ctt acc cag acc tgg gcg ggc tcc cac tcc ttg aag tat ttc cac 216Ala Leu Thr Gln Thr Trp Ala Gly Ser His Ser Leu Lys Tyr Phe His 15 20 25 30 act tcc gtg tcc cgg ccc ggc cgc ggg gag ccc cgc ttc atc tct gtg 264Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser Val 35 40 45 ggc tac gtg gac gac acc cag ttc gtg cgc ttc gac aac gac gcc gcg 312Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Asn Asp Ala Ala 50 55 60 agt ccg agg atg gtg ccg cgg gcg ccg tgg atg gag cag gag ggg tca 360Ser Pro Arg Met Val Pro Arg Ala Pro Trp Met Glu Gln Glu Gly Ser 65 70 75 gag tat tgg gac cgg gag aca cgg agc gcc agg gac acc gca cag att 408Glu Tyr Trp Asp Arg Glu Thr Arg Ser Ala Arg Asp Thr Ala Gln Ile 80 85 90 ttc cga gtg aat ctg cgg acg ctg cgc ggc tac tac aat cag agc gag 456Phe Arg Val Asn Leu Arg Thr Leu Arg Gly Tyr Tyr Asn Gln Ser Glu 95 100 105 110 gcc ggg tct cac acc ctg cag tgg atg cat ggc tgc gag ctg ggg ccc 504Ala Gly Ser His Thr Leu Gln Trp Met His Gly Cys Glu Leu Gly Pro 115 120 125 gac ggg cgc ttc ctc cgc ggg tat gaa cag ttc gcc tac gac ggc aag 552Asp Gly Arg Phe Leu Arg Gly Tyr Glu Gln Phe Ala Tyr Asp Gly Lys 130 135 140 gat tat ctc acc ctg aat gag gac ctg cgc tcc tgg acc gcg gtg gac 600Asp Tyr Leu Thr Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Val Asp 145 150 155 acg gcg gct cag atc tcc gag caa aag tca aat gat gcc tct gag gcg 648Thr Ala Ala Gln Ile Ser Glu Gln Lys Ser Asn Asp Ala Ser Glu Ala 160 165 170 gag cac cag aga gcc tac ctg gaa gac aca tgc gtg gag tgg ctc cac 696Glu His Gln Arg Ala Tyr Leu Glu Asp Thr Cys Val Glu Trp Leu His 175 180 185 190 aaa tac ctg gag aag ggg aag gag acg ctg ctt cac ctg gag ccc cca 744Lys Tyr Leu Glu Lys Gly Lys Glu Thr Leu Leu His Leu Glu Pro Pro 195 200 205 aag aca cac gtg act cac cac ccc atc tct gac cat gag gcc acc ctg 792Lys Thr His Val Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu 210 215 220 agg tgc tgg gcc ctg ggc ttc tac cct gcg gag atc aca ctg acc tgg 840Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp 225 230 235 cag cag gat ggg gag ggc cat acc cag gac acg gag ctc gtg gag acc 888Gln Gln Asp Gly Glu Gly His Thr Gln Asp Thr Glu Leu Val Glu Thr 240 245 250 agg cct gca ggg gat gga acc ttc cag aag tgg gca gct gtg gtg gtg 936Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val 255 260 265 270 cct tct gga gag gag cag aga tac acg tgc cat gtg cag cat gag ggg 984Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly 275 280 285 cta ccc gag ccc gtc acc ctg aga tgg aag ccg gct tcc cag ccc acc 1032Leu Pro Glu Pro Val Thr Leu Arg Trp Lys Pro Ala Ser Gln Pro Thr 290 295 300 atc ccc atc gtg ggc atc att gct ggc ctg gtt ctc ctt gga tct gtg 1080Ile Pro Ile Val Gly Ile Ile Ala Gly Leu Val Leu Leu Gly Ser Val 305 310 315 gtc tct gga gct gtg gtt gct gct gtg ata tgg agg aag aag agc tca 1128Val Ser Gly Ala Val Val Ala Ala Val Ile Trp Arg Lys Lys Ser Ser 320 325 330 ggt gga aaa gga ggg agc tac tct aag gct gag tgg agc gac agt gcc 1176Gly Gly Lys Gly Gly Ser Tyr Ser Lys Ala Glu Trp Ser Asp Ser Ala 335 340 345 350 cag ggg tct gag tct cac agc ttg taa agcctgagac agctgccttg 1223Gln Gly Ser Glu Ser His Ser Leu 355 tgtgcgactg agatgcacag ctgccttgtg tgcgactgag atgcaggatt tcctcacgcc 1283tcccctatgt gtcttagggg actctggctt ctctttttgc aagggcctct gaatctgtct 1343gtgtccctgt tagcacaatg tgaggaggta gagaaacagt ccacctctgt gtctaccatg 1403acccccttcc tcacactgac ctgtgttcct tccctgttct cttttctatt aaaaataaga 1463acctgggcag agtgcggcag ctcatgcctg taatcccagc acttagggag gccgaggagg 1523gcagatcacg aggtcaggag atcgaaacca tcctggctaa cacggtgaaa ccccgtctct 1583actaaaaaat acaaaaaatt agctgggcgc agaggcacgg gcctgtagtc ccagctactc 1643aggaggcgga ggcaggagaa tggcgtcaac ccgggaggcg gaggttgcag tgagccagga 1703ttgtgcgact gcactccagc ctgggtgaca gggtgaaacg ccatctcaaa aaataaaaat 1763tgaaaaataa aaaaagaacc tggatctcaa tttaattttt catattcttg caatgaaatg 1823gacttgagga agctaagatc atagctagaa atacagataa ttccacagca catctctagc 1883aaatttagcc tattcctatt ctctagccta ttccttacca cctgtaatct tgaccatata 1943ccttggagtt gaatattgtt ttcatactgc tgtggtttga atgttccctc caacactcat 2003gttgagactt aatccctaat gtggcaatac tgaaaggtgg ggcctttgag atgtgattgg 2063atcgtaaggc tgtgccttca ttcatgggtt aatggattaa tgggttatca caggaatggg 2123actggtggct ttataagaag aggaaaagag aactgagcta gcatgcccag cccacagaga 2183gcctccacta gagtgatgct aagtggaaat gtgaggtgca gctgccacag agggccccca 2243ccagggaaat gtctagtgtc tagtggatcc aggccacagg agagagtgcc ttgtggagcg 2303ctgggagcag gacctgacca ccaccaggac cccagaactg tggagtcagt ggcagcatgc 2363agcgccccct tgggaaagct ttaggcacca gcctgcaacc cattcgagca gccacgtagg 2423ctgcacccag caaagccaca ggcacggggc tacctgaggc cttgggggcc caatccctgc 2483tccagtgtgt ccgtgaggca gcacacgaag tcaaaagaga ttattctctt cccacagata 2543ccttttctct cccatgaccc tttaacagca tctgcttcat tcccctcacc ttcccaggct 2603gatctgaggt aaactttgaa gtaaaataaa agctgtgttt gagcatcatt tgtatttcaa 2663aaaaaaaaaa aaaaaa 267910358PRTHomo sapiens 10Met Val Asp Gly Thr Leu Leu Leu Leu Leu Ser Glu Ala Leu Ala Leu 1 5 10

15 Thr Gln Thr Trp Ala Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser 20 25 30 Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr 35 40 45 Val Asp Asp Thr Gln Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro 50 55 60 Arg Met Val Pro Arg Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr 65 70 75 80 Trp Asp Arg Glu Thr Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg 85 90 95 Val Asn Leu Arg Thr Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly 100 105 110 Ser His Thr Leu Gln Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly 115 120 125 Arg Phe Leu Arg Gly Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr 130 135 140 Leu Thr Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala 145 150 155 160 Ala Gln Ile Ser Glu Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His 165 170 175 Gln Arg Ala Tyr Leu Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr 180 185 190 Leu Glu Lys Gly Lys Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr 195 200 205 His Val Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys 210 215 220 Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln 225 230 235 240 Asp Gly Glu Gly His Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro 245 250 255 Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser 260 265 270 Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro 275 280 285 Glu Pro Val Thr Leu Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro 290 295 300 Ile Val Gly Ile Ile Ala Gly Leu Val Leu Leu Gly Ser Val Val Ser 305 310 315 320 Gly Ala Val Val Ala Ala Val Ile Trp Arg Lys Lys Ser Ser Gly Gly 325 330 335 Lys Gly Gly Ser Tyr Ser Lys Ala Glu Trp Ser Asp Ser Ala Gln Gly 340 345 350 Ser Glu Ser His Ser Leu 355 111301DNAHomo sapiensCDS(125)..(1165) 11tttctcactc ccattgggcg tcgcgtttct agagaagcca atcagtgtcg ccgcagttcc 60caggttctaa agtcccacgc accccgcggg actcatattt ttcccagacg cggaggttgg 120ggtc atg gcg ccc cga agc ctc ctc ctg ctg ctc tca ggg gcc ctg gcc 169 Met Ala Pro Arg Ser Leu Leu Leu Leu Leu Ser Gly Ala Leu Ala 1 5 10 15 ctg acc gat act tgg gcg ggc tcc cac tcc ttg agg tat ttc agc acc 217Leu Thr Asp Thr Trp Ala Gly Ser His Ser Leu Arg Tyr Phe Ser Thr 20 25 30 gct gtg tcg cgg ccc ggc cgc ggg gag ccc cgc tac atc gcc gtg gag 265Ala Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Tyr Ile Ala Val Glu 35 40 45 tac gta gac gac acg caa ttc ctg cgg ttc gac agc gac gcc gcg att 313Tyr Val Asp Asp Thr Gln Phe Leu Arg Phe Asp Ser Asp Ala Ala Ile 50 55 60 ccg agg atg gag ccg cgg gag ccg tgg gtg gag caa gag ggg ccg cag 361Pro Arg Met Glu Pro Arg Glu Pro Trp Val Glu Gln Glu Gly Pro Gln 65 70 75 tat tgg gag tgg acc aca ggg tac gcc aag gcc aac gca cag act gac 409Tyr Trp Glu Trp Thr Thr Gly Tyr Ala Lys Ala Asn Ala Gln Thr Asp 80 85 90 95 cga gtg gcc ctg agg aac ctg ctc cgc cgc tac aac cag agc gag gct 457Arg Val Ala Leu Arg Asn Leu Leu Arg Arg Tyr Asn Gln Ser Glu Ala 100 105 110 ggg tct cac acc ctc cag gga atg aat ggc tgc gac atg ggg ccc gac 505Gly Ser His Thr Leu Gln Gly Met Asn Gly Cys Asp Met Gly Pro Asp 115 120 125 gga cgc ctc ctc cgc ggg tat cac cag cac gcg tac gac ggc aag gat 553Gly Arg Leu Leu Arg Gly Tyr His Gln His Ala Tyr Asp Gly Lys Asp 130 135 140 tac atc tcc ctg aac gag gac ctg cgc tcc tgg acc gcg gcg gac acc 601Tyr Ile Ser Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr 145 150 155 gtg gct cag atc acc cag cgc ttc tat gag gca gag gaa tat gca gag 649Val Ala Gln Ile Thr Gln Arg Phe Tyr Glu Ala Glu Glu Tyr Ala Glu 160 165 170 175 gag ttc agg acc tac ctg gag ggc gag tgc ctg gag ttg ctc cgc aga 697Glu Phe Arg Thr Tyr Leu Glu Gly Glu Cys Leu Glu Leu Leu Arg Arg 180 185 190 tac ttg gag aat ggg aag gag acg cta cag cgc gca gat cct cca aag 745Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys 195 200 205 gca cac gtt gcc cac cac ccc atc tct gac cat gag gcc acc ctg agg 793Ala His Val Ala His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg 210 215 220 tgc tgg gcc ctg ggc ttc tac cct gcg gag atc acg ctg acc tgg cag 841Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln 225 230 235 cgg gat ggg gag gaa cag acc cag gac aca gag ctt gtg gag acc agg 889Arg Asp Gly Glu Glu Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg 240 245 250 255 cct gca ggg gat gga acc ttc cag aag tgg gcc gct gtg gtg gtg cct 937Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro 260 265 270 cct gga gag gaa cag aga tac aca tgc cat gtg cag cac gag ggg ctg 985Pro Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu 275 280 285 ccc cag ccc ctc atc ctg aga tgg gag cag tct ccc cag ccc acc atc 1033Pro Gln Pro Leu Ile Leu Arg Trp Glu Gln Ser Pro Gln Pro Thr Ile 290 295 300 ccc atc gtg ggc atc gtt gct ggc ctt gtt gtc ctt gga gct gtg gtc 1081Pro Ile Val Gly Ile Val Ala Gly Leu Val Val Leu Gly Ala Val Val 305 310 315 act gga gct gtg gtc gct gct gtg atg tgg agg aag aag agc tca gat 1129Thr Gly Ala Val Val Ala Ala Val Met Trp Arg Lys Lys Ser Ser Asp 320 325 330 335 aga aac aga ggg agc tac tct cag gct gca gtg tga gacagcttcc 1175Arg Asn Arg Gly Ser Tyr Ser Gln Ala Ala Val 340 345 ttgtgtggga ctgagaagca agatatcaat gtagcagaat tgcacttgtg cctcacgaac 1235atacataaat tttaaaaata aagaataaaa atatatcttt ttatagataa aaaaaaaaaa 1295aaaaaa 130112346PRTHomo sapiens 12Met Ala Pro Arg Ser Leu Leu Leu Leu Leu Ser Gly Ala Leu Ala Leu 1 5 10 15 Thr Asp Thr Trp Ala Gly Ser His Ser Leu Arg Tyr Phe Ser Thr Ala 20 25 30 Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Tyr Ile Ala Val Glu Tyr 35 40 45 Val Asp Asp Thr Gln Phe Leu Arg Phe Asp Ser Asp Ala Ala Ile Pro 50 55 60 Arg Met Glu Pro Arg Glu Pro Trp Val Glu Gln Glu Gly Pro Gln Tyr 65 70 75 80 Trp Glu Trp Thr Thr Gly Tyr Ala Lys Ala Asn Ala Gln Thr Asp Arg 85 90 95 Val Ala Leu Arg Asn Leu Leu Arg Arg Tyr Asn Gln Ser Glu Ala Gly 100 105 110 Ser His Thr Leu Gln Gly Met Asn Gly Cys Asp Met Gly Pro Asp Gly 115 120 125 Arg Leu Leu Arg Gly Tyr His Gln His Ala Tyr Asp Gly Lys Asp Tyr 130 135 140 Ile Ser Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Thr Val 145 150 155 160 Ala Gln Ile Thr Gln Arg Phe Tyr Glu Ala Glu Glu Tyr Ala Glu Glu 165 170 175 Phe Arg Thr Tyr Leu Glu Gly Glu Cys Leu Glu Leu Leu Arg Arg Tyr 180 185 190 Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg Ala Asp Pro Pro Lys Ala 195 200 205 His Val Ala His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys 210 215 220 Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg 225 230 235 240 Asp Gly Glu Glu Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro 245 250 255 Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Pro 260 265 270 Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro 275 280 285 Gln Pro Leu Ile Leu Arg Trp Glu Gln Ser Pro Gln Pro Thr Ile Pro 290 295 300 Ile Val Gly Ile Val Ala Gly Leu Val Val Leu Gly Ala Val Val Thr 305 310 315 320 Gly Ala Val Val Ala Ala Val Met Trp Arg Lys Lys Ser Ser Asp Arg 325 330 335 Asn Arg Gly Ser Tyr Ser Gln Ala Ala Val 340 345 131578DNAHomo sapiensCDS(179)..(1195) 13agtgtggtac tttgtcttga ggagatgtcc tggactcaca cggaaactta gggctacgga 60atgaagttct cactcccatt aggtgacagg tttttagaga agccaatcag cgtcgccgcg 120gtcctggttc taaagtcctc gctcacccac ccggactcat tctccccaga cgccaagg 178atg gtg gtc atg gcg ccc cga acc ctc ttc ctg ctg ctc tcg ggg gcc 226Met Val Val Met Ala Pro Arg Thr Leu Phe Leu Leu Leu Ser Gly Ala 1 5 10 15 ctg acc ctg acc gag acc tgg gcg ggc tcc cac tcc atg agg tat ttc 274Leu Thr Leu Thr Glu Thr Trp Ala Gly Ser His Ser Met Arg Tyr Phe 20 25 30 agc gcc gcc gtg tcc cgg ccc ggc cgc ggg gag ccc cgc ttc atc gcc 322Ser Ala Ala Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala 35 40 45 atg ggc tac gtg gac gac acg cag ttc gtg cgg ttc gac agc gac tcg 370Met Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ser 50 55 60 gcg tgt ccg agg atg gag ccg cgg gcg ccg tgg gtg gag cag gag ggg 418Ala Cys Pro Arg Met Glu Pro Arg Ala Pro Trp Val Glu Gln Glu Gly 65 70 75 80 ccg gag tat tgg gaa gag gag aca cgg aac acc aag gcc cac gca cag 466Pro Glu Tyr Trp Glu Glu Glu Thr Arg Asn Thr Lys Ala His Ala Gln 85 90 95 act gac aga atg aac ctg cag acc ctg cgc ggc tac tac aac cag agc 514Thr Asp Arg Met Asn Leu Gln Thr Leu Arg Gly Tyr Tyr Asn Gln Ser 100 105 110 gag gcc agt tct cac acc ctc cag tgg atg att ggc tgc gac ctg ggg 562Glu Ala Ser Ser His Thr Leu Gln Trp Met Ile Gly Cys Asp Leu Gly 115 120 125 tcc gac gga cgc ctc ctc cgc ggg tat gaa cag tat gcc tac gat ggc 610Ser Asp Gly Arg Leu Leu Arg Gly Tyr Glu Gln Tyr Ala Tyr Asp Gly 130 135 140 aag gat tac ctc gcc ctg aac gag gac ctg cgc tcc tgg acc gca gcg 658Lys Asp Tyr Leu Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala 145 150 155 160 gac act gcg gct cag atc tcc aag cgc aag tgt gag gcg gcc aat gtg 706Asp Thr Ala Ala Gln Ile Ser Lys Arg Lys Cys Glu Ala Ala Asn Val 165 170 175 gct gaa caa agg aga gcc tac ctg gag ggc acg tgc gtg gag tgg ctc 754Ala Glu Gln Arg Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu 180 185 190 cac aga tac ctg gag aac ggg aag gag atg ctg cag cgc gcg gac ccc 802His Arg Tyr Leu Glu Asn Gly Lys Glu Met Leu Gln Arg Ala Asp Pro 195 200 205 ccc aag aca cac gtg acc cac cac cct gtc ttt gac tat gag gcc acc 850Pro Lys Thr His Val Thr His His Pro Val Phe Asp Tyr Glu Ala Thr 210 215 220 ctg agg tgc tgg gcc ctg ggc ttc tac cct gcg gag atc ata ctg acc 898Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Ile Leu Thr 225 230 235 240 tgg cag cgg gat ggg gag gac cag acc cag gac gtg gag ctc gtg gag 946Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Val Glu Leu Val Glu 245 250 255 acc agg cct gca ggg gat gga acc ttc cag aag tgg gca gct gtg gtg 994Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val 260 265 270 gtg cct tct gga gag gag cag aga tac acg tgc cat gtg cag cat gag 1042Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu 275 280 285 ggg ctg ccg gag ccc ctc atg ctg aga tgg aag cag tct tcc ctg ccc 1090Gly Leu Pro Glu Pro Leu Met Leu Arg Trp Lys Gln Ser Ser Leu Pro 290 295 300 acc atc ccc atc atg ggt atc gtt gct ggc ctg gtt gtc ctt gca gct 1138Thr Ile Pro Ile Met Gly Ile Val Ala Gly Leu Val Val Leu Ala Ala 305 310 315 320 gta gtc act gga gct gcg gtc gct gct gtg ctg tgg aga aag aag agc 1186Val Val Thr Gly Ala Ala Val Ala Ala Val Leu Trp Arg Lys Lys Ser 325 330 335 tca gat tga aaaggaggga gctactctca ggctgcaatg tgaaacagct 1235Ser Asp gccctgtgtg ggactgagtg gcaagtccct ttgtgacttc aagaaccctg actcctcttt 1295gtgcagagac cagcccaccc ctgtgcccac catgaccctc ttcctcatgc tgaactgcat 1355tccttcccca atcacctttc ctgttccaga aaaggggctg ggatgtctcc gtctctgtct 1415caaatttgtg gtccactgag ctataactta cttctgtatt aaaattagaa tctgagtata 1475aatttacttt ttcaaattat ttccaagaga gattgatggg ttaattaaag gagaagattc 1535ctgaaatttg agagacaaaa taaatggaag acatgagaac ttt 157814338PRTHomo sapiens 14Met Val Val Met Ala Pro Arg Thr Leu Phe Leu Leu Leu Ser Gly Ala 1 5 10 15 Leu Thr Leu Thr Glu Thr Trp Ala Gly Ser His Ser Met Arg Tyr Phe 20 25 30 Ser Ala Ala Val Ser Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ala 35 40 45 Met Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp Ser Asp Ser 50 55 60 Ala Cys Pro Arg Met Glu Pro Arg Ala Pro Trp Val Glu Gln Glu Gly 65 70 75 80 Pro Glu Tyr Trp Glu Glu Glu Thr Arg Asn Thr Lys Ala His Ala Gln 85 90 95 Thr Asp Arg Met Asn Leu Gln Thr Leu Arg Gly Tyr Tyr Asn Gln Ser 100 105 110 Glu Ala Ser Ser His Thr Leu Gln Trp Met Ile Gly Cys Asp Leu Gly 115 120 125 Ser Asp Gly Arg Leu Leu Arg Gly Tyr Glu Gln Tyr Ala Tyr Asp Gly 130 135 140 Lys Asp Tyr Leu Ala Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Ala 145 150 155 160 Asp Thr Ala Ala Gln Ile Ser Lys Arg Lys Cys Glu Ala Ala Asn Val 165 170 175 Ala Glu Gln Arg Arg Ala Tyr Leu Glu Gly Thr Cys Val Glu Trp Leu 180 185 190 His Arg Tyr Leu Glu Asn Gly Lys Glu Met Leu Gln Arg Ala Asp Pro 195 200 205 Pro Lys Thr His Val Thr His His Pro Val Phe Asp Tyr Glu Ala Thr 210 215 220 Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile Ile Leu Thr 225 230 235 240 Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Val Glu Leu Val Glu 245 250 255 Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val 260 265 270 Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val Gln His Glu 275

280 285 Gly Leu Pro Glu Pro Leu Met Leu Arg Trp Lys Gln Ser Ser Leu Pro 290 295 300 Thr Ile Pro Ile Met Gly Ile Val Ala Gly Leu Val Val Leu Ala Ala 305 310 315 320 Val Val Thr Gly Ala Ala Val Ala Ala Val Leu Trp Arg Lys Lys Ser 325 330 335 Ser Asp 159232DNAArtificial SequenceVector sequence for human B2M-HLA-A0201 fusion protein 15ctcgaggagc ttggcccatt gcatacgttg tatccatatc ataatatgta catttatatt 60ggctcatgtc caacattacc gccatgttga cattgattat tgactagtta ttaatagtaa 120tcaattacgg ggtcattagt tcatagccca tatatggagt tccgcgttac ataacttacg 180gtaaatggcc cgcctggctg accgcccaac gacccccgcc cattgacgtc aataatgacg 240tatgttccca tagtaacgcc aatagggact ttccattgac gtcaatgggt ggagtattta 300cgctaaactg cccacttggc agtacatcaa gtgtatcata tgccaagtac gccccctatt 360gacgtcaatg acggtaaatg gcccgcctgg cattatgccc agtacatgac cttatgggac 420tttcctactt ggcagtacat ctacgtatta gtcatcgcta ttaccatggt gatgcggttt 480tggcagtaca tcaatgggcg tggatagcgg tttgactcac ggggatttcc aagtctccac 540cccattgacg tcaatgggag tttgttttgg caccaaaatc aacgggactt tccaaaatgt 600cgtaacaact ccgccccatt gacgcaaatg ggcggtaggc gtgtacggtg ggaggtctat 660ataagcagag cttctagatt gtacgggagc tcttcactac tcgctgcgtc gagagtgtac 720gagactctcc aggtttggta agaaatattt tatattgtta taatgttact atgatccatt 780aacactctgc ttatagattg taagggtgat tgcaatgctt tctgcataaa actttggttt 840tcttgttaat caataaaccg acttgattcg agaacctact catatattat tgtctctttt 900atactttatt aagtaaaagg atttgtatat tagccttgct aagggagaca tctagtgata 960taagtgtgaa ctacacttat cttaaatgat gtaactcctt aggataatca atatacaaaa 1020ttccatgaca attggcgccc aacgtggggc tcgaatataa gtcgggttta tttgtaaatt 1080atccctaggg acctccgagc aagcgagcat agcgggaggc atataaaagc caatagacaa 1140tggctagcag gaagtaatgt tgaagaatat gaacttgatg ttgaagctct ggttgtaatt 1200ttaagagata gaaatatacc aagaaatcct ttacatggag aagttatagg tcttcgcctt 1260actgaaggat ggtggggaca aattgagaga tttcagatgg tacgttgatc taaggctatg 1320gatttggcca tgggacaaga aatattagtt tatagtccca ttgtatctat gactaaaata 1380caaaaaactc cactaccaga aagaaaagct ttacccatta gatggataac atggatgact 1440tatttagaag atccaagaat ccaatttcat tatgataaaa ccttaccaga acttaagcat 1500attccagatg tatatacatc tagtcagtct cctgttaaac atccttctca atatgaagga 1560gtgttttata ctgatggctc ggccatcaaa agtcctgatc ctacaaaaag caataatgct 1620ggcatgggaa tagtacatgc cacatacaaa cctgaatatc aagttttgaa tcaatggtca 1680ataccactag gtaatcatac tgctcagatg gctgaaatag ctgcagttga atttgcctgt 1740aaaaaagctt taaaaatacc tggtcctgta ttagttataa ctgatagttt ctatgtagca 1800gaaagtgcta ataaagaatt accatactgg aaatctaatg ggtttgttaa taataagaaa 1860aagcctctta aacatatctc caaatggaaa tctattgctg agtgtttatc tatgaaacca 1920gacattacta ttcaacatga aaaaggcatc agcctacaaa taccagtatt catactgaaa 1980ggcaatgccc tagcagataa gcttgccacc caaggaagtt atgtggttaa ttgtaatacc 2040aaaaaaccaa acctggatgc agagttggat caattattac agggtcatta tataaaagga 2100tatcccaaac aatatacata ttttttagaa gatggcaaag taaaagtttc cagacctgaa 2160ggggttaaaa ttattccccc tcagtcagac agacaaaaaa ttgtgcttca agcccacaat 2220ttggctcaca ccggacgtga agccactctt ttaaaaattg ccaaccttta ttggtggcca 2280aatatgagaa aggatgtggt taaacaacta ggacgctgtc aacagtgttt aatcacaaat 2340gcttccaaca aagcctctgg tcctattcta agaccagata ggcctcaaaa accttttgat 2400aaattcttta ttgactatat tggacctttg ccaccttcac agggatacct atatgtatta 2460gtagttgttg atggaatgac aggattcact tggttatacc ccactaaggc tccttctact 2520agcgcaactg ttaaatctct caatgtactc actagtattg caattccaaa ggtgattcac 2580tctgatcaag gtgcagcatt cacttcttca acctttgctg aatgggcaaa ggaaagaggt 2640atacatttgg aattcagtac tccttatcac ccccaaagtg gtagtaaggt ggaaaggaaa 2700aatagtgata taaaacgact tttaactaaa ctgctagtag gaagacccac aaagtggtat 2760gacctattgc ctgttgtaca acttgcttta aacaacacct atagccctgt attaaaatat 2820actccacatc aactcttatt tggtatagat tcaaatactc catttgcaaa tcaagataca 2880cttgacttga ccagagaaga agaactttct cttttacagg aaattcgtac ttctttatac 2940catccatcca cccctccagc ctcctctcgt tcctggtctc ctgttgttgg ccaattggtc 3000caggagaggg tggctaggcc tgcttctttg agacctcgtt ggcataaacc gtctactgta 3060cttaaggtgt tgaatccaag gactgttgtt attttggacc atcttggcaa caacagaact 3120gtaagtatag ataatttaaa acctacttct catcagaatg gcaccaccaa tgacactgca 3180acaatggatc atttggaaaa aaatgaataa agcgcatgag gcacttcaaa atacaacaac 3240tgtgactgaa cagcagaagg aacaaattat actggacatt caaaatgaag aagtacaacc 3300aactaggaga gataaattta gatatctgct ttatacttgt tgtgctacta gctcaagagt 3360attggcctgg atgtttttag tttgtatatt gttaatcatt gttttggttt catgctttgt 3420gactatatcc agaatacaat ggaataagga tattcaggta ttaggacctg taatagactg 3480gaatgttact caaagagctg tttatcaacc cttacagact agaaggattg cacgttccct 3540tagaatgcag catcctgttc caaaatatgt ggaggtaaat atgactagta ttccacaagg 3600tgtatactat gaaccccatc cggcctcgac ggtatcgatg gtaccggtat cgataagctt 3660gataacctcg agagatctaa ttctaccggg taggggaggc gcttttccca aggcagtctg 3720gagcatgcgc tttagcagcc ccgctggcac ttggcgctac acaagtggcc tctggcctcg 3780cacacattcc acatccaccg gtagcgccaa ccggctccgt tctttggtgg ccccttcgcg 3840ccacttctac tcctccccta gtcaggaagt ttcccccagc aagctcgcgt cgtgcaggac 3900gtgacaaatg gaagtagcac gtctcactag tctcgtgcag atggacagca ccgctgagca 3960atggaagcgg gtaggccttt ggggcagcgg ccaatagcag ctttgttcct tcgctttctg 4020ggctcagagg ctgggaaggg gtgggtccgg gggcgggctc aggggcgggc tcaggggcgg 4080gcgggcgccc gaaggtcctc ccgaggcccg gcattctgca cgcttcaaaa gcgcacgtct 4140gccgcgctgt tctcctcttc ctcatctccg ggcctttcga cctgcagccc gggggatcga 4200tcctaggtga tttaaatcca ccatgaccga gtacaagccc acggtgcgcc tcgccacccg 4260cgacgacgtc ccccgggccg tacgcaccct cgccgccgcg ttcgccgact accccgccac 4320gcgccacacc gtcgacccgg accgccacat cgagcgggtc accgagctgc aagaactctt 4380cctcacgcgc gtcgggctcg acatcggcaa ggtgtgggtc gcggacgacg gcgccgcggt 4440ggcggtctgg accacgccgg agagcgtcga agcgggggcg gtgttcgccg agatcggccc 4500gcgcatggcc gagttgagcg gttcccggct ggccgcgcag caacagatgg aaggcctcct 4560ggcgccgcac cggcccaagg agcccgcgtg gttcctggcc accgtcggcg tctcgcccga 4620ccaccagggc aagggtctgg gcagcgccgt cgtgctcccc ggagtggagg cggccgagcg 4680cgccggggtg cccgccttcc tggagacctc cgcgccccgc aacctcccct tctacgagcg 4740gctcggcttc accgtcaccg ccgacgtcga gtgcccgaag gaccgcgcga cctggtgcat 4800gacccgcaag cccggtgcct gacggatcca tcgctccggt gcccgtcagt gggcagagcg 4860cacatcgccc acagtccccg agaagttggg gggaggggtc ggcaattgaa ccggtgccta 4920gagaaggtgg cgcggggtaa actgggaaag tgatgtcgtg tactggctcc gcctttttcc 4980cgagggtggg ggagaaccgt atataagtgc agtagtcgcc gtgaacgttc tttttcgcaa 5040cgggtttgcc gccagaacac agctgcggcc gcgccgccac catgtctcgc tccgtggcct 5100tagctgtgct cgcgctactc tctctttctg gcctggaggc tatccagcgt actccaaaga 5160ttcaggttta ctcacgtcat ccagcagaga atggaaagtc aaatttcctg aattgctatg 5220tgtctgggtt tcatccatcc gacattgaag ttgacttact gaagaatgga gagagaattg 5280aaaaagtgga gcattcagac ttgtctttca gcaaggactg gtctttctat ctcttgtact 5340acactgaatt cacccccact gaaaaagatg agtatgcctg ccgtgtgaac catgtgactt 5400tgtcacagcc caagatagtt aagtgggatc gagacatggg cggaggcgga agcgggggcg 5460gcggatccgg cggaggcgga agcggcggcg ggggaagcgg ctctcactcc atgaggtatt 5520tcttcacatc cgtgtcccgg cccggccgcg gggagccccg cttcatcgca gtgggctacg 5580tggacgacac gcagttcgtg cggttcgaca gcgacgccgc gagccagagg atggagccgc 5640gggcgccgtg gatagagcag gagggtccgg agtattggga cggggagaca cggaaagtga 5700aggcccactc acagactcac cgagtggacc tggggaccct gcgcggctac tacaaccaga 5760gcgaggccgg ttctcacacc gtccagagga tgtatggctg cgacgtgggg tcggactggc 5820gcttcctccg cgggtaccac cagtacgcct acgacggcaa ggattacatc gccctgaaag 5880aggacctgcg ctcttggacc gcggcggaca tggcagctca gaccaccaag cacaagtggg 5940aggcggccca tgtggcggag cagttgagag cctacctgga gggcacgtgc gtggagtggc 6000tccgcagata cctggagaac gggaaggaga cgctgcagcg cacggacgcc cccaaaacgc 6060atatgactca ccacgctgtc tctgaccatg aagccaccct gaggtgctgg gccctgagct 6120tctaccctgc ggagatcaca ctgacctggc agcgggatgg ggaggaccag acccaggaca 6180cggagctcgt ggagaccagg cctgcagggg atggaacctt ccagaagtgg gcggctgtgg 6240tggtgccttc tggacaggag cagagataca cctgccatgt gcagcatgag ggtttgccca 6300agcccctcac cctgagatgg gagccgtctt cccagcccac catccccatc gtgggcatca 6360ttgctggcct ggttctcttt ggagctgtga tcactggagc tgtggtcgct gctgtgatgt 6420ggaggaggaa gagctcagat agaaaaggag ggagctactc tcaggctgca agcagtgaca 6480gtgcccaggg ctctgatgtg tctctcacag cttgtaaagt gtgagcggcc gcgactctag 6540atcaggcgcg ccgttaccaa gcagctatgg aagcttatgg acctcagaga ggaagtaacg 6600aggagagggt gtggtggaat gtcactagaa accagggaaa acaaggagga gagtattaca 6660gggaaggagg tgaagaacct cattacccaa atactcctgc tcctcataga cgtacctggg 6720atgagagaca caaggttctt aaattgtcct cattcgctac tccctctgac atccaacgct 6780gggctactaa ctctagattg tacgggagct ctcttcacta ctcgctgcgt cgagagtgta 6840cgagactctc caggtttggt aagaaatatt ttatattgtt ataatgttac tatgatccat 6900taacactctg cttatagatt gtaagggtga ttgcaatgct ttctgcataa aactttggtt 6960ttcttgttaa tcaataaacc gacttgattc gagaacctac tcatatatta ttgtctcttt 7020tatactttat taagtaaaag gatttgtata ttagccttgc taagggagac atctagtgat 7080ataagtgtga actacactta tcttaaatga tgtaactcct taggataatc aatatacaaa 7140attccatgac aattggcgat accgtcgacc gttcagctgc attaatgaat cggccaacgc 7200gcggggagag gcggtttgcg tattgggcgc tcttccgctt cctcgctcac tgactcgctg 7260cgctcggtcg ttcggctgcg gcgagcggta tcagctcact caaaggcggt aatacggtta 7320tccacagaat caggggataa cgcaggaaag aacatgtgag caaaaggcca gcaaaaggcc 7380aggaaccgta aaaaggccgc gttgctggcg tttttccata ggctccgccc ccctgacgag 7440catcacaaaa atcgacgctc aagtcagagg tggcgaaacc cgacaggact ataaagatac 7500caggcgtttc cccctggaag ctccctcgtg cgctctcctg ttccgaccct gccgcttacc 7560ggatacctgt ccgcctttct cccttcggga agcgtggcgc tttctcaatg ctcacgctgt 7620aggtatctca gttcggtgta ggtcgttcgc tccaagctgg gctgtgtgca cgaacccccc 7680gttcagcccg accgctgcgc cttatccggt aactatcgtc ttgagtccaa cccggtaaga 7740cacgacttat cgccactggc agcagccact ggtaacagga ttagcagagc gaggtatgta 7800ggcggtgcta cagagttctt gaagtggtgg cctaactacg gctacactag aaggacagta 7860tttggtatct gcgctctgct gaagccagtt accttcggaa aaagagttgg tagctcttga 7920tccggcaaac aaaccaccgc tggtagcggt ggtttttttg tttgcaagca gcagattacg 7980cgcagaaaaa aaggatctca agaagatcct ttgatctttt ctacggggtc tgacgctcag 8040tggaacgaaa actcacgtta agggattttg gtcatgagat tatcaaaaag gatcttcacc 8100tagatccttt taaattaaaa atgaagtttt aaatcaatct aaagtatata tgagtaaact 8160tggtctgaca gttaccaatg cttaatcagt gaggcaccta tctcagcgat ctgtctattt 8220cgttcatcca tagttgcctg actccccgtc gtgtagataa ctacgatacg ggagggctta 8280ccatctggcc ccagtgctgc aatgataccg cgagacccac gctcaccggc tccagattta 8340tcagcaataa accagccagc cggaagggcc gagcgcagaa gtggtcctgc aactttatcc 8400gcctccatcc agtctattaa ttgttgccgg gaagctagag taagtagttc gccagttaat 8460agtttgcgca acgttgttgc cattgctaca ggcatcgtgg tgtcacgctc gtcgtttggt 8520atggcttcat tcagctccgg ttcccaacga tcaaggcgag ttacatgatc ccccatgttg 8580tgcaaaaaag cggttagctc cttcggtcct ccgatcgttg tcagaagtaa gttggccgca 8640gtgttatcac tcatggttat ggcagcactg cataattctc ttactgtcat gccatccgta 8700agatgctttt ctgtgactgg tgagtactca accaagtcat tctgagaata gtgtatgcgg 8760cgaccgagtt gctcttgccc ggcgtcaata cgggataata ccgcgccaca tagcagaact 8820ttaaaagtgc tcatcattgg aaaacgttct tcggggcgaa aactctcaag gatcttaccg 8880ctgttgagat ccagttcgat gtaacccact cgtgcaccca actgatcttc agcatctttt 8940actttcacca gcgtttctgg gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga 9000ataagggcga cacggaaatg ttgaatactc atactcttcc tttttcaata ttattgaagc 9060atttatcagg gttattgtct catgagcgga tacatatttg aatgtattta gaaaaataaa 9120caaatagggg ttccgcgcac atttccccga aaagtgccac ctgacgtcta agaaaccatt 9180attatcatga cattaaccta taaaaatagg cgtatcacga ggccctttcg tc 923216480PRTArtificial SequenceHLA-bBA0201 (human B2M-HLA-A0201 fusion peptide) 16Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser 1 5 10 15 Gly Leu Glu Ala Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg 20 25 30 His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser 35 40 45 Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu 50 55 60 Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp 65 70 75 80 Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp 85 90 95 Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile 100 105 110 Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Met 130 135 140 Arg Tyr Phe Phe Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg 145 150 155 160 Phe Ile Ala Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp 165 170 175 Ser Asp Ala Ala Ser Gln Arg Met Glu Pro Arg Ala Pro Trp Ile Glu 180 185 190 Gln Glu Gly Pro Glu Tyr Trp Asp Gly Glu Thr Arg Lys Val Lys Ala 195 200 205 His Ser Gln Thr His Arg Val Asp Leu Gly Thr Leu Arg Gly Tyr Tyr 210 215 220 Asn Gln Ser Glu Ala Gly Ser His Thr Val Gln Arg Met Tyr Gly Cys 225 230 235 240 Asp Val Gly Ser Asp Trp Arg Phe Leu Arg Gly Tyr His Gln Tyr Ala 245 250 255 Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Lys Glu Asp Leu Arg Ser Trp 260 265 270 Thr Ala Ala Asp Met Ala Ala Gln Thr Thr Lys His Lys Trp Glu Ala 275 280 285 Ala His Val Ala Glu Gln Leu Arg Ala Tyr Leu Glu Gly Thr Cys Val 290 295 300 Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly Lys Glu Thr Leu Gln Arg 305 310 315 320 Thr Asp Ala Pro Lys Thr His Met Thr His His Ala Val Ser Asp His 325 330 335 Glu Ala Thr Leu Arg Cys Trp Ala Leu Ser Phe Tyr Pro Ala Glu Ile 340 345 350 Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp Gln Thr Gln Asp Thr Glu 355 360 365 Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala 370 375 380 Ala Val Val Val Pro Ser Gly Gln Glu Gln Arg Tyr Thr Cys His Val 385 390 395 400 Gln His Glu Gly Leu Pro Lys Pro Leu Thr Leu Arg Trp Glu Pro Ser 405 410 415 Ser Gln Pro Thr Ile Pro Ile Val Gly Ile Ile Ala Gly Leu Val Leu 420 425 430 Phe Gly Ala Val Ile Thr Gly Ala Val Val Ala Ala Val Met Trp Arg 435 440 445 Arg Lys Ser Ser Asp Arg Lys Gly Gly Ser Tyr Ser Gln Ala Ala Ser 450 455 460 Ser Asp Ser Ala Gln Gly Ser Asp Val Ser Leu Thr Ala Cys Lys Val 465 470 475 480 179224DNAArtificial SequenceVector sequence for HLA-gBE 17ctcgaggagc ttggcccatt gcatacgttg tatccatatc ataatatgta catttatatt 60ggctcatgtc caacattacc gccatgttga cattgattat tgactagtta ttaatagtaa 120tcaattacgg ggtcattagt tcatagccca tatatggagt tccgcgttac ataacttacg 180gtaaatggcc cgcctggctg accgcccaac gacccccgcc cattgacgtc aataatgacg 240tatgttccca tagtaacgcc aatagggact ttccattgac gtcaatgggt ggagtattta 300cgctaaactg cccacttggc agtacatcaa gtgtatcata tgccaagtac gccccctatt 360gacgtcaatg acggtaaatg gcccgcctgg cattatgccc agtacatgac cttatgggac 420tttcctactt ggcagtacat ctacgtatta gtcatcgcta ttaccatggt gatgcggttt 480tggcagtaca tcaatgggcg tggatagcgg tttgactcac ggggatttcc aagtctccac 540cccattgacg tcaatgggag tttgttttgg caccaaaatc aacgggactt tccaaaatgt 600cgtaacaact ccgccccatt gacgcaaatg ggcggtaggc gtgtacggtg ggaggtctat 660ataagcagag cttctagatt gtacgggagc tcttcactac tcgctgcgtc gagagtgtac 720gagactctcc aggtttggta agaaatattt tatattgtta taatgttact atgatccatt 780aacactctgc ttatagattg taagggtgat tgcaatgctt tctgcataaa actttggttt 840tcttgttaat caataaaccg acttgattcg agaacctact catatattat tgtctctttt 900atactttatt aagtaaaagg atttgtatat tagccttgct aagggagaca tctagtgata 960taagtgtgaa ctacacttat cttaaatgat gtaactcctt aggataatca atatacaaaa 1020ttccatgaca attggcgccc aacgtggggc tcgaatataa gtcgggttta tttgtaaatt 1080atccctaggg acctccgagc atagcgggag gcatataaaa gccaatagac aatggctagc 1140aggaagtaat gttgaagaat atgaacttga tgttgaagct ctggttgtaa ttttaagaga 1200tagaaatata ccaagaaatc ctttacatgg agaagttata ggtcttcgcc ttactgaagg 1260atggtgggga caaattgaga gatttcagat ggtacgttga tctaaggcta tggatttggc 1320catgggacaa gaaatattag tttatagtcc cattgtatct atgactaaaa tacaaaaaac 1380tccactacca gaaagaaaag ctttacccat tagatggata acatggatga cttatttaga 1440agatccaaga atccaatttc attatgataa aaccttacca gaacttaagc atattccaga 1500tgtatataca tctagtcagt ctcctgttaa acatccttct caatatgaag gagtgtttta 1560tactgatggc tcggccatca aaagtcctga tcctacaaaa agcaataatg ctggcatggg 1620aatagtacat gccacataca aacctgaata tcaagttttg aatcaatggt caataccact 1680aggtaatcat actgctcaga tggctgaaat agctgcagtt gaatttgcct gtaaaaaagc 1740tttaaaaata cctggtcctg tattagttat aactgatagt ttctatgtag cagaaagtgc 1800taataaagaa ttaccatact ggaaatctaa tgggtttgtt aataataaga aaaagcctct 1860taaacatatc tccaaatgga aatctattgc tgagtgttta tctatgaaac cagacattac 1920tattcaacat gaaaaaggca tcagcctaca aataccagta ttcatactga aaggcaatgc 1980cctagcagat aagcttgcca cccaaggaag ttatgtggtt aattgtaata ccaaaaaacc 2040aaacctggat gcagagttgg atcaattatt acagggtcat tatataaaag gatatcccaa 2100acaatataca

tattttttag aagatggcaa agtaaaagtt tccagacctg aaggggttaa 2160aattattccc cctcagtcag acagacaaaa aattgtgctt caagcccaca atttggctca 2220caccggacgt gaagccactc ttttaaaaat tgccaacctt tattggtggc caaatatgag 2280aaaggatgtg gttaaacaac taggacgctg tcaacagtgt ttaatcacaa atgcttccaa 2340caaagcctct ggtcctattc taagaccaga taggcctcaa aaaccttttg ataaattctt 2400tattgactat attggacctt tgccaccttc acagggatac ctatatgtat tagtagttgt 2460tgatggaatg acaggattca cttggttata ccccactaag gctccttcta ctagcgcaac 2520tgttaaatct ctcaatgtac tcactagtat tgcaattcca aaggtgattc actctgatca 2580aggtgcagca ttcacttctt caacctttgc tgaatgggca aaggaaagag gtatacattt 2640ggaattcagt actccttatc acccccaaag tggtagtaag gtggaaagga aaaatagtga 2700tataaaacga cttttaacta aactgctagt aggaagaccc acaaagtggt atgacctatt 2760gcctgttgta caacttgctt taaacaacac ctatagccct gtattaaaat atactccaca 2820tcaactctta tttggtatag attcaaatac tccatttgca aatcaagata cacttgactt 2880gaccagagaa gaagaacttt ctcttttaca ggaaattcgt acttctttat accatccatc 2940cacccctcca gcctcctctc gttcctggtc tcctgttgtt ggccaattgg tccaggagag 3000ggtggctagg cctgcttctt tgagacctcg ttggcataaa ccgtctactg tacttaaggt 3060gttgaatcca aggactgttg ttattttgga ccatcttggc aacaacagaa ctgtaagtat 3120agataattta aaacctactt ctcatcagaa tggcaccacc aatgacactg caacaatgga 3180tcatttggaa aaaaatgaat aaagcgcatg aggcacttca aaatacaaca actgtgactg 3240aacagcagaa ggaacaaatt atactggaca ttcaaaatga agaagtacaa ccaactagga 3300gagataaatt tagatatctg ctttatactt gttgtgctac tagctcaaga gtattggcct 3360ggatgttttt agtttgtata ttgttaatca ttgttttggt ttcatgcttt gtgactatat 3420ccagaataca atggaataag gatattcagg tattaggacc tgtaatagac tggaatgtta 3480ctcaaagagc tgtttatcaa cccttacaga ctagaaggat tgcacgttcc cttagaatgc 3540agcatcctgt tccaaaatat gtggaggtaa atatgactag tattccacaa ggtgtatact 3600atgaacccca tccggcctcg acggtatcga tggtaccggt atcgataagc ttgataacct 3660cgagagatct aattctaccg ggtaggggag gcgcttttcc caaggcagtc tggagcatgc 3720gctttagcag ccccgctggc acttggcgct acacaagtgg cctctggcct cgcacacatt 3780ccacatccac cggtagcgcc aaccggctcc gttctttggt ggccccttcg cgccacttct 3840actcctcccc tagtcaggaa gtttccccca gcaagctcgc gtcgtgcagg acgtgacaaa 3900tggaagtagc acgtctcact agtctcgtgc agatggacag caccgctgag caatggaagc 3960gggtaggcct ttggggcagc ggccaatagc agctttgttc cttcgctttc tgggctcaga 4020ggctgggaag gggtgggtcc gggggcgggc tcaggggcgg gctcaggggc gggcgggcgc 4080ccgaaggtcc tcccgaggcc cggcattctg cacgcttcaa aagcgcacgt ctgccgcgct 4140gttctcctct tcctcatctc cgggcctttc gacctgcagc ccgggggatc gatcctaggt 4200gatttaaatc caccatgacc gagtacaagc ccacggtgcg cctcgccacc cgcgacgacg 4260tcccccgggc cgtacgcacc ctcgccgccg cgttcgccga ctaccccgcc acgcgccaca 4320ccgtcgaccc ggaccgccac atcgagcggg tcaccgagct gcaagaactc ttcctcacgc 4380gcgtcgggct cgacatcggc aaggtgtggg tcgcggacga cggcgccgcg gtggcggtct 4440ggaccacgcc ggagagcgtc gaagcggggg cggtgttcgc cgagatcggc ccgcgcatgg 4500ccgagttgag cggttcccgg ctggccgcgc agcaacagat ggaaggcctc ctggcgccgc 4560accggcccaa ggagcccgcg tggttcctgg ccaccgtcgg cgtctcgccc gaccaccagg 4620gcaagggtct gggcagcgcc gtcgtgctcc ccggagtgga ggcggccgag cgcgccgggg 4680tgcccgcctt cctggagacc tccgcgcccc gcaacctccc cttctacgag cggctcggct 4740tcaccgtcac cgccgacgtc gagtgcccga aggaccgcgc gacctggtgc atgacccgca 4800agcccggtgc ctgacggatc catcgctccg gtgcccgtca gtgggcagag cgcacatcgc 4860ccacagtccc cgagaagttg gggggagggg tcggcaattg aaccggtgcc tagagaaggt 4920ggcgcggggt aaactgggaa agtgatgtcg tgtactggct ccgccttttt cccgagggtg 4980ggggagaacc gtatataagt gcagtagtcg ccgtgaacgt tctttttcgc aacgggtttg 5040ccgccagaac acagctgcgg ccgcgttaac catggtggtc atggcccctc gaactctgtt 5100cctgctgctg agtggggctc tgaccctgac agagtccgga atccagcgga cccccaagat 5160tcaggtgtac agcagacacc ctgcagagaa cggcaaatcc aacttcctga attgctatgt 5220gtctgggttt catcccagtg acatcgaagt cgatctgctg aagaatggcg agagaattga 5280aaaagtcgag cactctgacc tgagcttctc caaggattgg tccttttacc tgctgtacta 5340taccgagttt actccaaccg aaaaagacga gtatgcctgt agggtgaacc atgtcacact 5400gagccagccc aagatcgtga aatgggaccg cgatatgggc gggggaggct cagggggagg 5460cgggagcgga ggcgggggct ccggcggggg aggatccggt tctcactcct tgaagtattt 5520ccacacttcc gtgtcccggc ccggccgcgg ggagccccgc ttcatctctg tgggctacgt 5580ggacgacacc cagttcgtgc gcttcgacaa cgacgccgcg agtccgagga tggtgccgcg 5640ggcgccgtgg atggagcagg aggggtcaga gtattgggac cgggagacac ggagcgccag 5700ggacaccgca cagattttcc gagtgaatct gcggacgctg cgcggctact acaatcagag 5760cgaggccggg tctcacaccc tgcagtggat gcatggctgc gagctggggc ccgacgggcg 5820cttcctccgc gggtatgaac agttcgccta cgacggcaag gattatctca ccctgaatga 5880ggacctgcgc tcctggaccg cggtggacac ggcggctcag atctccgagc aaaagtcaaa 5940tgatgcctct gaggcggagc accagagagc ctacctggaa gacacatgcg tggagtggct 6000ccacaaatac ctggagaagg ggaaggagac gctgcttcac ctggagcccc caaagacaca 6060cgtgactcac caccccatct ctgaccatga ggccaccctg aggtgctggg ccctgggctt 6120ctaccctgcg gagatcacac tgacctggca gcaggatggg gagggccata cccaggacac 6180ggagctcgtg gagaccaggc ctgcagggga tggaaccttc cagaagtggg cagctgtggt 6240ggtgccttct ggagaggagc agagatacac gtgccatgtg cagcatgagg ggctacccga 6300gcccgtcacc ctgagatgga agccggcttc ccagcccacc atccccatcg tgggcatcat 6360tgctggcctg gttctccttg gatctgtggt ctctggagct gtggttgctg ctgtgatatg 6420gaggaagaag agctcaggtg gaaaaggagg gagctactct aaggctgagt ggagcgacag 6480tgcccagggg tctgagtctc acagcttgta atctagagcg gccgcgactc tagatcaggc 6540gcgccgttac caagcagcta tggaagctta tggacctcag agaggaagta acgaggagag 6600ggtgtggtgg aatgtcacta gaaaccaggg aaaacaagga ggagagtatt acagggaagg 6660aggtgaagaa cctcattacc caaatactcc tgctcctcat agacgtacct gggatgagag 6720acacaaggtt cttaaattgt cctcattcgc tactccctct gacatccaac gctggactac 6780taactctaga ttgtacggga ggctcttcac tactcgctgc gtcgagagtg tacgagactc 6840tccaggtttg gtaagaaata ttttatattg ttataatgtt actatgatcc attaacactc 6900tgcttataga ttgtaagggt gattgcaatg ctttctgcat aaaactttgg ttttcttgtt 6960aatcaataaa ccgacttgat tcgagaacca actcctatat tattgtctct tttatacttt 7020attaagtaaa aggatttgta tattagcctt gctaagggag acatctagtg atataagtgt 7080gaactacact tatcttaaat gatgtaactc cttaggataa tcaatataca aaattccatg 7140acaattggcg ataccgtcga ccgttcagct gcattaatga atcggccaac gcgcggggag 7200aggcggtttg cgtattgggc gctcttccgc ttcctcgctc actgactcgc tgcgctcggt 7260cgttcggctg cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt tatccacaga 7320atcaggggat aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg 7380taaaaaggcc gcgttgctgg cgtttttcca taggctccgc ccccctgacg agcatcacaa 7440aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat accaggcgtt 7500tccccctgga agctccctcg tgcgctctcc tgttccgacc ctgccgctta ccggatacct 7560gtccgccttt ctcccttcgg gaagcgtggc gctttctcaa tgctcacgct gtaggtatct 7620cagttcggtg taggtcgttc gctccaagct gggctgtgtg cacgaacccc ccgttcagcc 7680cgaccgctgc gccttatccg gtaactatcg tcttgagtcc aacccggtaa gacacgactt 7740atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatg taggcggtgc 7800tacagagttc ttgaagtggt ggcctaacta cggctacact agaaggacag tatttggtat 7860ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa 7920acaaaccacc gctggtagcg gtggtttttt tgtttgcaag cagcagatta cgcgcagaaa 7980aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgctc agtggaacga 8040aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca cctagatcct 8100tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa cttggtctga 8160cagttaccaa tgcttaatca gtgaggcacc tatctcagcg atctgtctat ttcgttcatc 8220catagttgcc tgactccccg tcgtgtagat aactacgata cgggagggct taccatctgg 8280ccccagtgct gcaatgatac cgcgagaccc acgctcaccg gctccagatt tatcagcaat 8340aaaccagcca gccggaaggg ccgagcgcag aagtggtcct gcaactttat ccgcctccat 8400ccagtctatt aattgttgcc gggaagctag agtaagtagt tcgccagtta atagtttgcg 8460caacgttgtt gccattgcta caggcatcgt ggtgtcacgc tcgtcgtttg gtatggcttc 8520attcagctcc ggttcccaac gatcaaggcg agttacatga tcccccatgt tgtgcaaaaa 8580agcggttagc tccttcggtc ctccgatcgt tgtcagaagt aagttggccg cagtgttatc 8640actcatggtt atggcagcac tgcataattc tcttactgtc atgccatccg taagatgctt 8700ttctgtgact ggtgagtact caaccaagtc attctgagaa tagtgtatgc ggcgaccgag 8760ttgctcttgc ccggcgtcaa tacgggataa taccgcgcca catagcagaa ctttaaaagt 8820gctcatcatt ggaaaacgtt cttcggggcg aaaactctca aggatcttac cgctgttgag 8880atccagttcg atgtaaccca ctcgtgcacc caactgatct tcagcatctt ttactttcac 8940cagcgtttct gggtgagcaa aaacaggaag gcaaaatgcc gcaaaaaagg gaataagggc 9000gacacggaaa tgttgaatac tcatactctt cctttttcaa tattattgaa gcatttatca 9060gggttattgt ctcatgagcg gatacatatt tgaatgtatt tagaaaaata aacaaatagg 9120ggttccgcgc acatttcccc gaaaagtgcc acctgacgtc taagaaacca ttattatcat 9180gacattaacc tataaaaata ggcgtatcac gaggcccttt cgtc 922418476PRTArtificial SequenceHLA-gBE 18Met Ala Pro Arg Thr Leu Phe Leu Leu Leu Ser Gly Ala Leu Thr Leu 1 5 10 15 Thr Glu Ser Gly Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg 20 25 30 His Pro Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser 35 40 45 Gly Phe His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu 50 55 60 Arg Ile Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp 65 70 75 80 Ser Phe Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp 85 90 95 Glu Tyr Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile 100 105 110 Val Lys Trp Asp Arg Asp Met Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser His Ser Leu 130 135 140 Lys Tyr Phe His Thr Ser Val Ser Arg Pro Gly Arg Gly Glu Pro Arg 145 150 155 160 Phe Ile Ser Val Gly Tyr Val Asp Asp Thr Gln Phe Val Arg Phe Asp 165 170 175 Asn Asp Ala Ala Ser Pro Arg Met Val Pro Arg Ala Pro Trp Met Glu 180 185 190 Gln Glu Gly Ser Glu Tyr Trp Asp Arg Glu Thr Arg Ser Ala Arg Asp 195 200 205 Thr Ala Gln Ile Phe Arg Val Asn Leu Arg Thr Leu Arg Gly Tyr Tyr 210 215 220 Asn Gln Ser Glu Ala Gly Ser His Thr Leu Gln Trp Met His Gly Cys 225 230 235 240 Glu Leu Gly Pro Asp Gly Arg Phe Leu Arg Gly Tyr Glu Gln Phe Ala 245 250 255 Tyr Asp Gly Lys Asp Tyr Leu Thr Leu Asn Glu Asp Leu Arg Ser Trp 260 265 270 Thr Ala Val Asp Thr Ala Ala Gln Ile Ser Glu Gln Lys Ser Asn Asp 275 280 285 Ala Ser Glu Ala Glu His Gln Arg Ala Tyr Leu Glu Asp Thr Cys Val 290 295 300 Glu Trp Leu His Lys Tyr Leu Glu Lys Gly Lys Glu Thr Leu Leu His 305 310 315 320 Leu Glu Pro Pro Lys Thr His Val Thr His His Pro Ile Ser Asp His 325 330 335 Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly Phe Tyr Pro Ala Glu Ile 340 345 350 Thr Leu Thr Trp Gln Gln Asp Gly Glu Gly His Thr Gln Asp Thr Glu 355 360 365 Leu Val Glu Thr Arg Pro Ala Gly Asp Gly Thr Phe Gln Lys Trp Ala 370 375 380 Ala Val Val Val Pro Ser Gly Glu Glu Gln Arg Tyr Thr Cys His Val 385 390 395 400 Gln His Glu Gly Leu Pro Glu Pro Val Thr Leu Arg Trp Lys Pro Ala 405 410 415 Ser Gln Pro Thr Ile Pro Ile Val Gly Ile Ile Ala Gly Leu Val Leu 420 425 430 Leu Gly Ser Val Val Ser Gly Ala Val Val Ala Ala Val Ile Trp Arg 435 440 445 Lys Lys Ser Ser Gly Gly Lys Gly Gly Ser Tyr Ser Lys Ala Glu Trp 450 455 460 Ser Asp Ser Ala Gln Gly Ser Glu Ser His Ser Leu 465 470 475 199287DNAArtificial SequenceVector sequence for HLA-bGBE 19ctcgaggagc ttggcccatt gcatacgttg tatccatatc ataatatgta catttatatt 60ggctcatgtc caacattacc gccatgttga cattgattat tgactagtta ttaatagtaa 120tcaattacgg ggtcattagt tcatagccca tatatggagt tccgcgttac ataacttacg 180gtaaatggcc cgcctggctg accgcccaac gacccccgcc cattgacgtc aataatgacg 240tatgttccca tagtaacgcc aatagggact ttccattgac gtcaatgggt ggagtattta 300cgctaaactg cccacttggc agtacatcaa gtgtatcata tgccaagtac gccccctatt 360gacgtcaatg acggtaaatg gcccgcctgg cattatgccc agtacatgac cttatgggac 420tttcctactt ggcagtacat ctacgtatta gtcatcgcta ttaccatggt gatgcggttt 480tggcagtaca tcaatgggcg tggatagcgg tttgactcac ggggatttcc aagtctccac 540cccattgacg tcaatgggag tttgttttgg caccaaaatc aacgggactt tccaaaatgt 600cgtaacaact ccgccccatt gacgcaaatg ggcggtaggc gtgtacggtg ggaggtctat 660ataagcagag cttctagatt gtacgggagc tcttcactac tcgctgcgtc gagagtgtac 720gagactctcc aggtttggta agaaatattt tatattgtta taatgttact atgatccatt 780aacactctgc ttatagattg taagggtgat tgcaatgctt tctgcataaa actttggttt 840tcttgttaat caataaaccg acttgattcg agaacctact catatattat tgtctctttt 900atactttatt aagtaaaagg atttgtatat tagccttgct aagggagaca tctagtgata 960taagtgtgaa ctacacttat cttaaatgat gtaactcctt aggataatca atatacaaaa 1020ttccatgaca attggcgccc aacgtggggc tcgaatataa gtcgggttta tttgtaaatt 1080atccctaggg acctccgagc atagcgggag gcatataaaa gccaatagac aatggctagc 1140aggaagtaat gttgaagaat atgaacttga tgttgaagct ctggttgtaa ttttaagaga 1200tagaaatata ccaagaaatc ctttacatgg agaagttata ggtcttcgcc ttactgaagg 1260atggtgggga caaattgaga gatttcagat ggtacgttga tctaaggcta tggatttggc 1320catgggacaa gaaatattag tttatagtcc cattgtatct atgactaaaa tacaaaaaac 1380tccactacca gaaagaaaag ctttacccat tagatggata acatggatga cttatttaga 1440agatccaaga atccaatttc attatgataa aaccttacca gaacttaagc atattccaga 1500tgtatataca tctagtcagt ctcctgttaa acatccttct caatatgaag gagtgtttta 1560tactgatggc tcggccatca aaagtcctga tcctacaaaa agcaataatg ctggcatggg 1620aatagtacat gccacataca aacctgaata tcaagttttg aatcaatggt caataccact 1680aggtaatcat actgctcaga tggctgaaat agctgcagtt gaatttgcct gtaaaaaagc 1740tttaaaaata cctggtcctg tattagttat aactgatagt ttctatgtag cagaaagtgc 1800taataaagaa ttaccatact ggaaatctaa tgggtttgtt aataataaga aaaagcctct 1860taaacatatc tccaaatgga aatctattgc tgagtgttta tctatgaaac cagacattac 1920tattcaacat gaaaaaggca tcagcctaca aataccagta ttcatactga aaggcaatgc 1980cctagcagat aagcttgcca cccaaggaag ttatgtggtt aattgtaata ccaaaaaacc 2040aaacctggat gcagagttgg atcaattatt acagggtcat tatataaaag gatatcccaa 2100acaatataca tattttttag aagatggcaa agtaaaagtt tccagacctg aaggggttaa 2160aattattccc cctcagtcag acagacaaaa aattgtgctt caagcccaca atttggctca 2220caccggacgt gaagccactc ttttaaaaat tgccaacctt tattggtggc caaatatgag 2280aaaggatgtg gttaaacaac taggacgctg tcaacagtgt ttaatcacaa atgcttccaa 2340caaagcctct ggtcctattc taagaccaga taggcctcaa aaaccttttg ataaattctt 2400tattgactat attggacctt tgccaccttc acagggatac ctatatgtat tagtagttgt 2460tgatggaatg acaggattca cttggttata ccccactaag gctccttcta ctagcgcaac 2520tgttaaatct ctcaatgtac tcactagtat tgcaattcca aaggtgattc actctgatca 2580aggtgcagca ttcacttctt caacctttgc tgaatgggca aaggaaagag gtatacattt 2640ggaattcagt actccttatc acccccaaag tggtagtaag gtggaaagga aaaatagtga 2700tataaaacga cttttaacta aactgctagt aggaagaccc acaaagtggt atgacctatt 2760gcctgttgta caacttgctt taaacaacac ctatagccct gtattaaaat atactccaca 2820tcaactctta tttggtatag attcaaatac tccatttgca aatcaagata cacttgactt 2880gaccagagaa gaagaacttt ctcttttaca ggaaattcgt acttctttat accatccatc 2940cacccctcca gcctcctctc gttcctggtc tcctgttgtt ggccaattgg tccaggagag 3000ggtggctagg cctgcttctt tgagacctcg ttggcataaa ccgtctactg tacttaaggt 3060gttgaatcca aggactgttg ttattttgga ccatcttggc aacaacagaa ctgtaagtat 3120agataattta aaacctactt ctcatcagaa tggcaccacc aatgacactg caacaatgga 3180tcatttggaa aaaaatgaat aaagcgcatg aggcacttca aaatacaaca actgtgactg 3240aacagcagaa ggaacaaatt atactggaca ttcaaaatga agaagtacaa ccaactagga 3300gagataaatt tagatatctg ctttatactt gttgtgctac tagctcaaga gtattggcct 3360ggatgttttt agtttgtata ttgttaatca ttgttttggt ttcatgcttt gtgactatat 3420ccagaataca atggaataag gatattcagg tattaggacc tgtaatagac tggaatgtta 3480ctcaaagagc tgtttatcaa cccttacaga ctagaaggat tgcacgttcc cttagaatgc 3540agcatcctgt tccaaaatat gtggaggtaa atatgactag tattccacaa ggtgtatact 3600atgaacccca tccggcctcg acggtatcga tggtaccggt atcgataagc ttgataacct 3660cgagagatct aattctaccg ggtaggggag gcgcttttcc caaggcagtc tggagcatgc 3720gctttagcag ccccgctggc acttggcgct acacaagtgg cctctggcct cgcacacatt 3780ccacatccac cggtagcgcc aaccggctcc gttctttggt ggccccttcg cgccacttct 3840actcctcccc tagtcaggaa gtttccccca gcaagctcgc gtcgtgcagg acgtgacaaa 3900tggaagtagc acgtctcact agtctcgtgc agatggacag caccgctgag caatggaagc 3960gggtaggcct ttggggcagc ggccaatagc agctttgttc cttcgctttc tgggctcaga 4020ggctgggaag gggtgggtcc gggggcgggc tcaggggcgg gctcaggggc gggcgggcgc 4080ccgaaggtcc tcccgaggcc cggcattctg cacgcttcaa aagcgcacgt ctgccgcgct 4140gttctcctct tcctcatctc cgggcctttc gacctgcagc ccgggggatc gatcctaggt 4200gatttaaatc caccatgacc gagtacaagc ccacggtgcg cctcgccacc cgcgacgacg 4260tcccccgggc cgtacgcacc ctcgccgccg cgttcgccga ctaccccgcc acgcgccaca 4320ccgtcgaccc ggaccgccac atcgagcggg tcaccgagct gcaagaactc ttcctcacgc 4380gcgtcgggct cgacatcggc aaggtgtggg tcgcggacga cggcgccgcg gtggcggtct 4440ggaccacgcc ggagagcgtc gaagcggggg cggtgttcgc cgagatcggc ccgcgcatgg 4500ccgagttgag cggttcccgg ctggccgcgc agcaacagat ggaaggcctc ctggcgccgc 4560accggcccaa ggagcccgcg tggttcctgg ccaccgtcgg cgtctcgccc gaccaccagg 4620gcaagggtct gggcagcgcc gtcgtgctcc ccggagtgga ggcggccgag cgcgccgggg 4680tgcccgcctt cctggagacc tccgcgcccc gcaacctccc cttctacgag

cggctcggct 4740tcaccgtcac cgccgacgtc gagtgcccga aggaccgcgc gacctggtgc atgacccgca 4800agcccggtgc ctgacggatc catcgctccg gtgcccgtca gtgggcagag cgcacatcgc 4860ccacagtccc cgagaagttg gggggagggg tcggcaattg aaccggtgcc tagagaaggt 4920ggcgcggggt aaactgggaa agtgatgtcg tgtactggct ccgccttttt cccgagggtg 4980ggggagaacc gtatataagt gcagtagtcg ccgtgaacgt tctttttcgc aacgggtttg 5040ccgccagaac acagctgcgg ccgcgttaac catgagccga tccgtggcac tggctgtcct 5100ggctctgctg tctctgagtg gcctggaagc agtgatggcc cctagaacac tgttcctggg 5160cggaggcggc tccggaggag gagggtctgg aggcggggga agtatccagc ggactcccaa 5220gattcaggtc tacagcagac accctgccga aaacgggaaa tccaacttcc tgaattgcta 5280tgtgtcaggc tttcatccca gcgacatcga ggtcgatctg ctgaagaatg gcgagcggat 5340tgaaaaagtg gagcactctg acctgtcatt cagcaaggat tggagctttt acctgctgta 5400ctatactgag tttaccccaa cagaaaaaga cgagtatgcc tgtagggtga accatgtcac 5460cctgagtcag cccaagatcg tgaaatggga ccgcgatatg ggcgggggag gctccggggg 5520aggcggctcc ggcggcgggg gaagtggcgg gggaggatcc ggttctcact ccttgaagta 5580tttccacact tccgtgtccc ggcccggccg cggggagccc cgcttcatct ctgtgggcta 5640cgtggacgac acccagttcg tgcgcttcga caacgacgcc gcgagtccga ggatggtgcc 5700gcgggcgccg tggatggagc aggaggggtc agagtattgg gaccgggaga cacggagcgc 5760cagggacacc gcacagattt tccgagtgaa tctgcggacg ctgcgcggct actacaatca 5820gagcgaggcc gggtctcaca ccctgcagtg gatgcatggc tgcgagctgg ggcccgacgg 5880gcgcttcctc cgcgggtatg aacagttcgc ctacgacggc aaggattatc tcaccctgaa 5940tgaggacctg cgctcctgga ccgcggtgga cacggcggct cagatctccg agcaaaagtc 6000aaatgatgcc tctgaggcgg agcaccagag agcctacctg gaagacacat gcgtggagtg 6060gctccacaaa tacctggaga aggggaagga gacgctgctt cacctggagc ccccaaagac 6120acacgtgact caccacccca tctctgacca tgaggccacc ctgaggtgct gggccctggg 6180cttctaccct gcggagatca cactgacctg gcagcaggat ggggagggcc atacccagga 6240cacggagctc gtggagacca ggcctgcagg ggatggaacc ttccagaagt gggcagctgt 6300ggtggtgcct tctggagagg agcagagata cacgtgccat gtgcagcatg aggggctacc 6360cgagcccgtc accctgagat ggaagccggc ttcccagccc accatcccca tcgtgggcat 6420cattgctggc ctggttctcc ttggatctgt ggtctctgga gctgtggttg ctgctgtgat 6480atggaggaag aagagctcag gtggaaaagg agggagctac tctaaggctg agtggagcga 6540cagtgcccag gggtctgagt ctcacagctt gtaatctaga gcggccgcga ctctagatca 6600ggcgcgccgt taccaagcag ctatggaagc ttatggacct cagagaggaa gtaacgagga 6660gagggtgtgg tggaatgtca ctagaaacca gggaaaacaa ggaggagagt attacaggga 6720aggaggtgaa gaacctcatt acccaaatac tcctgctcct catagacgta cctgggatga 6780gagacacaag gttcttaaat tgtcctcatt cgctactccc tctgacatcc aacgctggac 6840tactaactct agattgtacg ggaggctctt cactactcgc tgcgtcgaga gtgtacgaga 6900ctctccaggt ttggtaagaa atattttata ttgttataat gttactatga tccattaaca 6960ctctgcttat agattgtaag ggtgattgca atgctttctg cataaaactt tggttttctt 7020gttaatcaat aaaccgactt gattcgagaa ccaactccta tattattgtc tcttttatac 7080tttattaagt aaaaggattt gtatattagc cttgctaagg gagacatcta gtgatataag 7140tgtgaactac acttatctta aatgatgtaa ctccttagga taatcaatat acaaaattcc 7200atgacaattg gcgataccgt cgaccgttca gctgcattaa tgaatcggcc aacgcgcggg 7260gagaggcggt ttgcgtattg ggcgctcttc cgcttcctcg ctcactgact cgctgcgctc 7320ggtcgttcgg ctgcggcgag cggtatcagc tcactcaaag gcggtaatac ggttatccac 7380agaatcaggg gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa aggccaggaa 7440ccgtaaaaag gccgcgttgc tggcgttttt ccataggctc cgcccccctg acgagcatca 7500caaaaatcga cgctcaagtc agaggtggcg aaacccgaca ggactataaa gataccaggc 7560gtttccccct ggaagctccc tcgtgcgctc tcctgttccg accctgccgc ttaccggata 7620cctgtccgcc tttctccctt cgggaagcgt ggcgctttct caatgctcac gctgtaggta 7680tctcagttcg gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac cccccgttca 7740gcccgaccgc tgcgccttat ccggtaacta tcgtcttgag tccaacccgg taagacacga 7800cttatcgcca ctggcagcag ccactggtaa caggattagc agagcgaggt atgtaggcgg 7860tgctacagag ttcttgaagt ggtggcctaa ctacggctac actagaagga cagtatttgg 7920tatctgcgct ctgctgaagc cagttacctt cggaaaaaga gttggtagct cttgatccgg 7980caaacaaacc accgctggta gcggtggttt ttttgtttgc aagcagcaga ttacgcgcag 8040aaaaaaagga tctcaagaag atcctttgat cttttctacg gggtctgacg ctcagtggaa 8100cgaaaactca cgttaaggga ttttggtcat gagattatca aaaaggatct tcacctagat 8160ccttttaaat taaaaatgaa gttttaaatc aatctaaagt atatatgagt aaacttggtc 8220tgacagttac caatgcttaa tcagtgaggc acctatctca gcgatctgtc tatttcgttc 8280atccatagtt gcctgactcc ccgtcgtgta gataactacg atacgggagg gcttaccatc 8340tggccccagt gctgcaatga taccgcgaga cccacgctca ccggctccag atttatcagc 8400aataaaccag ccagccggaa gggccgagcg cagaagtggt cctgcaactt tatccgcctc 8460catccagtct attaattgtt gccgggaagc tagagtaagt agttcgccag ttaatagttt 8520gcgcaacgtt gttgccattg ctacaggcat cgtggtgtca cgctcgtcgt ttggtatggc 8580ttcattcagc tccggttccc aacgatcaag gcgagttaca tgatccccca tgttgtgcaa 8640aaaagcggtt agctccttcg gtcctccgat cgttgtcaga agtaagttgg ccgcagtgtt 8700atcactcatg gttatggcag cactgcataa ttctcttact gtcatgccat ccgtaagatg 8760cttttctgtg actggtgagt actcaaccaa gtcattctga gaatagtgta tgcggcgacc 8820gagttgctct tgcccggcgt caatacggga taataccgcg ccacatagca gaactttaaa 8880agtgctcatc attggaaaac gttcttcggg gcgaaaactc tcaaggatct taccgctgtt 8940gagatccagt tcgatgtaac ccactcgtgc acccaactga tcttcagcat cttttacttt 9000caccagcgtt tctgggtgag caaaaacagg aaggcaaaat gccgcaaaaa agggaataag 9060ggcgacacgg aaatgttgaa tactcatact cttccttttt caatattatt gaagcattta 9120tcagggttat tgtctcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat 9180aggggttccg cgcacatttc cccgaaaagt gccacctgac gtctaagaaa ccattattat 9240catgacatta acctataaaa ataggcgtat cacgaggccc tttcgtc 928720500PRTArtificial SequenceHLA-bGBE 20Met Ser Arg Ser Val Ala Leu Ala Val Leu Ala Leu Leu Ser Leu Ser 1 5 10 15 Gly Leu Glu Ala Val Met Ala Pro Arg Thr Leu Phe Leu Gly Gly Gly 20 25 30 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr 35 40 45 Pro Lys Ile Gln Val Tyr Ser Arg His Pro Ala Glu Asn Gly Lys Ser 50 55 60 Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe His Pro Ser Asp Ile Glu 65 70 75 80 Val Asp Leu Leu Lys Asn Gly Glu Arg Ile Glu Lys Val Glu His Ser 85 90 95 Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe Tyr Leu Leu Tyr Tyr Thr 100 105 110 Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr Ala Cys Arg Val Asn His 115 120 125 Val Thr Leu Ser Gln Pro Lys Ile Val Lys Trp Asp Arg Asp Met Gly 130 135 140 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 145 150 155 160 Gly Gly Ser Gly Ser His Ser Leu Lys Tyr Phe His Thr Ser Val Ser 165 170 175 Arg Pro Gly Arg Gly Glu Pro Arg Phe Ile Ser Val Gly Tyr Val Asp 180 185 190 Asp Thr Gln Phe Val Arg Phe Asp Asn Asp Ala Ala Ser Pro Arg Met 195 200 205 Val Pro Arg Ala Pro Trp Met Glu Gln Glu Gly Ser Glu Tyr Trp Asp 210 215 220 Arg Glu Thr Arg Ser Ala Arg Asp Thr Ala Gln Ile Phe Arg Val Asn 225 230 235 240 Leu Arg Thr Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Ala Gly Ser His 245 250 255 Thr Leu Gln Trp Met His Gly Cys Glu Leu Gly Pro Asp Gly Arg Phe 260 265 270 Leu Arg Gly Tyr Glu Gln Phe Ala Tyr Asp Gly Lys Asp Tyr Leu Thr 275 280 285 Leu Asn Glu Asp Leu Arg Ser Trp Thr Ala Val Asp Thr Ala Ala Gln 290 295 300 Ile Ser Glu Gln Lys Ser Asn Asp Ala Ser Glu Ala Glu His Gln Arg 305 310 315 320 Ala Tyr Leu Glu Asp Thr Cys Val Glu Trp Leu His Lys Tyr Leu Glu 325 330 335 Lys Gly Lys Glu Thr Leu Leu His Leu Glu Pro Pro Lys Thr His Val 340 345 350 Thr His His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala 355 360 365 Leu Gly Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Gln Asp Gly 370 375 380 Glu Gly His Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly 385 390 395 400 Asp Gly Thr Phe Gln Lys Trp Ala Ala Val Val Val Pro Ser Gly Glu 405 410 415 Glu Gln Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Glu Pro 420 425 430 Val Thr Leu Arg Trp Lys Pro Ala Ser Gln Pro Thr Ile Pro Ile Val 435 440 445 Gly Ile Ile Ala Gly Leu Val Leu Leu Gly Ser Val Val Ser Gly Ala 450 455 460 Val Val Ala Ala Val Ile Trp Arg Lys Lys Ser Ser Gly Gly Lys Gly 465 470 475 480 Gly Ser Tyr Ser Lys Ala Glu Trp Ser Asp Ser Ala Gln Gly Ser Glu 485 490 495 Ser His Ser Leu 500 217159DNAArtificial SequenceVector sequence for pA2-B2METKNpA 21ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120aggggttcct gcggccgcga tgcagtccaa actctcacta aaattgccga gccctttgtc 180ttccagtgtc taaaatatta atgtcaatgg aatcaggcca gagtttgaat tctagtctct 240tagcctttgt ttcccctgtc cataaaatga atgggggtaa ttctttcctc ctacagttta 300tttatatatt cactaattca ttcattcatc catccattcg ttcattcggt ttactgagta 360cctactatgt gccagcccct gttctagggt ggaaactaag agaatgatgt acctagaggg 420cgctggaagc tctaaagccc tagcagttac tgcttttact attagtggtc gtttttttct 480cccccccgcc ccccgacaaa tcaacagaac aaagaaaatt acctaaacag caaggacata 540gggaggaact tcttggcaca gaactttcca aacacttttt cctgaaggga tacaagaagc 600aagaaaggta ctctttcact aggaccttct ctgagctgtc ctcaggatgc ttttgggact 660atttttctta cccagagaat ggagaaaccc tgcagggaat tcccaagctg tagttataaa 720cagaagttct ccttctgcta ggtagcattc aaagatctta atcttctggg tttccgtttt 780ctcgaatgaa aaatgcaggt ccgagcagtt aactggctgg ggcaccatta gcaagtcact 840tagcatctct ggggccagtc tgcaaagcga gggggcagcc ttaatgtgcc tccagcctga 900agtcctagaa tgagcgcccg gtgtcccaag ctggggcgcg caccccagat cggagggcgc 960cgatgtacag acagcaaact cacccagtct agtgcatgcc ttcttaaaca tcacgagact 1020ctaagaaaag gaaactgaaa acgggaaagt ccctctctct aacctggcac tgcgtcgctg 1080gcttggagac aggtgacggt ccctgcgggc cttgtcctga ttggctgggc acgcgtttaa 1140tataagtgga ggcgtcgcgc tggcgggcat tcctgaagct gacagcattc gggccgagat 1200ctagataact tcgtataatg tatgctatac gaagttatgg atccatcgat tctgcgatcg 1260ctccggtgcc cgtcagtggg cagagcgcac atcgcccaca gtccccgaga agttgggggg 1320aggggtcggc aattgaaccg gtgcctagag aaggtggcgc ggggtaaact gggaaagtga 1380tgtcgtgtac tggctccgcc tttttcccga gggtggggga gaaccgtata taagtgcagt 1440agtcgccgtg aacgttcttt ttcgcaacgg gtttgccgcc agaacacagc tgaagcttcc 1500accatgccca cgctactgcg ggtttatata gacggtcccc acgggatggg gaaaaccacc 1560accacgcaac tgctggtggc cctgggttcg cgcgacgata tcgtctacgt acccgagccg 1620atgacttact ggcgggtgct gggggcttcc gagacaatcg cgaacatcta caccacacaa 1680caccgcctcg accagggtga gatatcggcc ggggacgcgg cggtggtaat gacaagcgcc 1740cagataacaa tgggcatgcc ttatgccgtg accgacgccg ttctggctcc tcatatcggg 1800ggggaggctg ggagctcaca tgccccgccc ccggccctca ccctcatctt cgaccgccat 1860cccatcgccg ccctcctgtg ctacccggcc gcgcggtacc ttatgggcag catgaccccc 1920caggccgtgc tggcgttcgt ggccctcatc ccgccgacct tgcccggcac caacatcgtg 1980cttggggccc ttccggagga cagacacatc gaccgcctgg ccaaacgcca gcgccccggc 2040gagcggctgg acctggctat gctggctgcg attcgccgcg tttacgggct acttgccaat 2100acggtgcggt atctgcagtg cggcgggtcg tggcgggagg actggggaca gctttcgggg 2160acggccgtgc cgccccaggg tgccgagccc cagagcaacg cgggcccacg accccatatc 2220ggggacacgt tatttaccct gtttcgggcc cccgagttgc tggcccccaa cggcgacctg 2280tataacgtgt ttgcctgggc cttggacgtc ttggccaaac gcctccgttc catgcacgtc 2340tttatcctgg attacgacca atcgcccgcc ggctgccggg acgccctgct gcaacttacc 2400tccgggatgg tccagaccca cgtcaccacc cccggctcca taccgacgat atgcgacctg 2460gcgcgcacgt ttgcccggga gatgggatcg gccattgaac aagatggatt gcacgcaggt 2520tctccggccg cttgggtgga gaggctattc ggctatgact gggcacaaca gacaatcggc 2580tgctctgatg ccgccgtgtt ccggctgtca gcgcaggggc gcccggttct ttttgtcaag 2640accgacctgt ccggtgccct gaatgaactg caggacgagg cagcgcggct atcgtggctg 2700gccacgacgg gcgttccttg cgcagctgtg ctcgacgttg tcactgaagc gggaagggac 2760tggctgctat tgggcgaagt gccggggcag gatctcctgt catctcacct tgctcctgcc 2820gagaaagtat ccatcatggc tgatgcaatg cggcggctgc atacgcttga tccggctacc 2880tgcccattcg accaccaagc gaaacatcgc atcgagcgag cacgtactcg gatggaagcc 2940ggtcttgtcg atcaggatga tctggacgaa gagcatcagg ggctcgcgcc agccgaactg 3000ttcgccaggc tcaaggcgcg catgcccgac ggcgaggatc tcgtcgtgac ccatggcgat 3060gcctgcttgc cgaatatcat ggtggaaaat ggccgctttt ctggattcat cgactgtggc 3120cggctgggtg tggcggaccg ctatcaggac atagcgttgg ctacccgtga tattgctgaa 3180gagcttggcg gcgaatgggc tgaccgcttc ctcgtgcttt acggtatcgc cgctcccgat 3240tcgcagcgca tcgccttcta tcgccttctt gacgagttct tctgagggtc tctagcataa 3300cttcgtataa tgtatgctat acgaagttat aataaaagat ccttattttc attggatctg 3360tgtgttggtt ttttgtgtgg gatccgtcga taccgtcgac tgtctcgctc cgtggcctta 3420gctgtgctcg cgctactctc tctttctggc ctggaggcta tccagcgtga gtctctccta 3480ccctcccgct ctggtccttc ctctcccgct ctgcaccctc tgtggccctc gctgtgctct 3540ctcgctccgt gacttccctt ctccaagttc tccttggtgg cccgccgtgg ggctagtcca 3600gggctggatc tcggggaagc ggcggggtgg cctgggagtg gggaaggggg tgcgcacccg 3660ggacgcgcgc tacttgcccc tttcggcggg gagcagggga gacctttggc ctacggcgac 3720gggagggtcg ggacaaagtt tagggcgtcg ataagcgtca gagcgccgag gttgggggag 3780ggtttctctt ccgctctttc gcggggcctc tggctccccc agcgcagctg gagtggggga 3840cgggtaggct cgtcccaaag gcgcggcgct gaggtttgtg aacgcgtgga ggggcgcttg 3900gggtctgggg gaggcgtcgc ccgggtaagc ctgtctgctg cggctctgct tcccttagac 3960tggagagctg tggacttcgt ctaggcgccc gctaagttcg catgtcctag cacctctggg 4020tctatgtggg gccacaccgt ggggaggaaa cagcacgcga cgtttgtaga atgcttggct 4080gtgatacaaa gcggtttcga ataattaact tatttgttcc catcacatgt cacttttaaa 4140aaattataag aactacccgt tattgacatc tttctgtgtg ccaaggactt tatgtgcttt 4200gcgtcattta attttgaaaa cagttatctt ccgccataga taactactat ggttatcttc 4260tgcctctcac agatgaagaa actaaggcac cgagatttta agaaacttaa ttacacaggg 4320gataaatggc agcaatcgag attgaagtca agcctaacca gggcttttgc gggagcgcat 4380gccttttggc tgtaattcgt gcgcggccgc aggaacccct agtgatggag ttggccactc 4440cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg 4500gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag ctgcctgcag gggcgcctga 4560tgcggtattt tctccttacg catctgtgcg gtatttcaca ccgcatacgt caaagcaacc 4620atagtacgcg ccctgtagcg gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt 4680gaccgctaca cttgccagcg ccctagcgcc cgctcctttc gctttcttcc cttcctttct 4740cgccacgttc gccggctttc cccgtcaagc tctaaatcgg gggctccctt tagggttccg 4800atttagtgct ttacggcacc tcgaccccaa aaaacttgat ttgggtgatg gttcacgtag 4860tgggccatcg ccctgataga cggtttttcg ccctttgacg ttggagtcca cgttctttaa 4920tagtggactc ttgttccaaa ctggaacaac actcaaccct atctcgggct attcttttga 4980tttataaggg attttgccga tttcggccta ttggttaaaa aatgagctga tttaacaaaa 5040atttaacgcg aattttaaca aaatattaac gtttacaatt ttatggtgca ctctcagtac 5100aatctgctct gatgccgcat agttaagcca gccccgacac ccgccaacac ccgctgacgc 5160gccctgacgg gcttgtctgc tcccggcatc cgcttacaga caagctgtga ccgtctccgg 5220gagctgcatg tgtcagaggt tttcaccgtc atcaccgaaa cgcgcgagac gaaagggcct 5280cgtgatacgc ctatttttat aggttaatgt catgataata atggtttctt agacgtcagg 5340tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 5400aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 5460gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg 5520ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 5580gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 5640tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 5700attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 5760tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 5820agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 5880aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 5940tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 6000cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac 6060tctagcttcc cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact 6120tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg 6180tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt 6240tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat 6300aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta 6360gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa 6420tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga 6480aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac 6540aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt 6600tccgaaggta actggcttca gcagagcgca gataccaaat actgtccttc tagtgtagcc 6660gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat 6720cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag 6780acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc 6840cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag 6900cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac 6960aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg 7020gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct 7080atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc

7140tcacatgtcc tgcaggcag 7159227199DNAArtificial SequenceVector sequence for pA2-B2MEHyTKpA 22cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc 60gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca 120actccatcac taggggttcc tgcggccgcg aaactaagag aatgatgtac ctagagggcg 180ctggaagctc taaagcccta gcagttactg cttttactat tagtggtcgt ttttttctcc 240cccccgcccc ccgacaaatc aacagaacaa agaaaattac ctaaacagca aggacatagg 300gaggaacttc ttggcacaga actttccaaa cactttttcc tgaagggata caagaagcaa 360gaaaggtact ctttcactag gaccttctct gagctgtcct caggatgctt ttgggactat 420ttttcttacc cagagaatgg agaaaccctg cagggaattc ccaagctgta gttataaaca 480gaagttctcc ttctgctagg tagcattcaa agatcttaat cttctgggtt tccgttttct 540cgaatgaaaa atgcaggtcc gagcagttaa ctggctgggg caccattagc aagtcactta 600gcatctctgg ggccagtctg caaagcgagg gggcagcctt aatgtgcctc cagcctgaag 660tcctagaatg agcgcccggt gtcccaagct ggggcgcgca ccccagatcg gagggcgccg 720atgtacagac agcaaactca cccagtctag tgcatgcctt cttaaacatc acgagactct 780aagaaaagga aactgaaaac gggaaagtcc ctctctctaa cctggcactg cgtcgctggc 840ttggagacag gtgacggtcc ctgcgggcct tgtcctgatt ggctgggcac gcgtttaata 900taagtggagg cgtcgcgctg gcgggcattc ctgaagctga cagcattcgg gccgagatct 960agataacttc gtataatgta tgctatacga agttatggat ccatcgattc tgcgatcgct 1020ccggtgcccg tcagtgggca gagcgcacat cgcccacagt ccccgagaag ttggggggag 1080gggtcggcaa ttgaaccggt gcctagagaa ggtggcgcgg ggtaaactgg gaaagtgatg 1140tcgtgtactg gctccgcctt tttcccgagg gtgggggaga accgtatata agtgcagtag 1200tcgccgtgaa cgttcttttt cgcaacgggt ttgccgccag aacacagctg aagcttccac 1260catgaaaaag cctgaactca ccgcgacgtc tgtcgagaag tttctgatcg aaaagttcga 1320cagcgtctcc gacctgatgc agctctcgga gggcgaagaa tctcgtgctt tcagcttcga 1380tgtaggaggg cgtggatatg tcctgcgggt aaatagctgc gccgatggtt tctacaaaga 1440tcgttatgtt tatcggcact ttgcatcggc cgcgctcccg attccggaag tgcttgacat 1500tggggaattc agcgagagcc tgacctattg catctcccgc cgtgcacagg gtgtcacgtt 1560gcaagacctg cctgaaaccg aactgcccgc tgttctgcag ccggtcgcgg aggccatgga 1620tgcgatcgct gcggccgatc ttagccagac gagcgggttc ggcccattcg gaccgcaagg 1680aatcggtcaa tacactacat ggcgtgattt catatgcgcg attgctgatc cccatgtgta 1740tcactggcaa actgtgatgg acgacaccgt cagtgcgtcc gtcgcgcagg ctctcgatga 1800gctgatgctt tgggccgagg actgccccga agtccggcac ctcgtgcacg cggatttcgg 1860ctccaacaat gtcctgacgg acaatggccg cataacagcg gtcattgact ggagcgaggc 1920gatgttcggg gattcccaat acgaggtcgc caacatcttc ttctggaggc cgtggttggc 1980ttgtatggag cagcagacgc gctacttcga gcggaggcat ccggagcttg caggatcgcc 2040gcggctccgg gcgtatatgc tccgcattgg tcttgaccaa ctctatcaga gcttggttga 2100cggcaatttc gatgatgcag cttgggcgca gggtcgatgc gacgcaatcg tccgatccgg 2160agccgggact gtcgggcgta cacaaatcgc ccgcagaagc gcggccgtct ggaccgatgg 2220ctgtgtagaa gtcgcgtctg cgttcgacca ggctgcgcgt tctcgcggcc atagcaaccg 2280acgtacggcg ttgcgccctc gccggcagca agaagccacg gaagtccgcc cggagcagaa 2340aatgcccacg ctactgcggg tttatataga cggtccccac gggatgggga aaaccaccac 2400cacgcaactg ctggtggccc tgggttcgcg cgacgatatc gtctacgtac ccgagccgat 2460gacttactgg cgggtgctgg gggcttccga gacaatcgcg aacatctaca ccacacaaca 2520ccgcctcgac cagggtgaga tatcggccgg ggacgcggcg gtggtaatga caagcgccca 2580gataacaatg ggcatgcctt atgccgtgac cgacgccgtt ctggctcctc atatcggggg 2640ggaggctggg agctcacatg ccccgccccc ggccctcacc ctcatcttcg accgccatcc 2700catcgccgcc ctcctgtgct acccggccgc gcggtacctt atgggcagca tgacccccca 2760ggccgtgctg gcgttcgtgg ccctcatccc gccgaccttg cccggcacca acatcgtgct 2820tggggccctt ccggaggaca gacacatcga ccgcctggcc aaacgccagc gccccggcga 2880gcggctggac ctggctatgc tggctgcgat tcgccgcgtt tacgggctac ttgccaatac 2940ggtgcggtat ctgcagtgcg gcgggtcgtg gcgggaggac tggggacagc tttcggggac 3000ggccgtgccg ccccagggtg ccgagcccca gagcaacgcg ggcccacgac cccatatcgg 3060ggacacgtta tttaccctgt ttcgggcccc cgagttgctg gcccccaacg gcgacctgta 3120taacgtgttt gcctgggcct tggacgtctt ggccaaacgc ctccgttcca tgcacgtctt 3180tatcctggat tacgaccaat cgcccgccgg ctgccgggac gccctgctgc aacttacctc 3240cgggatggtc cagacccacg tcaccacccc cggctccata ccgacgatat gcgacctggc 3300gcgcacgttt gcccgggaga tgggggaggc taactgaggt ctctagcata acttcgtata 3360atgtatgcta tacgaagtta taataaaaga tccttatttt cattggatct gtgtgttggt 3420tttttgtgtg ggatccgtcg ataccgtcga ctgtctcgct ccgtggcctt agctgtgctc 3480gcgctactct ctctttctgg cctggaggct atccagcgtg agtctctcct accctcccgc 3540tctggtcctt cctctcccgc tctgcaccct ctgtggccct cgctgtgctc tctcgctccg 3600tgacttccct tctccaagtt ctccttggtg gcccgccgtg gggctagtcc agggctggat 3660ctcggggaag cggcggggtg gcctgggagt ggggaagggg gtgcgcaccc gggacgcgcg 3720ctacttgccc ctttcggcgg ggagcagggg agacctttgg cctacggcga cgggagggtc 3780gggacaaagt ttagggcgtc gataagcgtc agagcgccga ggttggggga gggtttctct 3840tccgctcttt cgcggggcct ctggctcccc cagcgcagct ggagtggggg acgggtaggc 3900tcgtcccaaa ggcgcggcgc tgaggtttgt gaacgcgtgg aggggcgctt ggggtctggg 3960ggaggcgtcg cccgggtaag cctgtctgct gcggctctgc ttcccttaga ctggagagct 4020gtggacttcg tctaggcgcc cgctaagttc gcatgtccta gcacctctgg gtctatgtgg 4080ggccacaccg tggggaggaa acagcacgcg acgtttgtag aatgcttggc tgtgatacaa 4140agcggtttcg aataattaac ttatttgttc ccatcacatg tcacttttaa aaaattataa 4200gaactacccg ttattgacat ctttctgtgt gccaaggact ttatgtgctt tgcgtcattt 4260aattttgaaa acagttatct tccgccatag ataactacta tggttatctt ctgcctctca 4320cagatgaaga aactaaggca ccgagatttt aagaaactta attacacagg ggataaatgg 4380cagcaatcga gattgaagtc aagcctaacc agggcttttg cgggagcgca tgccttttgg 4440ctgtaattcg tgcgcggccg caggaacccc tagtgatgga gttggccact ccctctctgc 4500gcgctcgctc gctcactgag gccgggcgac caaaggtcgc ccgacgcccg ggctttgccc 4560gggcggcctc agtgagcgag cgagcgcgca gctgcctgca ggggcgcctg atgcggtatt 4620ttctccttac gcatctgtgc ggtatttcac accgcatacg tcaaagcaac catagtacgc 4680gccctgtagc ggcgcattaa gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac 4740acttgccagc gccctagcgc ccgctccttt cgctttcttc ccttcctttc tcgccacgtt 4800cgccggcttt ccccgtcaag ctctaaatcg ggggctccct ttagggttcc gatttagtgc 4860tttacggcac ctcgacccca aaaaacttga tttgggtgat ggttcacgta gtgggccatc 4920gccctgatag acggtttttc gccctttgac gttggagtcc acgttcttta atagtggact 4980cttgttccaa actggaacaa cactcaaccc tatctcgggc tattcttttg atttataagg 5040gattttgccg atttcggcct attggttaaa aaatgagctg atttaacaaa aatttaacgc 5100gaattttaac aaaatattaa cgtttacaat tttatggtgc actctcagta caatctgctc 5160tgatgccgca tagttaagcc agccccgaca cccgccaaca cccgctgacg cgccctgacg 5220ggcttgtctg ctcccggcat ccgcttacag acaagctgtg accgtctccg ggagctgcat 5280gtgtcagagg ttttcaccgt catcaccgaa acgcgcgaga cgaaagggcc tcgtgatacg 5340cctattttta taggttaatg tcatgataat aatggtttct tagacgtcag gtggcacttt 5400tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 5460tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat 5520gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt 5580ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg 5640agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga 5700agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg 5760tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt 5820tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg 5880cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg 5940aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga 6000tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc 6060tgtagcaatg gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc 6120ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc 6180ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg 6240cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac 6300gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc 6360actgattaag cattggtaac tgtcagacca agtttactca tatatacttt agattgattt 6420aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 6480caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 6540aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 6600accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 6660aactggcttc agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg 6720ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 6780agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 6840accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 6900gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 6960tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 7020cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 7080cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 7140cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgt 71992329PRTArtificial SequenceHLA-G peptide 23Met Ala Pro Arg Thr Leu Phe Leu Gly Gly Gly Gly Ser Gly Gly Gly 1 5 10 15 Gly Ser Gly Gly Gly Gly Ser Ile Gln Arg Thr Pro Lys 20 25 241369DNAHomo sapiensCDS(506)..(1219) 24ccggacgccg cacggctcct gttccggtgt cagagggccc gccctccccg ctcctcagtc 60tttgcggaca agaaaggggc tgtgtgagac gcagggaagg aggcacaccc gggggtggcg 120cagtgaggag ggggcgcgac ggccaggagg ctggtggagc gacacccagg caggagaggg 180ggaagaactc tctccctttc tgaaccccct tttccttgag agacgagttg ggggagtcct 240ccacgcatta cccactcggg ccgcaaaaac tcccttcttt agccctctgc ccccgccctt 300gcttataagc ctttgagacc gcagaaggga ccttgttgtg gaacgggacg gccaagagga 360agccagatcg ctgagggtcc ggtctccagt ttgcctcctg ctatatccat tggaagagaa 420aagtttgtga cttgggcccc caagttttga gagaactggg ctttcggcgc ggggggacag 480aggaggctcg tggggagctt tcccc atg gag ctt acc cag cct gca gaa gac 532 Met Glu Leu Thr Gln Pro Ala Glu Asp 1 5 ctc atc cag acc cag cag acc cct gcc tca gaa ctt ggg gac cct gaa 580Leu Ile Gln Thr Gln Gln Thr Pro Ala Ser Glu Leu Gly Asp Pro Glu 10 15 20 25 gac ccc gga gag gag gct gca gat ggc tca gac act gtg gtc ctc agt 628Asp Pro Gly Glu Glu Ala Ala Asp Gly Ser Asp Thr Val Val Leu Ser 30 35 40 ctc ttt ccc tgc acc cct gag cct gtg aat cct gaa ccg gat gcc agt 676Leu Phe Pro Cys Thr Pro Glu Pro Val Asn Pro Glu Pro Asp Ala Ser 45 50 55 gtt tcc tct cca cag ggc agc tcc ctg aag cac tcc acc act ctc acc 724Val Ser Ser Pro Gln Gly Ser Ser Leu Lys His Ser Thr Thr Leu Thr 60 65 70 aac cgg cag cga ggg aac gag gtg tca gct ctg ccg gcc acc cta gac 772Asn Arg Gln Arg Gly Asn Glu Val Ser Ala Leu Pro Ala Thr Leu Asp 75 80 85 tgt gac aac ctc gtc aac aag cca gac gag cgc ggc ttc acc ccc ctc 820Cys Asp Asn Leu Val Asn Lys Pro Asp Glu Arg Gly Phe Thr Pro Leu 90 95 100 105 atc tgg gcc tcc gcc ttt gga gag att gag acc gtt cgc ttc ctg ctg 868Ile Trp Ala Ser Ala Phe Gly Glu Ile Glu Thr Val Arg Phe Leu Leu 110 115 120 gag tgg ggt gcc gac ccc cac atc ctg gca aaa gag cga gag agc gcc 916Glu Trp Gly Ala Asp Pro His Ile Leu Ala Lys Glu Arg Glu Ser Ala 125 130 135 ctg tcg ctg gcc agc aca ggc ggc tac aca gac att gtg ggg ctg ctg 964Leu Ser Leu Ala Ser Thr Gly Gly Tyr Thr Asp Ile Val Gly Leu Leu 140 145 150 ctg gag cgt gac gtg gac atc aac atc tat gat tgg aat gga ggg acg 1012Leu Glu Arg Asp Val Asp Ile Asn Ile Tyr Asp Trp Asn Gly Gly Thr 155 160 165 cca ctg ctg tac gct gtg cgc ggg aac cac gtg aaa tgc gtt gag gcc 1060Pro Leu Leu Tyr Ala Val Arg Gly Asn His Val Lys Cys Val Glu Ala 170 175 180 185 ttg ctg gcc cga ggc gct gac ctc acc acc gaa gcc gac tct ggc tac 1108Leu Leu Ala Arg Gly Ala Asp Leu Thr Thr Glu Ala Asp Ser Gly Tyr 190 195 200 acc ccg atg gac ctt gcc gtg gcc ctg gga tac cgg aaa gtg caa cag 1156Thr Pro Met Asp Leu Ala Val Ala Leu Gly Tyr Arg Lys Val Gln Gln 205 210 215 gtg atc gag aac cac atc ctc aag ctc ttc cag agc aac ctg gtg ccc 1204Val Ile Glu Asn His Ile Leu Lys Leu Phe Gln Ser Asn Leu Val Pro 220 225 230 gct gac cct gag tga aggccgcctg ccggggactc agacactcag ggaacaaaat 1259Ala Asp Pro Glu 235 ggtcagccag agctggggaa acccagaact gacttcaaag gcagcttctg gacaggtggt 1319gggaggggac ccttcccaag aggaaccaat aaaccttctg tgcagaatga 136925237PRTHomo sapiens 25Met Glu Leu Thr Gln Pro Ala Glu Asp Leu Ile Gln Thr Gln Gln Thr 1 5 10 15 Pro Ala Ser Glu Leu Gly Asp Pro Glu Asp Pro Gly Glu Glu Ala Ala 20 25 30 Asp Gly Ser Asp Thr Val Val Leu Ser Leu Phe Pro Cys Thr Pro Glu 35 40 45 Pro Val Asn Pro Glu Pro Asp Ala Ser Val Ser Ser Pro Gln Gly Ser 50 55 60 Ser Leu Lys His Ser Thr Thr Leu Thr Asn Arg Gln Arg Gly Asn Glu 65 70 75 80 Val Ser Ala Leu Pro Ala Thr Leu Asp Cys Asp Asn Leu Val Asn Lys 85 90 95 Pro Asp Glu Arg Gly Phe Thr Pro Leu Ile Trp Ala Ser Ala Phe Gly 100 105 110 Glu Ile Glu Thr Val Arg Phe Leu Leu Glu Trp Gly Ala Asp Pro His 115 120 125 Ile Leu Ala Lys Glu Arg Glu Ser Ala Leu Ser Leu Ala Ser Thr Gly 130 135 140 Gly Tyr Thr Asp Ile Val Gly Leu Leu Leu Glu Arg Asp Val Asp Ile 145 150 155 160 Asn Ile Tyr Asp Trp Asn Gly Gly Thr Pro Leu Leu Tyr Ala Val Arg 165 170 175 Gly Asn His Val Lys Cys Val Glu Ala Leu Leu Ala Arg Gly Ala Asp 180 185 190 Leu Thr Thr Glu Ala Asp Ser Gly Tyr Thr Pro Met Asp Leu Ala Val 195 200 205 Ala Leu Gly Tyr Arg Lys Val Gln Gln Val Ile Glu Asn His Ile Leu 210 215 220 Lys Leu Phe Gln Ser Asn Leu Val Pro Ala Asp Pro Glu 225 230 235 261438DNAHomo sapiensCDS(506)..(1288) 26ccggacgccg cacggctcct gttccggtgt cagagggccc gccctccccg ctcctcagtc 60tttgcggaca agaaaggggc tgtgtgagac gcagggaagg aggcacaccc gggggtggcg 120cagtgaggag ggggcgcgac ggccaggagg ctggtggagc gacacccagg caggagaggg 180ggaagaactc tctccctttc tgaaccccct tttccttgag agacgagttg ggggagtcct 240ccacgcatta cccactcggg ccgcaaaaac tcccttcttt agccctctgc ccccgccctt 300gcttataagc ctttgagacc gcagaaggga ccttgttgtg gaacgggacg gccaagagga 360agccagatcg ctgagggtcc ggtctccagt ttgcctcctg ctatatccat tggaagagaa 420aagtttgtga cttgggcccc caagttttga gagaactggg ctttcggcgc ggggggacag 480aggaggctcg tggggagctt tcccc atg gag ctt acc cag cct gca gaa gac 532 Met Glu Leu Thr Gln Pro Ala Glu Asp 1 5 ctc atc cag acc cag cag acc cct gcc tca gaa ctt ggg gac cct gaa 580Leu Ile Gln Thr Gln Gln Thr Pro Ala Ser Glu Leu Gly Asp Pro Glu 10 15 20 25 gac ccc gga gag gag gct gca gat ggc tca gac act gtg gtc ctc agt 628Asp Pro Gly Glu Glu Ala Ala Asp Gly Ser Asp Thr Val Val Leu Ser 30 35 40 ctc ttt ccc tgc acc cct gag cct gtg aat cct gaa ccg gat gcc agt 676Leu Phe Pro Cys Thr Pro Glu Pro Val Asn Pro Glu Pro Asp Ala Ser 45 50 55 gtt tcc tct cca cag gca ggc agc tcc ctg aag cac tcc acc act ctc 724Val Ser Ser Pro Gln Ala Gly Ser Ser Leu Lys His Ser Thr Thr Leu 60 65 70 acc aac cgg cag cga ggg aac gag gtg tca gct ctg ccg gcc acc cta 772Thr Asn Arg Gln Arg Gly Asn Glu Val Ser Ala Leu Pro Ala Thr Leu 75 80 85 gac tcc ctg tcc atc cac cag ctc gca gca cag ggg gag ctg gac cag 820Asp Ser Leu Ser Ile His Gln Leu Ala Ala Gln Gly Glu Leu Asp Gln 90 95 100 105 ctg aag gag cat ttg cgg aaa ggt gac aac ctc gtc aac aag cca gac 868Leu Lys Glu His Leu Arg Lys Gly Asp Asn Leu Val Asn Lys Pro Asp 110 115 120 gag cgc ggc ttc acc ccc ctc atc tgg gcc tcc gcc ttt gga gag att 916Glu Arg Gly Phe Thr Pro Leu Ile Trp Ala Ser Ala Phe Gly Glu Ile 125 130 135 gag acc gtt cgc ttc ctg ctg gag tgg ggt gcc gac ccc cac atc ctg 964Glu Thr Val Arg Phe Leu Leu Glu Trp Gly Ala Asp Pro His Ile Leu 140 145 150 gca aaa gag cga gag agc gcc ctg tcg ctg gcc agc aca ggc ggc tac 1012Ala Lys Glu Arg Glu Ser Ala Leu Ser Leu Ala Ser Thr Gly Gly Tyr 155 160 165

aca gac att gtg ggg ctg ctg ctg gag cgt gac gtg gac atc aac atc 1060Thr Asp Ile Val Gly Leu Leu Leu Glu Arg Asp Val Asp Ile Asn Ile 170 175 180 185 tat gat tgg aat gga ggg acg cca ctg ctg tac gct gtg cgc ggg aac 1108Tyr Asp Trp Asn Gly Gly Thr Pro Leu Leu Tyr Ala Val Arg Gly Asn 190 195 200 cac gtg aaa tgc gtt gag gcc ttg ctg gcc cga ggc gct gac ctc acc 1156His Val Lys Cys Val Glu Ala Leu Leu Ala Arg Gly Ala Asp Leu Thr 205 210 215 acc gaa gcc gac tct ggc tac acc ccg atg gac ctt gcc gtg gcc ctg 1204Thr Glu Ala Asp Ser Gly Tyr Thr Pro Met Asp Leu Ala Val Ala Leu 220 225 230 gga tac cgg aaa gtg caa cag gtg atc gag aac cac atc ctc aag ctc 1252Gly Tyr Arg Lys Val Gln Gln Val Ile Glu Asn His Ile Leu Lys Leu 235 240 245 ttc cag agc aac ctg gtg ccc gct gac cct gag tga aggccgcctg 1298Phe Gln Ser Asn Leu Val Pro Ala Asp Pro Glu 250 255 260 ccggggactc agacactcag ggaacaaaat ggtcagccag agctggggaa acccagaact 1358gacttcaaag gcagcttctg gacaggtggt gggaggggac ccttcccaag aggaaccaat 1418aaaccttctg tgcagaatga 143827260PRTHomo sapiens 27Met Glu Leu Thr Gln Pro Ala Glu Asp Leu Ile Gln Thr Gln Gln Thr 1 5 10 15 Pro Ala Ser Glu Leu Gly Asp Pro Glu Asp Pro Gly Glu Glu Ala Ala 20 25 30 Asp Gly Ser Asp Thr Val Val Leu Ser Leu Phe Pro Cys Thr Pro Glu 35 40 45 Pro Val Asn Pro Glu Pro Asp Ala Ser Val Ser Ser Pro Gln Ala Gly 50 55 60 Ser Ser Leu Lys His Ser Thr Thr Leu Thr Asn Arg Gln Arg Gly Asn 65 70 75 80 Glu Val Ser Ala Leu Pro Ala Thr Leu Asp Ser Leu Ser Ile His Gln 85 90 95 Leu Ala Ala Gln Gly Glu Leu Asp Gln Leu Lys Glu His Leu Arg Lys 100 105 110 Gly Asp Asn Leu Val Asn Lys Pro Asp Glu Arg Gly Phe Thr Pro Leu 115 120 125 Ile Trp Ala Ser Ala Phe Gly Glu Ile Glu Thr Val Arg Phe Leu Leu 130 135 140 Glu Trp Gly Ala Asp Pro His Ile Leu Ala Lys Glu Arg Glu Ser Ala 145 150 155 160 Leu Ser Leu Ala Ser Thr Gly Gly Tyr Thr Asp Ile Val Gly Leu Leu 165 170 175 Leu Glu Arg Asp Val Asp Ile Asn Ile Tyr Asp Trp Asn Gly Gly Thr 180 185 190 Pro Leu Leu Tyr Ala Val Arg Gly Asn His Val Lys Cys Val Glu Ala 195 200 205 Leu Leu Ala Arg Gly Ala Asp Leu Thr Thr Glu Ala Asp Ser Gly Tyr 210 215 220 Thr Pro Met Asp Leu Ala Val Ala Leu Gly Tyr Arg Lys Val Gln Gln 225 230 235 240 Val Ile Glu Asn His Ile Leu Lys Leu Phe Gln Ser Asn Leu Val Pro 245 250 255 Ala Asp Pro Glu 260 283618DNAHomo sapiensCDS(222)..(2072) 28attcagaaaa aggaaaataa agcaacgcac gagccggctg ggccaggacc ttggggctgg 60gctggagtga aggtggctac gagttttcca gatttaggag acttcagaaa ggtggggcag 120atagaatgga gatggcaaag atctctttgg gcatatatgg gcctggcgaa gtaatggaat 180aatttctaat tttcggagaa ggcaagtgcc ctcatgccgg g atg gca gaa gat gag 236 Met Ala Glu Asp Glu 1 5 cct gat gct aag agc ccc aag act ggg gga agg gcc ccc cca ggt ggt 284Pro Asp Ala Lys Ser Pro Lys Thr Gly Gly Arg Ala Pro Pro Gly Gly 10 15 20 gct gag gct ggg gaa cct acc acc ctt ctt cag agg ctc cga ggt acc 332Ala Glu Ala Gly Glu Pro Thr Thr Leu Leu Gln Arg Leu Arg Gly Thr 25 30 35 att tcc aag gcc gtg cag aac aaa gta gag ggg atc ctg caa gat gta 380Ile Ser Lys Ala Val Gln Asn Lys Val Glu Gly Ile Leu Gln Asp Val 40 45 50 cag aaa ttt tct gac aat gac aag ctg tat ctc tac ctt cag ctc ccc 428Gln Lys Phe Ser Asp Asn Asp Lys Leu Tyr Leu Tyr Leu Gln Leu Pro 55 60 65 tca gga ccc acc act gga gac aaa agc tca gag cca agt aca ctg agc 476Ser Gly Pro Thr Thr Gly Asp Lys Ser Ser Glu Pro Ser Thr Leu Ser 70 75 80 85 aat gag gag tac atg tat gcc tat agg tgg atc cgc aac cac ctg gaa 524Asn Glu Glu Tyr Met Tyr Ala Tyr Arg Trp Ile Arg Asn His Leu Glu 90 95 100 gag cac act gac acc tgt ctg cca aag caa agt gtt tat gat gcc tat 572Glu His Thr Asp Thr Cys Leu Pro Lys Gln Ser Val Tyr Asp Ala Tyr 105 110 115 cgg aag tac tgt gag agt ctt gcc tgt tgc cgc cca ctc agc aca gcc 620Arg Lys Tyr Cys Glu Ser Leu Ala Cys Cys Arg Pro Leu Ser Thr Ala 120 125 130 aac ttt ggc aag atc atc aga gag atc ttc cct gac atc aaa gct cga 668Asn Phe Gly Lys Ile Ile Arg Glu Ile Phe Pro Asp Ile Lys Ala Arg 135 140 145 agg ctt ggt ggc cgg ggc cag tcc aaa tat tgc tac agt ggc ata agg 716Arg Leu Gly Gly Arg Gly Gln Ser Lys Tyr Cys Tyr Ser Gly Ile Arg 150 155 160 165 agg aag acc ttg gtg tct atg cca ccc ctg cct gga ctt gac cta aag 764Arg Lys Thr Leu Val Ser Met Pro Pro Leu Pro Gly Leu Asp Leu Lys 170 175 180 ggt tct gag agt cca gaa atg ggc cca gaa gta acc cca gca cct cga 812Gly Ser Glu Ser Pro Glu Met Gly Pro Glu Val Thr Pro Ala Pro Arg 185 190 195 gat gaa ctg gtg gag gca gcg tgt gcc ctg acc tgt gac tgg gca gag 860Asp Glu Leu Val Glu Ala Ala Cys Ala Leu Thr Cys Asp Trp Ala Glu 200 205 210 cgg atc ctg aaa cgg tcc ttc agt tcc atc gtt gag gtc gcc cgc ttc 908Arg Ile Leu Lys Arg Ser Phe Ser Ser Ile Val Glu Val Ala Arg Phe 215 220 225 ctg cta cag cag cat ctc atc tct gcc cga tct gca cat gcc cat gtg 956Leu Leu Gln Gln His Leu Ile Ser Ala Arg Ser Ala His Ala His Val 230 235 240 245 ctt aag gcc atg ggg ctt gct gaa gag gac gaa cat gca cct cgg gaa 1004Leu Lys Ala Met Gly Leu Ala Glu Glu Asp Glu His Ala Pro Arg Glu 250 255 260 cgg tca tct aaa cca aag aat ggt tta gag aac cca gag ggt gga gcc 1052Arg Ser Ser Lys Pro Lys Asn Gly Leu Glu Asn Pro Glu Gly Gly Ala 265 270 275 cac aag aag cca gag aga ctg gcc cag cct cct aag gat ctg gaa gcc 1100His Lys Lys Pro Glu Arg Leu Ala Gln Pro Pro Lys Asp Leu Glu Ala 280 285 290 cga act ggg gcc ggt cct ctc gca cgt gga gag cgg aag aag agt gta 1148Arg Thr Gly Ala Gly Pro Leu Ala Arg Gly Glu Arg Lys Lys Ser Val 295 300 305 gtt gag agc tcg gcc cca gga gcc aat aac ctg cag gtt aat gcc cta 1196Val Glu Ser Ser Ala Pro Gly Ala Asn Asn Leu Gln Val Asn Ala Leu 310 315 320 325 gtg gct cgg ctg cct ctg ctc ctt ccc cgg gcc cct cgc tca cta att 1244Val Ala Arg Leu Pro Leu Leu Leu Pro Arg Ala Pro Arg Ser Leu Ile 330 335 340 ccg cca atc cca gtc tct cca cct att ctg gcc ccc agg ctt tct tca 1292Pro Pro Ile Pro Val Ser Pro Pro Ile Leu Ala Pro Arg Leu Ser Ser 345 350 355 ggt gcc ctg aaa gtg gct aca ctg cct ctg tct agt agg gcc ggg gca 1340Gly Ala Leu Lys Val Ala Thr Leu Pro Leu Ser Ser Arg Ala Gly Ala 360 365 370 ccc cca gca gct gtg ccc atc att aac atg atc tta cca act gtt cct 1388Pro Pro Ala Ala Val Pro Ile Ile Asn Met Ile Leu Pro Thr Val Pro 375 380 385 gct ttg cct gga cct gga cct ggg cct ggg cga gct cca cct ggg gga 1436Ala Leu Pro Gly Pro Gly Pro Gly Pro Gly Arg Ala Pro Pro Gly Gly 390 395 400 405 ctc act cag ccc cgg ggc aca gag aac aga gag gta ggc ata ggt ggt 1484Leu Thr Gln Pro Arg Gly Thr Glu Asn Arg Glu Val Gly Ile Gly Gly 410 415 420 gac caa gga cca cat gac aag ggt gtc aag agg aca gct gaa gta cct 1532Asp Gln Gly Pro His Asp Lys Gly Val Lys Arg Thr Ala Glu Val Pro 425 430 435 gtg agt gag gcc agt ggg cag gct cca cca gct aaa gca gca aag cag 1580Val Ser Glu Ala Ser Gly Gln Ala Pro Pro Ala Lys Ala Ala Lys Gln 440 445 450 gat ata gag gat aca gca agt gat gcc aaa agg aaa cgg ggg cgc cct 1628Asp Ile Glu Asp Thr Ala Ser Asp Ala Lys Arg Lys Arg Gly Arg Pro 455 460 465 cga aaa aag tca ggt gga agt ggg gaa agg aat tct acc cct ctc aag 1676Arg Lys Lys Ser Gly Gly Ser Gly Glu Arg Asn Ser Thr Pro Leu Lys 470 475 480 485 tca gca gct gcc atg gaa tct gcc cag tcc tca agg tta cca tgg gag 1724Ser Ala Ala Ala Met Glu Ser Ala Gln Ser Ser Arg Leu Pro Trp Glu 490 495 500 aca tgg ggc tca gga ggg gaa ggc aac tca gct gga ggg gca gag agg 1772Thr Trp Gly Ser Gly Gly Glu Gly Asn Ser Ala Gly Gly Ala Glu Arg 505 510 515 cca ggg cca atg gga gag gct gaa aag ggg gca gta ctt gcc cag ggt 1820Pro Gly Pro Met Gly Glu Ala Glu Lys Gly Ala Val Leu Ala Gln Gly 520 525 530 cag gga gat ggt act gtt tcc aaa gga gga agg ggc ccc ggt tcc cag 1868Gln Gly Asp Gly Thr Val Ser Lys Gly Gly Arg Gly Pro Gly Ser Gln 535 540 545 cat acc aaa gaa gca gaa gat aaa att ccc ttg gtc ccc tca aaa gtg 1916His Thr Lys Glu Ala Glu Asp Lys Ile Pro Leu Val Pro Ser Lys Val 550 555 560 565 agt gtc atc aag ggc agc aga agc caa aag gag gct ttt cct ttg gca 1964Ser Val Ile Lys Gly Ser Arg Ser Gln Lys Glu Ala Phe Pro Leu Ala 570 575 580 aag gga gag gta gac act gca cca cag ggt aat aaa gac tta aag gag 2012Lys Gly Glu Val Asp Thr Ala Pro Gln Gly Asn Lys Asp Leu Lys Glu 585 590 595 cat gtg ctt caa agt tcc tta tcc cag gag cat aaa gac cca aaa gca 2060His Val Leu Gln Ser Ser Leu Ser Gln Glu His Lys Asp Pro Lys Ala 600 605 610 aca ccc cca tga tacaggtctg tggggaagag tgtttatatc cctacgttaa 2112Thr Pro Pro 615 ctttgcctag tagaggccct tctttgcact tgcttctcat ttggctattc ttttcctaag 2172gaagtccatt ctcctctgta cagacagctg agtcacccag tctacttagt acctggttgc 2232tgcctctgac cttttcagct tgataccctg ggctttagtg taaccaataa atctgtagtg 2292accttacctg tattccctgt gctatcctgt gggaaggtag gaatgggcta agtatgatga 2352atatataggt tagggatctt ttggttttaa atcacagaaa acctaattca aactggctta 2412aaataaaaag gatttattgg ttcatgtaac tagaaagtcc ataggtagtg ctggctccag 2472gtgaagactt gacccagtag ttcagtatgt ctctaaatac cggactgact tttttctcac 2532tgttgcatct tctgtaggac catttaagtc tgggccactt aatggctgcc agcattccta 2592agattacact tttccccatt tatgtccaat cagaaaaaga aggcatcttt gtaccagaaa 2652tctcagcaaa agccctaata ttcacactga ttaggcctgg gtcacatgtc caccctgacc 2712aatcactgtg gccaggagga tgatacatgc taatttgctt attctatatc atggacaaca 2772cctttgggga aaagggtggg ggtcagcctc cccaaaatca catggattcc ccaagtggaa 2832actaggagca gggagttgct tgggtggccg ctaacaccag gctactctta ttttagcttg 2892ctaagttgag atcagctaga cctgctttct tttctcctca gtcttgcatt tccctcaata 2952caagctgtag cctctttcct cgtttctagt ctcagaagga aggagaggga agccattctc 3012ctctagggac tcttcagtct catttagatg atagtccctt tttttctacc tccatattag 3072agatggagct ccttcctttt cctgtttctt aatttttgtc ttctcattcc tgcttccctc 3132tcaccctatt gccagttcca ccaactagag tgaaagactt cctagccatt tcattaaatc 3192tattctgtat ccaccaggtg gcagcatctt gtcatacgtg tcaggactta ggactgcggg 3252gtttaggtta gatgtcacgg aaaaagctag ttctgtggtc aggcggcacc aatgagaaag 3312gaatgcagac cctccagatg tatccttggg aaaagcagta aaccaactaa tatttattga 3372agacctactt tgtcctctac atagggtagc ttctgtcagg gaatcttggt tcttcccaag 3432aaacactgat tttctttcag ggagacttca tgtgttcatt tatttccacc acagcagatt 3492ttaagaaatt ataatatgta atatttgata tctataaaga gtatatctaa cgtgaataaa 3552ttatgaagca tactaatgag tacctatgac ccataacaca tatacattaa aacattttaa 3612atacca 361829616PRTHomo sapiens 29Met Ala Glu Asp Glu Pro Asp Ala Lys Ser Pro Lys Thr Gly Gly Arg 1 5 10 15 Ala Pro Pro Gly Gly Ala Glu Ala Gly Glu Pro Thr Thr Leu Leu Gln 20 25 30 Arg Leu Arg Gly Thr Ile Ser Lys Ala Val Gln Asn Lys Val Glu Gly 35 40 45 Ile Leu Gln Asp Val Gln Lys Phe Ser Asp Asn Asp Lys Leu Tyr Leu 50 55 60 Tyr Leu Gln Leu Pro Ser Gly Pro Thr Thr Gly Asp Lys Ser Ser Glu 65 70 75 80 Pro Ser Thr Leu Ser Asn Glu Glu Tyr Met Tyr Ala Tyr Arg Trp Ile 85 90 95 Arg Asn His Leu Glu Glu His Thr Asp Thr Cys Leu Pro Lys Gln Ser 100 105 110 Val Tyr Asp Ala Tyr Arg Lys Tyr Cys Glu Ser Leu Ala Cys Cys Arg 115 120 125 Pro Leu Ser Thr Ala Asn Phe Gly Lys Ile Ile Arg Glu Ile Phe Pro 130 135 140 Asp Ile Lys Ala Arg Arg Leu Gly Gly Arg Gly Gln Ser Lys Tyr Cys 145 150 155 160 Tyr Ser Gly Ile Arg Arg Lys Thr Leu Val Ser Met Pro Pro Leu Pro 165 170 175 Gly Leu Asp Leu Lys Gly Ser Glu Ser Pro Glu Met Gly Pro Glu Val 180 185 190 Thr Pro Ala Pro Arg Asp Glu Leu Val Glu Ala Ala Cys Ala Leu Thr 195 200 205 Cys Asp Trp Ala Glu Arg Ile Leu Lys Arg Ser Phe Ser Ser Ile Val 210 215 220 Glu Val Ala Arg Phe Leu Leu Gln Gln His Leu Ile Ser Ala Arg Ser 225 230 235 240 Ala His Ala His Val Leu Lys Ala Met Gly Leu Ala Glu Glu Asp Glu 245 250 255 His Ala Pro Arg Glu Arg Ser Ser Lys Pro Lys Asn Gly Leu Glu Asn 260 265 270 Pro Glu Gly Gly Ala His Lys Lys Pro Glu Arg Leu Ala Gln Pro Pro 275 280 285 Lys Asp Leu Glu Ala Arg Thr Gly Ala Gly Pro Leu Ala Arg Gly Glu 290 295 300 Arg Lys Lys Ser Val Val Glu Ser Ser Ala Pro Gly Ala Asn Asn Leu 305 310 315 320 Gln Val Asn Ala Leu Val Ala Arg Leu Pro Leu Leu Leu Pro Arg Ala 325 330 335 Pro Arg Ser Leu Ile Pro Pro Ile Pro Val Ser Pro Pro Ile Leu Ala 340 345 350 Pro Arg Leu Ser Ser Gly Ala Leu Lys Val Ala Thr Leu Pro Leu Ser 355 360 365 Ser Arg Ala Gly Ala Pro Pro Ala Ala Val Pro Ile Ile Asn Met Ile 370 375 380 Leu Pro Thr Val Pro Ala Leu Pro Gly Pro Gly Pro Gly Pro Gly Arg 385 390 395 400 Ala Pro Pro Gly Gly Leu Thr Gln Pro Arg Gly Thr Glu Asn Arg Glu 405 410 415 Val Gly Ile Gly Gly Asp Gln Gly Pro His Asp Lys Gly Val Lys Arg 420 425 430 Thr Ala Glu Val Pro Val Ser Glu Ala Ser Gly Gln Ala Pro Pro Ala 435 440 445 Lys Ala Ala Lys Gln Asp Ile Glu Asp Thr Ala Ser Asp Ala Lys Arg 450 455 460 Lys Arg Gly Arg Pro Arg Lys Lys Ser Gly Gly Ser Gly Glu Arg Asn 465 470

475 480 Ser Thr Pro Leu Lys Ser Ala Ala Ala Met Glu Ser Ala Gln Ser Ser 485 490 495 Arg Leu Pro Trp Glu Thr Trp Gly Ser Gly Gly Glu Gly Asn Ser Ala 500 505 510 Gly Gly Ala Glu Arg Pro Gly Pro Met Gly Glu Ala Glu Lys Gly Ala 515 520 525 Val Leu Ala Gln Gly Gln Gly Asp Gly Thr Val Ser Lys Gly Gly Arg 530 535 540 Gly Pro Gly Ser Gln His Thr Lys Glu Ala Glu Asp Lys Ile Pro Leu 545 550 555 560 Val Pro Ser Lys Val Ser Val Ile Lys Gly Ser Arg Ser Gln Lys Glu 565 570 575 Ala Phe Pro Leu Ala Lys Gly Glu Val Asp Thr Ala Pro Gln Gly Asn 580 585 590 Lys Asp Leu Lys Glu His Val Leu Gln Ser Ser Leu Ser Gln Glu His 595 600 605 Lys Asp Pro Lys Ala Thr Pro Pro 610 615 303611DNAHomo sapiensCDS(215)..(2065) 30attcagaaaa aggaaaataa agcaacgcac gagccggctg ggccaggacc ttggggctgg 60gctggagtga aggtggctac gagttttcca gatttaggag acttcagaaa ggtggggcag 120atagaatgga gatggcaaag atctctttgg gcatatatgg gcctggcgaa gtaatggaat 180aatttctaat tttcggagaa gccctcatgc cggg atg gca gaa gat gag cct gat 235 Met Ala Glu Asp Glu Pro Asp 1 5 gct aag agc ccc aag act ggg gga agg gcc ccc cca ggt ggt gct gag 283Ala Lys Ser Pro Lys Thr Gly Gly Arg Ala Pro Pro Gly Gly Ala Glu 10 15 20 gct ggg gaa cct acc acc ctt ctt cag agg ctc cga ggt acc att tcc 331Ala Gly Glu Pro Thr Thr Leu Leu Gln Arg Leu Arg Gly Thr Ile Ser 25 30 35 aag gcc gtg cag aac aaa gta gag ggg atc ctg caa gat gta cag aaa 379Lys Ala Val Gln Asn Lys Val Glu Gly Ile Leu Gln Asp Val Gln Lys 40 45 50 55 ttt tct gac aat gac aag ctg tat ctc tac ctt cag ctc ccc tca gga 427Phe Ser Asp Asn Asp Lys Leu Tyr Leu Tyr Leu Gln Leu Pro Ser Gly 60 65 70 ccc acc act gga gac aaa agc tca gag cca agt aca ctg agc aat gag 475Pro Thr Thr Gly Asp Lys Ser Ser Glu Pro Ser Thr Leu Ser Asn Glu 75 80 85 gag tac atg tat gcc tat agg tgg atc cgc aac cac ctg gaa gag cac 523Glu Tyr Met Tyr Ala Tyr Arg Trp Ile Arg Asn His Leu Glu Glu His 90 95 100 act gac acc tgt ctg cca aag caa agt gtt tat gat gcc tat cgg aag 571Thr Asp Thr Cys Leu Pro Lys Gln Ser Val Tyr Asp Ala Tyr Arg Lys 105 110 115 tac tgt gag agt ctt gcc tgt tgc cgc cca ctc agc aca gcc aac ttt 619Tyr Cys Glu Ser Leu Ala Cys Cys Arg Pro Leu Ser Thr Ala Asn Phe 120 125 130 135 ggc aag atc atc aga gag atc ttc cct gac atc aaa gct cga agg ctt 667Gly Lys Ile Ile Arg Glu Ile Phe Pro Asp Ile Lys Ala Arg Arg Leu 140 145 150 ggt ggc cgg ggc cag tcc aaa tat tgc tac agt ggc ata agg agg aag 715Gly Gly Arg Gly Gln Ser Lys Tyr Cys Tyr Ser Gly Ile Arg Arg Lys 155 160 165 acc ttg gtg tct atg cca ccc ctg cct gga ctt gac cta aag ggt tct 763Thr Leu Val Ser Met Pro Pro Leu Pro Gly Leu Asp Leu Lys Gly Ser 170 175 180 gag agt cca gaa atg ggc cca gaa gta acc cca gca cct cga gat gaa 811Glu Ser Pro Glu Met Gly Pro Glu Val Thr Pro Ala Pro Arg Asp Glu 185 190 195 ctg gtg gag gca gcg tgt gcc ctg acc tgt gac tgg gca gag cgg atc 859Leu Val Glu Ala Ala Cys Ala Leu Thr Cys Asp Trp Ala Glu Arg Ile 200 205 210 215 ctg aaa cgg tcc ttc agt tcc atc gtt gag gtc gcc cgc ttc ctg cta 907Leu Lys Arg Ser Phe Ser Ser Ile Val Glu Val Ala Arg Phe Leu Leu 220 225 230 cag cag cat ctc atc tct gcc cga tct gca cat gcc cat gtg ctt aag 955Gln Gln His Leu Ile Ser Ala Arg Ser Ala His Ala His Val Leu Lys 235 240 245 gcc atg ggg ctt gct gaa gag gac gaa cat gca cct cgg gaa cgg tca 1003Ala Met Gly Leu Ala Glu Glu Asp Glu His Ala Pro Arg Glu Arg Ser 250 255 260 tct aaa cca aag aat ggt tta gag aac cca gag ggt gga gcc cac aag 1051Ser Lys Pro Lys Asn Gly Leu Glu Asn Pro Glu Gly Gly Ala His Lys 265 270 275 aag cca gag aga ctg gcc cag cct cct aag gat ctg gaa gcc cga act 1099Lys Pro Glu Arg Leu Ala Gln Pro Pro Lys Asp Leu Glu Ala Arg Thr 280 285 290 295 ggg gcc ggt cct ctc gca cgt gga gag cgg aag aag agt gta gtt gag 1147Gly Ala Gly Pro Leu Ala Arg Gly Glu Arg Lys Lys Ser Val Val Glu 300 305 310 agc tcg gcc cca gga gcc aat aac ctg cag gtt aat gcc cta gtg gct 1195Ser Ser Ala Pro Gly Ala Asn Asn Leu Gln Val Asn Ala Leu Val Ala 315 320 325 cgg ctg cct ctg ctc ctt ccc cgg gcc cct cgc tca cta att ccg cca 1243Arg Leu Pro Leu Leu Leu Pro Arg Ala Pro Arg Ser Leu Ile Pro Pro 330 335 340 atc cca gtc tct cca cct att ctg gcc ccc agg ctt tct tca ggt gcc 1291Ile Pro Val Ser Pro Pro Ile Leu Ala Pro Arg Leu Ser Ser Gly Ala 345 350 355 ctg aaa gtg gct aca ctg cct ctg tct agt agg gcc ggg gca ccc cca 1339Leu Lys Val Ala Thr Leu Pro Leu Ser Ser Arg Ala Gly Ala Pro Pro 360 365 370 375 gca gct gtg ccc atc att aac atg atc tta cca act gtt cct gct ttg 1387Ala Ala Val Pro Ile Ile Asn Met Ile Leu Pro Thr Val Pro Ala Leu 380 385 390 cct gga cct gga cct ggg cct ggg cga gct cca cct ggg gga ctc act 1435Pro Gly Pro Gly Pro Gly Pro Gly Arg Ala Pro Pro Gly Gly Leu Thr 395 400 405 cag ccc cgg ggc aca gag aac aga gag gta ggc ata ggt ggt gac caa 1483Gln Pro Arg Gly Thr Glu Asn Arg Glu Val Gly Ile Gly Gly Asp Gln 410 415 420 gga cca cat gac aag ggt gtc aag agg aca gct gaa gta cct gtg agt 1531Gly Pro His Asp Lys Gly Val Lys Arg Thr Ala Glu Val Pro Val Ser 425 430 435 gag gcc agt ggg cag gct cca cca gct aaa gca gca aag cag gat ata 1579Glu Ala Ser Gly Gln Ala Pro Pro Ala Lys Ala Ala Lys Gln Asp Ile 440 445 450 455 gag gat aca gca agt gat gcc aaa agg aaa cgg ggg cgc cct cga aaa 1627Glu Asp Thr Ala Ser Asp Ala Lys Arg Lys Arg Gly Arg Pro Arg Lys 460 465 470 aag tca ggt gga agt ggg gaa agg aat tct acc cct ctc aag tca gca 1675Lys Ser Gly Gly Ser Gly Glu Arg Asn Ser Thr Pro Leu Lys Ser Ala 475 480 485 gct gcc atg gaa tct gcc cag tcc tca agg tta cca tgg gag aca tgg 1723Ala Ala Met Glu Ser Ala Gln Ser Ser Arg Leu Pro Trp Glu Thr Trp 490 495 500 ggc tca gga ggg gaa ggc aac tca gct gga ggg gca gag agg cca ggg 1771Gly Ser Gly Gly Glu Gly Asn Ser Ala Gly Gly Ala Glu Arg Pro Gly 505 510 515 cca atg gga gag gct gaa aag ggg gca gta ctt gcc cag ggt cag gga 1819Pro Met Gly Glu Ala Glu Lys Gly Ala Val Leu Ala Gln Gly Gln Gly 520 525 530 535 gat ggt act gtt tcc aaa gga gga agg ggc ccc ggt tcc cag cat acc 1867Asp Gly Thr Val Ser Lys Gly Gly Arg Gly Pro Gly Ser Gln His Thr 540 545 550 aaa gaa gca gaa gat aaa att ccc ttg gtc ccc tca aaa gtg agt gtc 1915Lys Glu Ala Glu Asp Lys Ile Pro Leu Val Pro Ser Lys Val Ser Val 555 560 565 atc aag ggc agc aga agc caa aag gag gct ttt cct ttg gca aag gga 1963Ile Lys Gly Ser Arg Ser Gln Lys Glu Ala Phe Pro Leu Ala Lys Gly 570 575 580 gag gta gac act gca cca cag ggt aat aaa gac tta aag gag cat gtg 2011Glu Val Asp Thr Ala Pro Gln Gly Asn Lys Asp Leu Lys Glu His Val 585 590 595 ctt caa agt tcc tta tcc cag gag cat aaa gac cca aaa gca aca ccc 2059Leu Gln Ser Ser Leu Ser Gln Glu His Lys Asp Pro Lys Ala Thr Pro 600 605 610 615 cca tga tacaggtctg tggggaagag tgtttatatc cctacgttaa ctttgcctag 2115Pro tagaggccct tctttgcact tgcttctcat ttggctattc ttttcctaag gaagtccatt 2175ctcctctgta cagacagctg agtcacccag tctacttagt acctggttgc tgcctctgac 2235cttttcagct tgataccctg ggctttagtg taaccaataa atctgtagtg accttacctg 2295tattccctgt gctatcctgt gggaaggtag gaatgggcta agtatgatga atatataggt 2355tagggatctt ttggttttaa atcacagaaa acctaattca aactggctta aaataaaaag 2415gatttattgg ttcatgtaac tagaaagtcc ataggtagtg ctggctccag gtgaagactt 2475gacccagtag ttcagtatgt ctctaaatac cggactgact tttttctcac tgttgcatct 2535tctgtaggac catttaagtc tgggccactt aatggctgcc agcattccta agattacact 2595tttccccatt tatgtccaat cagaaaaaga aggcatcttt gtaccagaaa tctcagcaaa 2655agccctaata ttcacactga ttaggcctgg gtcacatgtc caccctgacc aatcactgtg 2715gccaggagga tgatacatgc taatttgctt attctatatc atggacaaca cctttgggga 2775aaagggtggg ggtcagcctc cccaaaatca catggattcc ccaagtggaa actaggagca 2835gggagttgct tgggtggccg ctaacaccag gctactctta ttttagcttg ctaagttgag 2895atcagctaga cctgctttct tttctcctca gtcttgcatt tccctcaata caagctgtag 2955cctctttcct cgtttctagt ctcagaagga aggagaggga agccattctc ctctagggac 3015tcttcagtct catttagatg atagtccctt tttttctacc tccatattag agatggagct 3075ccttcctttt cctgtttctt aatttttgtc ttctcattcc tgcttccctc tcaccctatt 3135gccagttcca ccaactagag tgaaagactt cctagccatt tcattaaatc tattctgtat 3195ccaccaggtg gcagcatctt gtcatacgtg tcaggactta ggactgcggg gtttaggtta 3255gatgtcacgg aaaaagctag ttctgtggtc aggcggcacc aatgagaaag gaatgcagac 3315cctccagatg tatccttggg aaaagcagta aaccaactaa tatttattga agacctactt 3375tgtcctctac atagggtagc ttctgtcagg gaatcttggt tcttcccaag aaacactgat 3435tttctttcag ggagacttca tgtgttcatt tatttccacc acagcagatt ttaagaaatt 3495ataatatgta atatttgata tctataaaga gtatatctaa cgtgaataaa ttatgaagca 3555tactaatgag tacctatgac ccataacaca tatacattaa aacattttaa atacca 361131616PRTHomo sapiens 31Met Ala Glu Asp Glu Pro Asp Ala Lys Ser Pro Lys Thr Gly Gly Arg 1 5 10 15 Ala Pro Pro Gly Gly Ala Glu Ala Gly Glu Pro Thr Thr Leu Leu Gln 20 25 30 Arg Leu Arg Gly Thr Ile Ser Lys Ala Val Gln Asn Lys Val Glu Gly 35 40 45 Ile Leu Gln Asp Val Gln Lys Phe Ser Asp Asn Asp Lys Leu Tyr Leu 50 55 60 Tyr Leu Gln Leu Pro Ser Gly Pro Thr Thr Gly Asp Lys Ser Ser Glu 65 70 75 80 Pro Ser Thr Leu Ser Asn Glu Glu Tyr Met Tyr Ala Tyr Arg Trp Ile 85 90 95 Arg Asn His Leu Glu Glu His Thr Asp Thr Cys Leu Pro Lys Gln Ser 100 105 110 Val Tyr Asp Ala Tyr Arg Lys Tyr Cys Glu Ser Leu Ala Cys Cys Arg 115 120 125 Pro Leu Ser Thr Ala Asn Phe Gly Lys Ile Ile Arg Glu Ile Phe Pro 130 135 140 Asp Ile Lys Ala Arg Arg Leu Gly Gly Arg Gly Gln Ser Lys Tyr Cys 145 150 155 160 Tyr Ser Gly Ile Arg Arg Lys Thr Leu Val Ser Met Pro Pro Leu Pro 165 170 175 Gly Leu Asp Leu Lys Gly Ser Glu Ser Pro Glu Met Gly Pro Glu Val 180 185 190 Thr Pro Ala Pro Arg Asp Glu Leu Val Glu Ala Ala Cys Ala Leu Thr 195 200 205 Cys Asp Trp Ala Glu Arg Ile Leu Lys Arg Ser Phe Ser Ser Ile Val 210 215 220 Glu Val Ala Arg Phe Leu Leu Gln Gln His Leu Ile Ser Ala Arg Ser 225 230 235 240 Ala His Ala His Val Leu Lys Ala Met Gly Leu Ala Glu Glu Asp Glu 245 250 255 His Ala Pro Arg Glu Arg Ser Ser Lys Pro Lys Asn Gly Leu Glu Asn 260 265 270 Pro Glu Gly Gly Ala His Lys Lys Pro Glu Arg Leu Ala Gln Pro Pro 275 280 285 Lys Asp Leu Glu Ala Arg Thr Gly Ala Gly Pro Leu Ala Arg Gly Glu 290 295 300 Arg Lys Lys Ser Val Val Glu Ser Ser Ala Pro Gly Ala Asn Asn Leu 305 310 315 320 Gln Val Asn Ala Leu Val Ala Arg Leu Pro Leu Leu Leu Pro Arg Ala 325 330 335 Pro Arg Ser Leu Ile Pro Pro Ile Pro Val Ser Pro Pro Ile Leu Ala 340 345 350 Pro Arg Leu Ser Ser Gly Ala Leu Lys Val Ala Thr Leu Pro Leu Ser 355 360 365 Ser Arg Ala Gly Ala Pro Pro Ala Ala Val Pro Ile Ile Asn Met Ile 370 375 380 Leu Pro Thr Val Pro Ala Leu Pro Gly Pro Gly Pro Gly Pro Gly Arg 385 390 395 400 Ala Pro Pro Gly Gly Leu Thr Gln Pro Arg Gly Thr Glu Asn Arg Glu 405 410 415 Val Gly Ile Gly Gly Asp Gln Gly Pro His Asp Lys Gly Val Lys Arg 420 425 430 Thr Ala Glu Val Pro Val Ser Glu Ala Ser Gly Gln Ala Pro Pro Ala 435 440 445 Lys Ala Ala Lys Gln Asp Ile Glu Asp Thr Ala Ser Asp Ala Lys Arg 450 455 460 Lys Arg Gly Arg Pro Arg Lys Lys Ser Gly Gly Ser Gly Glu Arg Asn 465 470 475 480 Ser Thr Pro Leu Lys Ser Ala Ala Ala Met Glu Ser Ala Gln Ser Ser 485 490 495 Arg Leu Pro Trp Glu Thr Trp Gly Ser Gly Gly Glu Gly Asn Ser Ala 500 505 510 Gly Gly Ala Glu Arg Pro Gly Pro Met Gly Glu Ala Glu Lys Gly Ala 515 520 525 Val Leu Ala Gln Gly Gln Gly Asp Gly Thr Val Ser Lys Gly Gly Arg 530 535 540 Gly Pro Gly Ser Gln His Thr Lys Glu Ala Glu Asp Lys Ile Pro Leu 545 550 555 560 Val Pro Ser Lys Val Ser Val Ile Lys Gly Ser Arg Ser Gln Lys Glu 565 570 575 Ala Phe Pro Leu Ala Lys Gly Glu Val Asp Thr Ala Pro Gln Gly Asn 580 585 590 Lys Asp Leu Lys Glu His Val Leu Gln Ser Ser Leu Ser Gln Glu His 595 600 605 Lys Asp Pro Lys Ala Thr Pro Pro 610 615 322825DNAHomo sapiensCDS(157)..(975) 32cgcgcaggct gcggtcgcgc aggcgcagtc ggggcgcctt cccggtatag gcgcctttta 60ccccagcgtg tcctgagtct ttggttcgcg aagtgccgtt aggccaagca ggtgctaaaa 120gcccggggtc gtggaccccg gccaggtctt agcagc atg gag gcg cag ggt gta 174 Met Glu Ala Gln Gly Val 1 5 gcg gag ggc gcg ggg ccg ggc gcc gcc agc ggc gtg ccc cac ccc gcg 222Ala Glu Gly Ala Gly Pro Gly Ala Ala Ser Gly Val Pro His Pro Ala 10 15 20 gcc cta gcc ccg gct gcg gct ccc acc ttg gcg cca gcc tcg gtg gcg 270Ala Leu Ala Pro Ala Ala Ala Pro Thr Leu Ala Pro Ala Ser Val Ala 25 30 35 gcc gcg gcc tct caa ttc acc ctg cta gtg atg caa ccc tgt gct ggg 318Ala Ala Ala Ser Gln Phe Thr Leu Leu Val Met Gln Pro Cys Ala Gly 40 45 50 cag gac gag gct gcg gcc ccc ggg ggc agc gtt ggg gcg ggc aag ccc 366Gln Asp Glu Ala Ala Ala Pro Gly Gly Ser Val Gly Ala Gly Lys Pro 55 60 65 70 gtt agg tac ctg tgc gaa ggg gcc ggg gat ggc gaa gag gag gct ggg 414Val Arg Tyr Leu Cys Glu Gly Ala Gly Asp Gly Glu Glu Glu Ala Gly 75 80 85

gag gac gag gcg gac ctg tta gac act tcg gac cct ccg ggg gga ggc 462Glu Asp Glu Ala Asp Leu Leu Asp Thr Ser Asp Pro Pro Gly Gly Gly 90 95 100 gag agc gcg gct agt ttg gag gat cta gag gac gag gag act cac tcg 510Glu Ser Ala Ala Ser Leu Glu Asp Leu Glu Asp Glu Glu Thr His Ser 105 110 115 ggg ggc gag ggc agc agc ggg ggc gcc cgg agg cgg ggc agc ggt ggg 558Gly Gly Glu Gly Ser Ser Gly Gly Ala Arg Arg Arg Gly Ser Gly Gly 120 125 130 ggc agc atg agc aag acc tgc acc tac gaa ggc tgc agc gag acc acg 606Gly Ser Met Ser Lys Thr Cys Thr Tyr Glu Gly Cys Ser Glu Thr Thr 135 140 145 150 agc cag gtg gcc aag cag cgc aaa ccg tgg atg tgc aag aaa cac cgc 654Ser Gln Val Ala Lys Gln Arg Lys Pro Trp Met Cys Lys Lys His Arg 155 160 165 aac aag atg tac aag gac aag tat aaa aag aag aag agc gac cag gcc 702Asn Lys Met Tyr Lys Asp Lys Tyr Lys Lys Lys Lys Ser Asp Gln Ala 170 175 180 ctg aac tgc ggt ggg act gcc tcg act ggc agc gcg gga aac gtc aaa 750Leu Asn Cys Gly Gly Thr Ala Ser Thr Gly Ser Ala Gly Asn Val Lys 185 190 195 ctc gag gaa agt gca gat aac ata ctc tcc att gtt aaa caa aga aca 798Leu Glu Glu Ser Ala Asp Asn Ile Leu Ser Ile Val Lys Gln Arg Thr 200 205 210 gga tct ttt ggg gat cgt cct gca aga cct act ctt tta gaa caa gtg 846Gly Ser Phe Gly Asp Arg Pro Ala Arg Pro Thr Leu Leu Glu Gln Val 215 220 225 230 tta aat caa aaa aga ctg tcg tta cta aga agt cca gaa gta gtg caa 894Leu Asn Gln Lys Arg Leu Ser Leu Leu Arg Ser Pro Glu Val Val Gln 235 240 245 ttt tta cag aaa cag caa cag cta tta aat cag caa gtt ttg gag caa 942Phe Leu Gln Lys Gln Gln Gln Leu Leu Asn Gln Gln Val Leu Glu Gln 250 255 260 aga caa cag cag ttt cca gga aca tca atg tga gggaacttac caagaacatc 995Arg Gln Gln Gln Phe Pro Gly Thr Ser Met 265 270 tacatggttt tttatcttat tgtaatagat gagcatattt ttttaccaga cataaatggg 1055gtaataatct atgcctgtag aacataaaca ttttcctgta aatgtatgtg tgcatttggg 1115gataagtaag tattgcactt tgtgcatcta atctttcaga ttactgtgag tttgaagaag 1175tcagcttatc tttccaaata acatttaatt ataatgtttt ttaaaaaata tattcctctt 1235cagtcattgt tactgaaggt aatgaagcag ttactttctg tggaagtcat aaagttaata 1295gatattaatc ttgactcatc tagctcagtg gttctcatca agggtcaatt tgattgtcat 1355agtgaccttg aaaaccactg gcttttagtg agtggccagg aatgctaaat gttctgcagt 1415gtcaggggta gtcccacata ctaaagattg tctcacccgc agtgccaata acactcctaa 1475gaaatgttga tggctatttt gtggtgctaa catgtagttg gggcacctat aattgggttc 1535tcttaataac ctttctttgc agttaagact gaagctgtca aagaggtaag cacattttat 1595atagacgtaa ggaaagtgat tattgtttaa tatctgtgaa tttaggatgt gcatctcttt 1655tcagaggtgt gttagtaaaa cctgacggat taactaagca cactgggatg tgtctcctac 1715agttggcttc tctctttgat gttacctgtt agtgctgatc tcttaaagca gacatttctt 1775gtttgttgaa tttgtgaaca gtatagatct cagcccacca atgccaagac aaaattattt 1835ttcttatact tattttttat taaacaaaat gaaaaagatc cttttcaaaa aggtgatcct 1895gaaaataaaa ctaacactcc agtattttgt cattgttttt cgcaattgag ctatctgaaa 1955actgttattc ctaagtaatg ttcaaaaatg ataagtaatc tggatacctt tttcttatac 2015tttctcctag gaaaacttta aaactttaaa aaggcaaacc taccaatagg aataacaaat 2075taaatgtcaa gagagtatat ccaatattag gatataaatg tatgtgtctc aagtttaact 2135ctacaaaaat ttgttacttg ttttttaaac tctatatata aagttcgact taatcatggc 2195tgttctaaga agtacttatg gagagcaaga acgtttttgt tcatttctta atgtgtgtgt 2255ttttacttgc atatctgttc aaaacacttt taacaaaatt aattcattaa agtccagttg 2315ttgacctttg agttagctga tttctttatt ctgttcttta gtttattctt actagatgca 2375gaggaattca tctactgtct gttattaact gttagtttat tctcatactt acgatgttga 2435gagttttttt gaagcttaag ttacccttta tggtggaaaa cattagctta tgcttcttta 2495gatggaataa tgggaaagga gggaaatggg aaatggatgg aaatgggaaa ggagggaaaa 2555taatagccca gtgagagctg aatgaaaagg gactgaattt aaatatttgt aagaactttg 2615tgatgatgag taattgtcag acgtgggata gataactgag aggctcagaa tctttaccaa 2675ggatattttt taggataagg tagctgcctg ttcatgaatt tggataagaa tagtaggaca 2735atattcaaca caatttaatt tttgtctgcc acattagaca tttttttacc ttataaaatg 2795atcaataaag caataaggtt tattttgggt 282533272PRTHomo sapiens 33Met Glu Ala Gln Gly Val Ala Glu Gly Ala Gly Pro Gly Ala Ala Ser 1 5 10 15 Gly Val Pro His Pro Ala Ala Leu Ala Pro Ala Ala Ala Pro Thr Leu 20 25 30 Ala Pro Ala Ser Val Ala Ala Ala Ala Ser Gln Phe Thr Leu Leu Val 35 40 45 Met Gln Pro Cys Ala Gly Gln Asp Glu Ala Ala Ala Pro Gly Gly Ser 50 55 60 Val Gly Ala Gly Lys Pro Val Arg Tyr Leu Cys Glu Gly Ala Gly Asp 65 70 75 80 Gly Glu Glu Glu Ala Gly Glu Asp Glu Ala Asp Leu Leu Asp Thr Ser 85 90 95 Asp Pro Pro Gly Gly Gly Glu Ser Ala Ala Ser Leu Glu Asp Leu Glu 100 105 110 Asp Glu Glu Thr His Ser Gly Gly Glu Gly Ser Ser Gly Gly Ala Arg 115 120 125 Arg Arg Gly Ser Gly Gly Gly Ser Met Ser Lys Thr Cys Thr Tyr Glu 130 135 140 Gly Cys Ser Glu Thr Thr Ser Gln Val Ala Lys Gln Arg Lys Pro Trp 145 150 155 160 Met Cys Lys Lys His Arg Asn Lys Met Tyr Lys Asp Lys Tyr Lys Lys 165 170 175 Lys Lys Ser Asp Gln Ala Leu Asn Cys Gly Gly Thr Ala Ser Thr Gly 180 185 190 Ser Ala Gly Asn Val Lys Leu Glu Glu Ser Ala Asp Asn Ile Leu Ser 195 200 205 Ile Val Lys Gln Arg Thr Gly Ser Phe Gly Asp Arg Pro Ala Arg Pro 210 215 220 Thr Leu Leu Glu Gln Val Leu Asn Gln Lys Arg Leu Ser Leu Leu Arg 225 230 235 240 Ser Pro Glu Val Val Gln Phe Leu Gln Lys Gln Gln Gln Leu Leu Asn 245 250 255 Gln Gln Val Leu Glu Gln Arg Gln Gln Gln Phe Pro Gly Thr Ser Met 260 265 270 344654DNAHomo sapiensCDS(134)..(3526) 34ggttagtgat gaggctagtg atgaggctgt gtgcttctga gctgggcatc cgaaggcatc 60cttggggaag ctgagggcac gaggaggggc tgccagactc cgggagctgc tgcctggctg 120ggattcctac aca atg cgt tgc ctg gct cca cgc cct gct ggg tcc tac 169 Met Arg Cys Leu Ala Pro Arg Pro Ala Gly Ser Tyr 1 5 10 ctg tca gag ccc caa ggc agc tca cag tgt gcc acc atg gag ttg ggg 217Leu Ser Glu Pro Gln Gly Ser Ser Gln Cys Ala Thr Met Glu Leu Gly 15 20 25 ccc cta gaa ggt ggc tac ctg gag ctt ctt aac agc gat gct gac ccc 265Pro Leu Glu Gly Gly Tyr Leu Glu Leu Leu Asn Ser Asp Ala Asp Pro 30 35 40 ctg tgc ctc tac cac ttc tat gac cag atg gac ctg gct gga gaa gaa 313Leu Cys Leu Tyr His Phe Tyr Asp Gln Met Asp Leu Ala Gly Glu Glu 45 50 55 60 gag att gag ctc tac tca gaa ccc gac aca gac acc atc aac tgc gac 361Glu Ile Glu Leu Tyr Ser Glu Pro Asp Thr Asp Thr Ile Asn Cys Asp 65 70 75 cag ttc agc agg ctg ttg tgt gac atg gaa ggt gat gaa gag acc agg 409Gln Phe Ser Arg Leu Leu Cys Asp Met Glu Gly Asp Glu Glu Thr Arg 80 85 90 gag gct tat gcc aat atc gcg gaa ctg gac cag tat gtc ttc cag gac 457Glu Ala Tyr Ala Asn Ile Ala Glu Leu Asp Gln Tyr Val Phe Gln Asp 95 100 105 tcc cag ctg gag ggc ctg agc aag gac att ttc aag cac ata gga cca 505Ser Gln Leu Glu Gly Leu Ser Lys Asp Ile Phe Lys His Ile Gly Pro 110 115 120 gat gaa gtg atc ggt gag agt atg gag atg cca gca gaa gtt ggg cag 553Asp Glu Val Ile Gly Glu Ser Met Glu Met Pro Ala Glu Val Gly Gln 125 130 135 140 aaa agt cag aaa aga ccc ttc cca gag gag ctt ccg gca gac ctg aag 601Lys Ser Gln Lys Arg Pro Phe Pro Glu Glu Leu Pro Ala Asp Leu Lys 145 150 155 cac tgg aag cca gct gag ccc ccc act gtg gtg act ggc agt ctc cta 649His Trp Lys Pro Ala Glu Pro Pro Thr Val Val Thr Gly Ser Leu Leu 160 165 170 gtg gga cca gtg agc gac tgc tcc acc ctg ccc tgc ctg cca ctg cct 697Val Gly Pro Val Ser Asp Cys Ser Thr Leu Pro Cys Leu Pro Leu Pro 175 180 185 gcg ctg ttc aac cag gag cca gcc tcc ggc cag atg cgc ctg gag aaa 745Ala Leu Phe Asn Gln Glu Pro Ala Ser Gly Gln Met Arg Leu Glu Lys 190 195 200 acc gac cag att ccc atg cct ttc tcc agt tcc tcg ttg agc tgc ctg 793Thr Asp Gln Ile Pro Met Pro Phe Ser Ser Ser Ser Leu Ser Cys Leu 205 210 215 220 aat ctc cct gag gga ccc atc cag ttt gtc ccc acc atc tcc act ctg 841Asn Leu Pro Glu Gly Pro Ile Gln Phe Val Pro Thr Ile Ser Thr Leu 225 230 235 ccc cat ggg ctc tgg caa atc tct gag gct gga aca ggg gtc tcc agt 889Pro His Gly Leu Trp Gln Ile Ser Glu Ala Gly Thr Gly Val Ser Ser 240 245 250 ata ttc atc tac cat ggt gag gtg ccc cag gcc agc caa gta ccc cct 937Ile Phe Ile Tyr His Gly Glu Val Pro Gln Ala Ser Gln Val Pro Pro 255 260 265 ccc agt gga ttc act gtc cac ggc ctc cca aca tct cca gac cgg cca 985Pro Ser Gly Phe Thr Val His Gly Leu Pro Thr Ser Pro Asp Arg Pro 270 275 280 ggc tcc acc agc ccc ttc gct cca tca gcc act gac ctg ccc agc atg 1033Gly Ser Thr Ser Pro Phe Ala Pro Ser Ala Thr Asp Leu Pro Ser Met 285 290 295 300 cct gaa cct gcc ctg acc tcc cga gca aac atg aca gag cac aag acg 1081Pro Glu Pro Ala Leu Thr Ser Arg Ala Asn Met Thr Glu His Lys Thr 305 310 315 tcc ccc acc caa tgc ccg gca gct gga gag gtc tcc aac aag ctt cca 1129Ser Pro Thr Gln Cys Pro Ala Ala Gly Glu Val Ser Asn Lys Leu Pro 320 325 330 aaa tgg cct gag ccg gtg gag cag ttc tac cgc tca ctg cag gac acg 1177Lys Trp Pro Glu Pro Val Glu Gln Phe Tyr Arg Ser Leu Gln Asp Thr 335 340 345 tat ggt gcc gag ccc gca ggc ccg gat ggc atc cta gtg gag gtg gat 1225Tyr Gly Ala Glu Pro Ala Gly Pro Asp Gly Ile Leu Val Glu Val Asp 350 355 360 ctg gtg cag gcc agg ctg gag agg agc agc agc aag agc ctg gag cgg 1273Leu Val Gln Ala Arg Leu Glu Arg Ser Ser Ser Lys Ser Leu Glu Arg 365 370 375 380 gaa ctg gcc acc ccg gac tgg gca gaa cgg cag ctg gcc caa gga ggc 1321Glu Leu Ala Thr Pro Asp Trp Ala Glu Arg Gln Leu Ala Gln Gly Gly 385 390 395 ctg gct gag gtg ctg ttg gct gcc aag gag cac cgg cgg ccg cgt gag 1369Leu Ala Glu Val Leu Leu Ala Ala Lys Glu His Arg Arg Pro Arg Glu 400 405 410 aca cga gtg att gct gtg ctg ggc aaa gct ggt cag ggc aag agc tat 1417Thr Arg Val Ile Ala Val Leu Gly Lys Ala Gly Gln Gly Lys Ser Tyr 415 420 425 tgg gct ggg gca gtg agc cgg gcc tgg gct tgt ggc cgg ctt ccc cag 1465Trp Ala Gly Ala Val Ser Arg Ala Trp Ala Cys Gly Arg Leu Pro Gln 430 435 440 tac gac ttt gtc ttc tct gtc ccc tgc cat tgc ttg aac cgt ccg ggg 1513Tyr Asp Phe Val Phe Ser Val Pro Cys His Cys Leu Asn Arg Pro Gly 445 450 455 460 gat gcc tat ggc ctg cag gat ctg ctc ttc tcc ctg ggc cca cag cca 1561Asp Ala Tyr Gly Leu Gln Asp Leu Leu Phe Ser Leu Gly Pro Gln Pro 465 470 475 ctc gtg gcg gcc gat gag gtt ttc agc cac atc ttg aag aga cct gac 1609Leu Val Ala Ala Asp Glu Val Phe Ser His Ile Leu Lys Arg Pro Asp 480 485 490 cgc gtt ctg ctc atc cta gac ggc ttc gag gag ctg gaa gcg caa gat 1657Arg Val Leu Leu Ile Leu Asp Gly Phe Glu Glu Leu Glu Ala Gln Asp 495 500 505 ggc ttc ctg cac agc acg tgc gga ccg gca ccg gcg gag ccc tgc tcc 1705Gly Phe Leu His Ser Thr Cys Gly Pro Ala Pro Ala Glu Pro Cys Ser 510 515 520 ctc cgg ggg ctg ctg gcc ggc ctt ttc cag aag aag ctg ctc cga ggt 1753Leu Arg Gly Leu Leu Ala Gly Leu Phe Gln Lys Lys Leu Leu Arg Gly 525 530 535 540 tgc acc ctc ctc ctc aca gcc cgg ccc cgg ggc cgc ctg gtc cag agc 1801Cys Thr Leu Leu Leu Thr Ala Arg Pro Arg Gly Arg Leu Val Gln Ser 545 550 555 ctg agc aag gcc gac gcc cta ttt gag ctg tcc ggc ttc tcc atg gag 1849Leu Ser Lys Ala Asp Ala Leu Phe Glu Leu Ser Gly Phe Ser Met Glu 560 565 570 cag gcc cag gca tac gtg atg cgc tac ttt gag agc tca ggg atg aca 1897Gln Ala Gln Ala Tyr Val Met Arg Tyr Phe Glu Ser Ser Gly Met Thr 575 580 585 gag cac caa gac aga gcc ctg acg ctc ctc cgg gac cgg cca ctt ctt 1945Glu His Gln Asp Arg Ala Leu Thr Leu Leu Arg Asp Arg Pro Leu Leu 590 595 600 ctc agt cac agc cac agc cct act ttg tgc cgg gca gtg tgc cag ctc 1993Leu Ser His Ser His Ser Pro Thr Leu Cys Arg Ala Val Cys Gln Leu 605 610 615 620 tca gag gcc ctg ctg gag ctt ggg gag gac gcc aag ctg ccc tcc acg 2041Ser Glu Ala Leu Leu Glu Leu Gly Glu Asp Ala Lys Leu Pro Ser Thr 625 630 635 ctc acg gga ctc tat gtc ggc ctg ctg ggc cgt gca gcc ctc gac agc 2089Leu Thr Gly Leu Tyr Val Gly Leu Leu Gly Arg Ala Ala Leu Asp Ser 640 645 650 ccc ccc ggg gcc ctg gca gag ctg gcc aag ctg gcc tgg gag ctg ggc 2137Pro Pro Gly Ala Leu Ala Glu Leu Ala Lys Leu Ala Trp Glu Leu Gly 655 660 665 cgc aga cat caa agt acc cta cag gag gac cag ttc cca tcc gca gac 2185Arg Arg His Gln Ser Thr Leu Gln Glu Asp Gln Phe Pro Ser Ala Asp 670 675 680 gtg agg acc tgg gcg atg gcc aaa ggc tta gtc caa cac cca ccg cgg 2233Val Arg Thr Trp Ala Met Ala Lys Gly Leu Val Gln His Pro Pro Arg 685 690 695 700 gcc gca gag tcc gag ctg gcc ttc ccc agc ttc ctc ctg caa tgc ttc 2281Ala Ala Glu Ser Glu Leu Ala Phe Pro Ser Phe Leu Leu Gln Cys Phe 705 710 715 ctg ggg gcc ctg tgg ctg gct ctg agt ggc gaa atc aag gac aag gag 2329Leu Gly Ala Leu Trp Leu Ala Leu Ser Gly Glu Ile Lys Asp Lys Glu 720 725 730 ctc ccg cag tac cta gca ttg acc cca agg aag aag agg ccc tat gac 2377Leu Pro Gln Tyr Leu Ala Leu Thr Pro Arg Lys Lys Arg Pro Tyr Asp 735 740 745 aac tgg ctg gag ggc gtg cca cgc ttt ctg gct ggg ctg atc ttc cag 2425Asn Trp Leu Glu Gly Val Pro Arg Phe Leu Ala Gly Leu Ile Phe Gln 750 755 760 cct ccc gcc cgc tgc ctg gga gcc cta ctc ggg cca tcg gcg gct gcc 2473Pro Pro Ala Arg Cys Leu Gly Ala Leu Leu Gly Pro Ser Ala Ala Ala 765 770 775 780 tcg gtg gac agg aag cag aag gtg ctt gcg agg tac ctg aag cgg ctg 2521Ser Val Asp Arg Lys Gln Lys Val Leu Ala Arg Tyr Leu Lys Arg Leu 785 790 795 cag ccg ggg aca ctg cgg gcg cgg cag ctg ctg gag ctg ctg cac tgc 2569Gln Pro Gly Thr Leu Arg Ala Arg Gln Leu Leu Glu Leu Leu His Cys

800 805 810 gcc cac gag gcc gag gag gct gga att tgg cag cac gtg gta cag gag 2617Ala His Glu Ala Glu Glu Ala Gly Ile Trp Gln His Val Val Gln Glu 815 820 825 ctc ccc ggc cgc ctc tct ttt ctg ggc acc cgc ctc acg cct cct gat 2665Leu Pro Gly Arg Leu Ser Phe Leu Gly Thr Arg Leu Thr Pro Pro Asp 830 835 840 gca cat gta ctg ggc aag gcc ttg gag gcg gcg ggc caa gac ttc tcc 2713Ala His Val Leu Gly Lys Ala Leu Glu Ala Ala Gly Gln Asp Phe Ser 845 850 855 860 ctg gac ctc cgc agc act ggc att tgc ccc tct gga ttg ggg agc ctc 2761Leu Asp Leu Arg Ser Thr Gly Ile Cys Pro Ser Gly Leu Gly Ser Leu 865 870 875 gtg gga ctc agc tgt gtc acc cgt ttc agg gct gcc ttg agc gac acg 2809Val Gly Leu Ser Cys Val Thr Arg Phe Arg Ala Ala Leu Ser Asp Thr 880 885 890 gtg gcg ctg tgg gag tcc ctg cag cag cat ggg gag acc aag cta ctt 2857Val Ala Leu Trp Glu Ser Leu Gln Gln His Gly Glu Thr Lys Leu Leu 895 900 905 cag gca gca gag gag aag ttc acc atc gag cct ttc aaa gcc aag tcc 2905Gln Ala Ala Glu Glu Lys Phe Thr Ile Glu Pro Phe Lys Ala Lys Ser 910 915 920 ctg aag gat gtg gaa gac ctg gga aag ctt gtg cag act cag agg acg 2953Leu Lys Asp Val Glu Asp Leu Gly Lys Leu Val Gln Thr Gln Arg Thr 925 930 935 940 aga agt tcc tcg gaa gac aca gct ggg gag ctc cct gct gtt cgg gac 3001Arg Ser Ser Ser Glu Asp Thr Ala Gly Glu Leu Pro Ala Val Arg Asp 945 950 955 cta aag aaa ctg gag ttt gcg ctg ggc cct gtc tca ggc ccc cag gct 3049Leu Lys Lys Leu Glu Phe Ala Leu Gly Pro Val Ser Gly Pro Gln Ala 960 965 970 ttc ccc aaa ctg gtg cgg atc ctc acg gcc ttt tcc tcc ctg cag cat 3097Phe Pro Lys Leu Val Arg Ile Leu Thr Ala Phe Ser Ser Leu Gln His 975 980 985 ctg gac ctg gat gcg ctg agt gag aac aag atc ggg gac gag ggt gtc 3145Leu Asp Leu Asp Ala Leu Ser Glu Asn Lys Ile Gly Asp Glu Gly Val 990 995 1000 tcg cag ctc tca gcc acc ttc ccc cag ctg aag tcc ttg gaa acc 3190Ser Gln Leu Ser Ala Thr Phe Pro Gln Leu Lys Ser Leu Glu Thr 1005 1010 1015 ctc aat ctg tcc cag aac aac atc act gac ctg ggt gcc tac aaa 3235Leu Asn Leu Ser Gln Asn Asn Ile Thr Asp Leu Gly Ala Tyr Lys 1020 1025 1030 ctc gcc gag gcc ctg cct tcg ctc gct gca tcc ctg ctc agg cta 3280Leu Ala Glu Ala Leu Pro Ser Leu Ala Ala Ser Leu Leu Arg Leu 1035 1040 1045 agc ttg tac aat aac tgc atc tgc gac gtg gga gcc gag agc ttg 3325Ser Leu Tyr Asn Asn Cys Ile Cys Asp Val Gly Ala Glu Ser Leu 1050 1055 1060 gct cgt gtg ctt ccg gac atg gtg tcc ctc cgg gtg atg gac gtc 3370Ala Arg Val Leu Pro Asp Met Val Ser Leu Arg Val Met Asp Val 1065 1070 1075 cag tac aac aag ttc acg gct gcc ggg gcc cag cag ctc gct gcc 3415Gln Tyr Asn Lys Phe Thr Ala Ala Gly Ala Gln Gln Leu Ala Ala 1080 1085 1090 agc ctt cgg agg tgt cct cat gtg gag acg ctg gcg atg tgg acg 3460Ser Leu Arg Arg Cys Pro His Val Glu Thr Leu Ala Met Trp Thr 1095 1100 1105 ccc acc atc cca ttc agt gtc cag gaa cac ctg caa caa cag gat 3505Pro Thr Ile Pro Phe Ser Val Gln Glu His Leu Gln Gln Gln Asp 1110 1115 1120 tca cgg atc agc ctg aga tga tcccagctgt gctctggaca ggcatgttct 3556Ser Arg Ile Ser Leu Arg 1125 1130 ctgaggacac taaccacgct ggaccttgaa ctgggtactt gtggacacag ctcttctcca 3616ggctgtatcc catgagcctc agcatcctgg cacccggccc ctgctggttc agggttggcc 3676cctgcccggc tgcggaatga accacatctt gctctgctga cagacacagg cccggctcca 3736ggctccttta gcgcccagtt gggtggatgc ctggtggcag ctgcggtcca cccaggagcc 3796ccgaggcctt ctctgaagga cattgcggac agccacggcc aggccagagg gagtgacaga 3856ggcagcccca ttctgcctgc ccaggcccct gccaccctgg ggagaaagta cttctttttt 3916tttattttta gacagagtct cactgttgcc caggctggcg tgcagtggtg cgatctgggt 3976tcactgcaac ctccgcctct tgggttcaag cgattcttct gcttcagcct cccgagtagc 4036tgggactaca ggcacccacc atcatgtctg gctaattttt catttttagt agagacaggg 4096ttttgccatg ttggccaggc tggtctcaaa ctcttgacct caggtgatcc acccacctca 4156gcctcccaaa gtgctgggat tacaagcgtg agccactgca ccgggccaca gagaaagtac 4216ttctccaccc tgctctccga ccagacacct tgacagggca caccgggcac tcagaagaca 4276ctgatgggca acccccagcc tgctaattcc ccagattgca acaggctggg cttcagtggc 4336agctgctttt gtctatggga ctcaatgcac tgacattgtt ggccaaagcc aaagctaggc 4396ctggccagat gcaccagccc ttagcaggga aacagctaat gggacactaa tggggcggtg 4456agaggggaac agactggaag cacagcttca tttcctgtgt cttttttcac tacattataa 4516atgtctcttt aatgtcacag gcaggtccag ggtttgagtt cataccctgt taccattttg 4576gggtacccac tgctctggtt atctaatatg taacaagcca ccccaaatca tagtggctta 4636aaacaacact cacattta 4654351130PRTHomo sapiens 35Met Arg Cys Leu Ala Pro Arg Pro Ala Gly Ser Tyr Leu Ser Glu Pro 1 5 10 15 Gln Gly Ser Ser Gln Cys Ala Thr Met Glu Leu Gly Pro Leu Glu Gly 20 25 30 Gly Tyr Leu Glu Leu Leu Asn Ser Asp Ala Asp Pro Leu Cys Leu Tyr 35 40 45 His Phe Tyr Asp Gln Met Asp Leu Ala Gly Glu Glu Glu Ile Glu Leu 50 55 60 Tyr Ser Glu Pro Asp Thr Asp Thr Ile Asn Cys Asp Gln Phe Ser Arg 65 70 75 80 Leu Leu Cys Asp Met Glu Gly Asp Glu Glu Thr Arg Glu Ala Tyr Ala 85 90 95 Asn Ile Ala Glu Leu Asp Gln Tyr Val Phe Gln Asp Ser Gln Leu Glu 100 105 110 Gly Leu Ser Lys Asp Ile Phe Lys His Ile Gly Pro Asp Glu Val Ile 115 120 125 Gly Glu Ser Met Glu Met Pro Ala Glu Val Gly Gln Lys Ser Gln Lys 130 135 140 Arg Pro Phe Pro Glu Glu Leu Pro Ala Asp Leu Lys His Trp Lys Pro 145 150 155 160 Ala Glu Pro Pro Thr Val Val Thr Gly Ser Leu Leu Val Gly Pro Val 165 170 175 Ser Asp Cys Ser Thr Leu Pro Cys Leu Pro Leu Pro Ala Leu Phe Asn 180 185 190 Gln Glu Pro Ala Ser Gly Gln Met Arg Leu Glu Lys Thr Asp Gln Ile 195 200 205 Pro Met Pro Phe Ser Ser Ser Ser Leu Ser Cys Leu Asn Leu Pro Glu 210 215 220 Gly Pro Ile Gln Phe Val Pro Thr Ile Ser Thr Leu Pro His Gly Leu 225 230 235 240 Trp Gln Ile Ser Glu Ala Gly Thr Gly Val Ser Ser Ile Phe Ile Tyr 245 250 255 His Gly Glu Val Pro Gln Ala Ser Gln Val Pro Pro Pro Ser Gly Phe 260 265 270 Thr Val His Gly Leu Pro Thr Ser Pro Asp Arg Pro Gly Ser Thr Ser 275 280 285 Pro Phe Ala Pro Ser Ala Thr Asp Leu Pro Ser Met Pro Glu Pro Ala 290 295 300 Leu Thr Ser Arg Ala Asn Met Thr Glu His Lys Thr Ser Pro Thr Gln 305 310 315 320 Cys Pro Ala Ala Gly Glu Val Ser Asn Lys Leu Pro Lys Trp Pro Glu 325 330 335 Pro Val Glu Gln Phe Tyr Arg Ser Leu Gln Asp Thr Tyr Gly Ala Glu 340 345 350 Pro Ala Gly Pro Asp Gly Ile Leu Val Glu Val Asp Leu Val Gln Ala 355 360 365 Arg Leu Glu Arg Ser Ser Ser Lys Ser Leu Glu Arg Glu Leu Ala Thr 370 375 380 Pro Asp Trp Ala Glu Arg Gln Leu Ala Gln Gly Gly Leu Ala Glu Val 385 390 395 400 Leu Leu Ala Ala Lys Glu His Arg Arg Pro Arg Glu Thr Arg Val Ile 405 410 415 Ala Val Leu Gly Lys Ala Gly Gln Gly Lys Ser Tyr Trp Ala Gly Ala 420 425 430 Val Ser Arg Ala Trp Ala Cys Gly Arg Leu Pro Gln Tyr Asp Phe Val 435 440 445 Phe Ser Val Pro Cys His Cys Leu Asn Arg Pro Gly Asp Ala Tyr Gly 450 455 460 Leu Gln Asp Leu Leu Phe Ser Leu Gly Pro Gln Pro Leu Val Ala Ala 465 470 475 480 Asp Glu Val Phe Ser His Ile Leu Lys Arg Pro Asp Arg Val Leu Leu 485 490 495 Ile Leu Asp Gly Phe Glu Glu Leu Glu Ala Gln Asp Gly Phe Leu His 500 505 510 Ser Thr Cys Gly Pro Ala Pro Ala Glu Pro Cys Ser Leu Arg Gly Leu 515 520 525 Leu Ala Gly Leu Phe Gln Lys Lys Leu Leu Arg Gly Cys Thr Leu Leu 530 535 540 Leu Thr Ala Arg Pro Arg Gly Arg Leu Val Gln Ser Leu Ser Lys Ala 545 550 555 560 Asp Ala Leu Phe Glu Leu Ser Gly Phe Ser Met Glu Gln Ala Gln Ala 565 570 575 Tyr Val Met Arg Tyr Phe Glu Ser Ser Gly Met Thr Glu His Gln Asp 580 585 590 Arg Ala Leu Thr Leu Leu Arg Asp Arg Pro Leu Leu Leu Ser His Ser 595 600 605 His Ser Pro Thr Leu Cys Arg Ala Val Cys Gln Leu Ser Glu Ala Leu 610 615 620 Leu Glu Leu Gly Glu Asp Ala Lys Leu Pro Ser Thr Leu Thr Gly Leu 625 630 635 640 Tyr Val Gly Leu Leu Gly Arg Ala Ala Leu Asp Ser Pro Pro Gly Ala 645 650 655 Leu Ala Glu Leu Ala Lys Leu Ala Trp Glu Leu Gly Arg Arg His Gln 660 665 670 Ser Thr Leu Gln Glu Asp Gln Phe Pro Ser Ala Asp Val Arg Thr Trp 675 680 685 Ala Met Ala Lys Gly Leu Val Gln His Pro Pro Arg Ala Ala Glu Ser 690 695 700 Glu Leu Ala Phe Pro Ser Phe Leu Leu Gln Cys Phe Leu Gly Ala Leu 705 710 715 720 Trp Leu Ala Leu Ser Gly Glu Ile Lys Asp Lys Glu Leu Pro Gln Tyr 725 730 735 Leu Ala Leu Thr Pro Arg Lys Lys Arg Pro Tyr Asp Asn Trp Leu Glu 740 745 750 Gly Val Pro Arg Phe Leu Ala Gly Leu Ile Phe Gln Pro Pro Ala Arg 755 760 765 Cys Leu Gly Ala Leu Leu Gly Pro Ser Ala Ala Ala Ser Val Asp Arg 770 775 780 Lys Gln Lys Val Leu Ala Arg Tyr Leu Lys Arg Leu Gln Pro Gly Thr 785 790 795 800 Leu Arg Ala Arg Gln Leu Leu Glu Leu Leu His Cys Ala His Glu Ala 805 810 815 Glu Glu Ala Gly Ile Trp Gln His Val Val Gln Glu Leu Pro Gly Arg 820 825 830 Leu Ser Phe Leu Gly Thr Arg Leu Thr Pro Pro Asp Ala His Val Leu 835 840 845 Gly Lys Ala Leu Glu Ala Ala Gly Gln Asp Phe Ser Leu Asp Leu Arg 850 855 860 Ser Thr Gly Ile Cys Pro Ser Gly Leu Gly Ser Leu Val Gly Leu Ser 865 870 875 880 Cys Val Thr Arg Phe Arg Ala Ala Leu Ser Asp Thr Val Ala Leu Trp 885 890 895 Glu Ser Leu Gln Gln His Gly Glu Thr Lys Leu Leu Gln Ala Ala Glu 900 905 910 Glu Lys Phe Thr Ile Glu Pro Phe Lys Ala Lys Ser Leu Lys Asp Val 915 920 925 Glu Asp Leu Gly Lys Leu Val Gln Thr Gln Arg Thr Arg Ser Ser Ser 930 935 940 Glu Asp Thr Ala Gly Glu Leu Pro Ala Val Arg Asp Leu Lys Lys Leu 945 950 955 960 Glu Phe Ala Leu Gly Pro Val Ser Gly Pro Gln Ala Phe Pro Lys Leu 965 970 975 Val Arg Ile Leu Thr Ala Phe Ser Ser Leu Gln His Leu Asp Leu Asp 980 985 990 Ala Leu Ser Glu Asn Lys Ile Gly Asp Glu Gly Val Ser Gln Leu Ser 995 1000 1005 Ala Thr Phe Pro Gln Leu Lys Ser Leu Glu Thr Leu Asn Leu Ser 1010 1015 1020 Gln Asn Asn Ile Thr Asp Leu Gly Ala Tyr Lys Leu Ala Glu Ala 1025 1030 1035 Leu Pro Ser Leu Ala Ala Ser Leu Leu Arg Leu Ser Leu Tyr Asn 1040 1045 1050 Asn Cys Ile Cys Asp Val Gly Ala Glu Ser Leu Ala Arg Val Leu 1055 1060 1065 Pro Asp Met Val Ser Leu Arg Val Met Asp Val Gln Tyr Asn Lys 1070 1075 1080 Phe Thr Ala Ala Gly Ala Gln Gln Leu Ala Ala Ser Leu Arg Arg 1085 1090 1095 Cys Pro His Val Glu Thr Leu Ala Met Trp Thr Pro Thr Ile Pro 1100 1105 1110 Phe Ser Val Gln Glu His Leu Gln Gln Gln Asp Ser Arg Ile Ser 1115 1120 1125 Leu Arg 1130 361697DNAHomo sapiensCDS(108)..(890) 36atttccagtg ctagaggccc acagtttcag tctcatctgc ctccactcgg cctcagttcc 60tcatcactgt tcctgtgctc acagtcatca attatagacc ccacaac atg cgc cct 116 Met Arg Pro 1 gaa gac aga atg ttc cat atc aga gct gtg atc ttg aga gcc ctc tcc 164Glu Asp Arg Met Phe His Ile Arg Ala Val Ile Leu Arg Ala Leu Ser 5 10 15 ttg gct ttc ctg ctg agt ctc cga gga gct ggg gcc atc aag gcg gac 212Leu Ala Phe Leu Leu Ser Leu Arg Gly Ala Gly Ala Ile Lys Ala Asp 20 25 30 35 cat gtg tca act tat gcc gcg ttt gta cag acg cat aga cca aca ggg 260His Val Ser Thr Tyr Ala Ala Phe Val Gln Thr His Arg Pro Thr Gly 40 45 50 gag ttt atg ttt gaa ttt gat gaa gat gag atg ttc tat gtg gat ctg 308Glu Phe Met Phe Glu Phe Asp Glu Asp Glu Met Phe Tyr Val Asp Leu 55 60 65 gac aag aag gag acc gtc tgg cat ctg gag gag ttt ggc caa gcc ttt 356Asp Lys Lys Glu Thr Val Trp His Leu Glu Glu Phe Gly Gln Ala Phe 70 75 80 tcc ttt gag gct cag ggc ggg ctg gct aac att gct ata ttg aac aac 404Ser Phe Glu Ala Gln Gly Gly Leu Ala Asn Ile Ala Ile Leu Asn Asn 85 90 95 aac ttg aat acc ttg atc cag cgt tcc aac cac act cag gcc acc aac 452Asn Leu Asn Thr Leu Ile Gln Arg Ser Asn His Thr Gln Ala Thr Asn 100 105 110 115 gat ccc cct gag gtg acc gtg ttt ccc aag gag cct gtg gag ctg ggc 500Asp Pro Pro Glu Val Thr Val Phe Pro Lys Glu Pro Val Glu Leu Gly 120 125 130 cag ccc aac acc ctc atc tgc cac att gac aag ttc ttc cca cca gtg 548Gln Pro Asn Thr Leu Ile Cys His Ile Asp Lys Phe Phe Pro Pro Val 135 140 145 ctc aac gtc acg tgg ctg tgc aac ggg gag ctg gtc act gag ggt gtc 596Leu Asn Val Thr Trp Leu Cys Asn Gly Glu Leu Val Thr Glu Gly Val 150 155 160 gct gag agc ctc ttc ctg ccc aga aca gat tac agc ttc cac aag ttc 644Ala Glu Ser Leu Phe Leu Pro Arg Thr Asp Tyr Ser Phe His Lys Phe 165 170 175 cat tac ctg acc ttt gtg ccc tca gca gag gac ttc tat gac tgc agg 692His Tyr Leu Thr Phe Val Pro Ser Ala Glu Asp Phe Tyr Asp Cys Arg 180 185 190 195 gtg gag cac tgg ggc ttg gac cag ccg ctc ctc aag cac tgg gag gcc 740Val Glu His Trp Gly Leu Asp Gln Pro Leu Leu Lys His Trp Glu Ala 200 205 210 caa gag cca atc cag atg cct gag aca acg gag act gtg ctc tgt gcc

788Gln Glu Pro Ile Gln Met Pro Glu Thr Thr Glu Thr Val Leu Cys Ala 215 220 225 ctg ggc ctg gtg ctg ggc cta gtc ggc atc atc gtg ggc acc gtc ctc 836Leu Gly Leu Val Leu Gly Leu Val Gly Ile Ile Val Gly Thr Val Leu 230 235 240 atc ata aag tct ctg cgt tct ggc cat gac ccc cgg gcc cag ggg acc 884Ile Ile Lys Ser Leu Arg Ser Gly His Asp Pro Arg Ala Gln Gly Thr 245 250 255 ctg tga aatactgtaa aggtgacaaa atatctgaac agaagaggac ttaggagaga 940Leu 260 tctgaactcc agctgcccta caaactccat ctcagctttt cttctcactt catgtgaaaa 1000ctactccagt ggctgactga attgctgacc cttcaagctc tgtccttatc cattacctca 1060aagcagtcat tccttagtaa agtttccaac aaatagaaat taatgacact ttggtagcac 1120taatatggag attatccttt cattgagcct tttatcctct gttctccttt gaagaacccc 1180tcactgtcac cttcccgaga ataccctaag accaataaat acttcagtat ttcagagcgg 1240ggagactctg agtcattctt actggaagtc taggaccagg tcacatgtga atactatttc 1300ttgaaggtgt ggtttcaacc tctgttgccg atgtggttac taaaggttct gatcccactt 1360gaacggaaag gtctgaggat attgattcag tcctgggttt ttccctaact acaggatagg 1420gtggggtaga gaaaggatat ttgggggaaa ttttacttgg atgaagattt tcttggatgt 1480agtttgaaga ctgcagtgtt tgaagtctct gagggaagag atttggtctg tctggatcaa 1540gatttcaggc agattaggat tccattcaca gcccctgagc ttccttccca aggctgtatt 1600gtaattatag caatatttca tggaggattt ttctacatga taaactaaga gccaagaaat 1660aaaattttta aaatgcccta aaaaaaaaaa aaaaaaa 169737260PRTHomo sapiens 37Met Arg Pro Glu Asp Arg Met Phe His Ile Arg Ala Val Ile Leu Arg 1 5 10 15 Ala Leu Ser Leu Ala Phe Leu Leu Ser Leu Arg Gly Ala Gly Ala Ile 20 25 30 Lys Ala Asp His Val Ser Thr Tyr Ala Ala Phe Val Gln Thr His Arg 35 40 45 Pro Thr Gly Glu Phe Met Phe Glu Phe Asp Glu Asp Glu Met Phe Tyr 50 55 60 Val Asp Leu Asp Lys Lys Glu Thr Val Trp His Leu Glu Glu Phe Gly 65 70 75 80 Gln Ala Phe Ser Phe Glu Ala Gln Gly Gly Leu Ala Asn Ile Ala Ile 85 90 95 Leu Asn Asn Asn Leu Asn Thr Leu Ile Gln Arg Ser Asn His Thr Gln 100 105 110 Ala Thr Asn Asp Pro Pro Glu Val Thr Val Phe Pro Lys Glu Pro Val 115 120 125 Glu Leu Gly Gln Pro Asn Thr Leu Ile Cys His Ile Asp Lys Phe Phe 130 135 140 Pro Pro Val Leu Asn Val Thr Trp Leu Cys Asn Gly Glu Leu Val Thr 145 150 155 160 Glu Gly Val Ala Glu Ser Leu Phe Leu Pro Arg Thr Asp Tyr Ser Phe 165 170 175 His Lys Phe His Tyr Leu Thr Phe Val Pro Ser Ala Glu Asp Phe Tyr 180 185 190 Asp Cys Arg Val Glu His Trp Gly Leu Asp Gln Pro Leu Leu Lys His 195 200 205 Trp Glu Ala Gln Glu Pro Ile Gln Met Pro Glu Thr Thr Glu Thr Val 210 215 220 Leu Cys Ala Leu Gly Leu Val Leu Gly Leu Val Gly Ile Ile Val Gly 225 230 235 240 Thr Val Leu Ile Ile Lys Ser Leu Arg Ser Gly His Asp Pro Arg Ala 245 250 255 Gln Gly Thr Leu 260 38777DNAHomo sapiensCDS(1)..(777) 38atg atg gtt ctg cag gtt tct gcg gcc ccc cgg aca gtg gct ctg acg 48Met Met Val Leu Gln Val Ser Ala Ala Pro Arg Thr Val Ala Leu Thr 1 5 10 15 gcg tta ctg atg gtg ctg ctc aca tct gtg gtc cag ggc agg gcc act 96Ala Leu Leu Met Val Leu Leu Thr Ser Val Val Gln Gly Arg Ala Thr 20 25 30 cca gag aat tac gtg tac cag gga cgg cag gaa tgc tac gcg ttt aat 144Pro Glu Asn Tyr Val Tyr Gln Gly Arg Gln Glu Cys Tyr Ala Phe Asn 35 40 45 ggg aca cag cgc ttc ctg gag aga tac atc tac aac cgg gag gag tac 192Gly Thr Gln Arg Phe Leu Glu Arg Tyr Ile Tyr Asn Arg Glu Glu Tyr 50 55 60 gcg cgc ttc gac agc gac gtg ggg gag ttc cgg gcg gtg acg gag ctg 240Ala Arg Phe Asp Ser Asp Val Gly Glu Phe Arg Ala Val Thr Glu Leu 65 70 75 80 ggg cgg cct gct gcg gag tac tgg aac agc cag aag gac atc ctg gag 288Gly Arg Pro Ala Ala Glu Tyr Trp Asn Ser Gln Lys Asp Ile Leu Glu 85 90 95 gag aag cgg gca gtg ccg gac agg gta tgc aga cac aac tac gag ctg 336Glu Lys Arg Ala Val Pro Asp Arg Val Cys Arg His Asn Tyr Glu Leu 100 105 110 gac gag gcc gtg acc ctg cag cgc cga gtc cag cct aag gtg aac gtt 384Asp Glu Ala Val Thr Leu Gln Arg Arg Val Gln Pro Lys Val Asn Val 115 120 125 tcc ccc tcc aag aag ggg ccc ctg cag cac cac aac ctg ctt gtc tgc 432Ser Pro Ser Lys Lys Gly Pro Leu Gln His His Asn Leu Leu Val Cys 130 135 140 cac gtg aca gat ttc tac cca ggc agc att caa gtc cga tgg ttc ctg 480His Val Thr Asp Phe Tyr Pro Gly Ser Ile Gln Val Arg Trp Phe Leu 145 150 155 160 aat gga cag gag gaa aca gct ggg gtc gtg tcc acc aac ctg atc cgt 528Asn Gly Gln Glu Glu Thr Ala Gly Val Val Ser Thr Asn Leu Ile Arg 165 170 175 aat gga gac tgg acc ttc cag atc ctg gtg atg ctg gaa atg acc ccc 576Asn Gly Asp Trp Thr Phe Gln Ile Leu Val Met Leu Glu Met Thr Pro 180 185 190 cag cag gga gac gtc tac atc tgc caa gtg gag cac acc agc ctg gac 624Gln Gln Gly Asp Val Tyr Ile Cys Gln Val Glu His Thr Ser Leu Asp 195 200 205 agt cct gtc acc gtg gag tgg aag gca cag tct gat tct gcc cag agt 672Ser Pro Val Thr Val Glu Trp Lys Ala Gln Ser Asp Ser Ala Gln Ser 210 215 220 aag aca ttg acg gga gct ggg ggc ttc gtg ctg ggg ctc atc atc tgt 720Lys Thr Leu Thr Gly Ala Gly Gly Phe Val Leu Gly Leu Ile Ile Cys 225 230 235 240 gga gtg ggc atc ttc atg cac agg agg agc aag aaa gtt caa cga gga 768Gly Val Gly Ile Phe Met His Arg Arg Ser Lys Lys Val Gln Arg Gly 245 250 255 tct gca taa 777Ser Ala 39258PRTHomo sapiens 39Met Met Val Leu Gln Val Ser Ala Ala Pro Arg Thr Val Ala Leu Thr 1 5 10 15 Ala Leu Leu Met Val Leu Leu Thr Ser Val Val Gln Gly Arg Ala Thr 20 25 30 Pro Glu Asn Tyr Val Tyr Gln Gly Arg Gln Glu Cys Tyr Ala Phe Asn 35 40 45 Gly Thr Gln Arg Phe Leu Glu Arg Tyr Ile Tyr Asn Arg Glu Glu Tyr 50 55 60 Ala Arg Phe Asp Ser Asp Val Gly Glu Phe Arg Ala Val Thr Glu Leu 65 70 75 80 Gly Arg Pro Ala Ala Glu Tyr Trp Asn Ser Gln Lys Asp Ile Leu Glu 85 90 95 Glu Lys Arg Ala Val Pro Asp Arg Val Cys Arg His Asn Tyr Glu Leu 100 105 110 Asp Glu Ala Val Thr Leu Gln Arg Arg Val Gln Pro Lys Val Asn Val 115 120 125 Ser Pro Ser Lys Lys Gly Pro Leu Gln His His Asn Leu Leu Val Cys 130 135 140 His Val Thr Asp Phe Tyr Pro Gly Ser Ile Gln Val Arg Trp Phe Leu 145 150 155 160 Asn Gly Gln Glu Glu Thr Ala Gly Val Val Ser Thr Asn Leu Ile Arg 165 170 175 Asn Gly Asp Trp Thr Phe Gln Ile Leu Val Met Leu Glu Met Thr Pro 180 185 190 Gln Gln Gly Asp Val Tyr Ile Cys Gln Val Glu His Thr Ser Leu Asp 195 200 205 Ser Pro Val Thr Val Glu Trp Lys Ala Gln Ser Asp Ser Ala Gln Ser 210 215 220 Lys Thr Leu Thr Gly Ala Gly Gly Phe Val Leu Gly Leu Ile Ile Cys 225 230 235 240 Gly Val Gly Ile Phe Met His Arg Arg Ser Lys Lys Val Gln Arg Gly 245 250 255 Ser Ala 40768DNAHomo sapiensCDS(1)..(768) 40atg atc cta aac aaa gct ctg ctg ctg ggg gcc ctc gct ctg acc acc 48Met Ile Leu Asn Lys Ala Leu Leu Leu Gly Ala Leu Ala Leu Thr Thr 1 5 10 15 gtg atg agc ccc tgt gga ggt gaa gac att gtg gct gac cac gtt gcc 96Val Met Ser Pro Cys Gly Gly Glu Asp Ile Val Ala Asp His Val Ala 20 25 30 tct tgt ggt gta aac ttg tac cag ttt tac ggt ccc tct ggc cag tac 144Ser Cys Gly Val Asn Leu Tyr Gln Phe Tyr Gly Pro Ser Gly Gln Tyr 35 40 45 acc cat gaa ttt gat gga gat gag gag ttc tac gtg gac ctg gag agg 192Thr His Glu Phe Asp Gly Asp Glu Glu Phe Tyr Val Asp Leu Glu Arg 50 55 60 aag gag act gcc tgg cgg tgg cct gag ttc agc aaa ttt gga ggt ttt 240Lys Glu Thr Ala Trp Arg Trp Pro Glu Phe Ser Lys Phe Gly Gly Phe 65 70 75 80 gac ccg cag ggt gca ctg aga aac atg gct gtg gca aaa cac aac ttg 288Asp Pro Gln Gly Ala Leu Arg Asn Met Ala Val Ala Lys His Asn Leu 85 90 95 aac atc atg att aaa cgc tac aac tct acc gct gct acc aat gag gtt 336Asn Ile Met Ile Lys Arg Tyr Asn Ser Thr Ala Ala Thr Asn Glu Val 100 105 110 cct gag gtc aca gtg ttt tcc aag tct ccc gtg aca ctg ggt cag ccc 384Pro Glu Val Thr Val Phe Ser Lys Ser Pro Val Thr Leu Gly Gln Pro 115 120 125 aac acc ctc att tgt ctt gtg gac aac atc ttt cct cct gtg gtc aac 432Asn Thr Leu Ile Cys Leu Val Asp Asn Ile Phe Pro Pro Val Val Asn 130 135 140 atc aca tgg ctg agc aat ggg cag tca gtc aca gaa ggt gtt tct gag 480Ile Thr Trp Leu Ser Asn Gly Gln Ser Val Thr Glu Gly Val Ser Glu 145 150 155 160 acc agc ttc ctc tcc aag agt gat cat tcc ttc ttc aag atc agt tac 528Thr Ser Phe Leu Ser Lys Ser Asp His Ser Phe Phe Lys Ile Ser Tyr 165 170 175 ctc acc ttc ctc cct tct gct gat gag att tat gac tgc aag gtg gag 576Leu Thr Phe Leu Pro Ser Ala Asp Glu Ile Tyr Asp Cys Lys Val Glu 180 185 190 cac tgg ggc ctg gac cag cct ctt ctg aaa cac tgg gag cct gag att 624His Trp Gly Leu Asp Gln Pro Leu Leu Lys His Trp Glu Pro Glu Ile 195 200 205 cca gcc cct atg tca gag ctc aca gag act gtg gtc tgc gcc ctg ggg 672Pro Ala Pro Met Ser Glu Leu Thr Glu Thr Val Val Cys Ala Leu Gly 210 215 220 ttg tct gtg ggc ctc gtg ggc att gtg gtg ggc act gtc ttc atc atc 720Leu Ser Val Gly Leu Val Gly Ile Val Val Gly Thr Val Phe Ile Ile 225 230 235 240 caa ggc ctg cgt tca gtt ggt gct tcc aga cac caa ggg cca ttg tga 768Gln Gly Leu Arg Ser Val Gly Ala Ser Arg His Gln Gly Pro Leu 245 250 255 41255PRTHomo sapiens 41Met Ile Leu Asn Lys Ala Leu Leu Leu Gly Ala Leu Ala Leu Thr Thr 1 5 10 15 Val Met Ser Pro Cys Gly Gly Glu Asp Ile Val Ala Asp His Val Ala 20 25 30 Ser Cys Gly Val Asn Leu Tyr Gln Phe Tyr Gly Pro Ser Gly Gln Tyr 35 40 45 Thr His Glu Phe Asp Gly Asp Glu Glu Phe Tyr Val Asp Leu Glu Arg 50 55 60 Lys Glu Thr Ala Trp Arg Trp Pro Glu Phe Ser Lys Phe Gly Gly Phe 65 70 75 80 Asp Pro Gln Gly Ala Leu Arg Asn Met Ala Val Ala Lys His Asn Leu 85 90 95 Asn Ile Met Ile Lys Arg Tyr Asn Ser Thr Ala Ala Thr Asn Glu Val 100 105 110 Pro Glu Val Thr Val Phe Ser Lys Ser Pro Val Thr Leu Gly Gln Pro 115 120 125 Asn Thr Leu Ile Cys Leu Val Asp Asn Ile Phe Pro Pro Val Val Asn 130 135 140 Ile Thr Trp Leu Ser Asn Gly Gln Ser Val Thr Glu Gly Val Ser Glu 145 150 155 160 Thr Ser Phe Leu Ser Lys Ser Asp His Ser Phe Phe Lys Ile Ser Tyr 165 170 175 Leu Thr Phe Leu Pro Ser Ala Asp Glu Ile Tyr Asp Cys Lys Val Glu 180 185 190 His Trp Gly Leu Asp Gln Pro Leu Leu Lys His Trp Glu Pro Glu Ile 195 200 205 Pro Ala Pro Met Ser Glu Leu Thr Glu Thr Val Val Cys Ala Leu Gly 210 215 220 Leu Ser Val Gly Leu Val Gly Ile Val Val Gly Thr Val Phe Ile Ile 225 230 235 240 Gln Gly Leu Arg Ser Val Gly Ala Ser Arg His Gln Gly Pro Leu 245 250 255 42786DNAHomo sapiensCDS(1)..(786) 42atg tct tgg aaa aag gct ttg cgg atc ccc gga ggc ctt cgg gca gca 48Met Ser Trp Lys Lys Ala Leu Arg Ile Pro Gly Gly Leu Arg Ala Ala 1 5 10 15 act gtg acc ttg atg ctg tcg atg ctg agc acc cca gtg gct gag ggc 96Thr Val Thr Leu Met Leu Ser Met Leu Ser Thr Pro Val Ala Glu Gly 20 25 30 aga gac tct ccc gag gat ttc gtg tac cag ttt aag ggc atg tgc tac 144Arg Asp Ser Pro Glu Asp Phe Val Tyr Gln Phe Lys Gly Met Cys Tyr 35 40 45 ttc acc aac ggg aca gag cgc gtg cgt ctt gtg agc aga agc atc tat 192Phe Thr Asn Gly Thr Glu Arg Val Arg Leu Val Ser Arg Ser Ile Tyr 50 55 60 aac cga gaa gag atc gtg cgc ttc gac agc gac gtg ggg gag ttc cgg 240Asn Arg Glu Glu Ile Val Arg Phe Asp Ser Asp Val Gly Glu Phe Arg 65 70 75 80 gcg gtg acg ctg ctg ggg ctg cct gcc gcc gag tac tgg aac agc cag 288Ala Val Thr Leu Leu Gly Leu Pro Ala Ala Glu Tyr Trp Asn Ser Gln 85 90 95 aag gac atc ctg gag agg aaa cgg gcg gcg gtg gac agg gtg tgc aga 336Lys Asp Ile Leu Glu Arg Lys Arg Ala Ala Val Asp Arg Val Cys Arg 100 105 110 cac aac tac cag ttg gag ctc cgc acg acc ttg cag cgg cga gtg gag 384His Asn Tyr Gln Leu Glu Leu Arg Thr Thr Leu Gln Arg Arg Val Glu 115 120 125 ccc aca gtg acc atc tcc cca tcc agg aca gag gcc ctc aac cac cac 432Pro Thr Val Thr Ile Ser Pro Ser Arg Thr Glu Ala Leu Asn His His 130 135 140 aac ctg ctg gtc tgc tcg gtg aca gat ttc tat cca gcc cag atc aaa 480Asn Leu Leu Val Cys Ser Val Thr Asp Phe Tyr Pro Ala Gln Ile Lys 145 150 155 160 gtc cgg tgg ttt cgg aat gac cag gag gag aca gct ggc gtt gtg tcc 528Val Arg Trp Phe Arg Asn Asp Gln Glu Glu Thr Ala Gly Val Val Ser 165 170 175 acc ccc ctt att agg aat ggt gac tgg acc ttc cag atc ctg gtg atg 576Thr Pro Leu Ile Arg Asn Gly Asp Trp Thr Phe Gln Ile Leu Val Met 180 185 190 ctg gaa atg act ccc cag cgt gga gac gtc tac acc tgc cac gtg gag 624Leu Glu Met Thr Pro Gln Arg Gly Asp Val Tyr Thr Cys His Val Glu 195 200 205 cac ccc agc ctc cag agc ccc atc acc gtg gag tgg cgg gct caa tct 672His Pro Ser Leu Gln Ser Pro Ile Thr Val Glu Trp Arg Ala Gln Ser 210 215 220 gaa tct gcc cag agc aag atg ctg agt ggc att gga ggc ttc gtg ctg 720Glu Ser Ala Gln Ser Lys Met Leu Ser Gly Ile Gly Gly Phe Val Leu

225 230 235 240 ggg ctg atc ttc ctc ggg ctg ggc ctt atc atc cat cac agg agt cag 768Gly Leu Ile Phe Leu Gly Leu Gly Leu Ile Ile His His Arg Ser Gln 245 250 255 aaa ggg ctc ctg cac tga 786Lys Gly Leu Leu His 260 43261PRTHomo sapiens 43Met Ser Trp Lys Lys Ala Leu Arg Ile Pro Gly Gly Leu Arg Ala Ala 1 5 10 15 Thr Val Thr Leu Met Leu Ser Met Leu Ser Thr Pro Val Ala Glu Gly 20 25 30 Arg Asp Ser Pro Glu Asp Phe Val Tyr Gln Phe Lys Gly Met Cys Tyr 35 40 45 Phe Thr Asn Gly Thr Glu Arg Val Arg Leu Val Ser Arg Ser Ile Tyr 50 55 60 Asn Arg Glu Glu Ile Val Arg Phe Asp Ser Asp Val Gly Glu Phe Arg 65 70 75 80 Ala Val Thr Leu Leu Gly Leu Pro Ala Ala Glu Tyr Trp Asn Ser Gln 85 90 95 Lys Asp Ile Leu Glu Arg Lys Arg Ala Ala Val Asp Arg Val Cys Arg 100 105 110 His Asn Tyr Gln Leu Glu Leu Arg Thr Thr Leu Gln Arg Arg Val Glu 115 120 125 Pro Thr Val Thr Ile Ser Pro Ser Arg Thr Glu Ala Leu Asn His His 130 135 140 Asn Leu Leu Val Cys Ser Val Thr Asp Phe Tyr Pro Ala Gln Ile Lys 145 150 155 160 Val Arg Trp Phe Arg Asn Asp Gln Glu Glu Thr Ala Gly Val Val Ser 165 170 175 Thr Pro Leu Ile Arg Asn Gly Asp Trp Thr Phe Gln Ile Leu Val Met 180 185 190 Leu Glu Met Thr Pro Gln Arg Gly Asp Val Tyr Thr Cys His Val Glu 195 200 205 His Pro Ser Leu Gln Ser Pro Ile Thr Val Glu Trp Arg Ala Gln Ser 210 215 220 Glu Ser Ala Gln Ser Lys Met Leu Ser Gly Ile Gly Gly Phe Val Leu 225 230 235 240 Gly Leu Ile Phe Leu Gly Leu Gly Leu Ile Ile His His Arg Ser Gln 245 250 255 Lys Gly Leu Leu His 260 441312DNAHomo sapiensCDS(110)..(874) 44ttttaatggt cagactctat tacaccccac attctctttt cttttattct tgtctgttct 60gcctcactcc cgagctctac tgactcccaa cagagcgccc aagaagaaa atg gcc ata 118 Met Ala Ile 1 agt gga gtc cct gtg cta gga ttt ttc atc ata gct gtg ctg atg agc 166Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val Leu Met Ser 5 10 15 gct cag gaa tca tgg gct atc aaa gaa gaa cat gtg atc atc cag gcc 214Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile Ile Gln Ala 20 25 30 35 gag ttc tat ctg aat cct gac caa tca ggc gag ttt atg ttt gac ttt 262Glu Phe Tyr Leu Asn Pro Asp Gln Ser Gly Glu Phe Met Phe Asp Phe 40 45 50 gat ggt gat gag att ttc cat gtg gat atg gca aag aag gag acg gtc 310Asp Gly Asp Glu Ile Phe His Val Asp Met Ala Lys Lys Glu Thr Val 55 60 65 tgg cgg ctt gaa gaa ttt gga cga ttt gcc agc ttt gag gct caa ggt 358Trp Arg Leu Glu Glu Phe Gly Arg Phe Ala Ser Phe Glu Ala Gln Gly 70 75 80 gca ttg gcc aac ata gct gtg gac aaa gcc aac ctg gaa atc atg aca 406Ala Leu Ala Asn Ile Ala Val Asp Lys Ala Asn Leu Glu Ile Met Thr 85 90 95 aag cgc tcc aac tat act ccg atc acc aat gta cct cca gag gta act 454Lys Arg Ser Asn Tyr Thr Pro Ile Thr Asn Val Pro Pro Glu Val Thr 100 105 110 115 gtg ctc aca aac agc cct gtg gaa ctg aga gag ccc aac gtc ctc atc 502Val Leu Thr Asn Ser Pro Val Glu Leu Arg Glu Pro Asn Val Leu Ile 120 125 130 tgt ttc ata gac aag ttc acc cca cca gtg gtc aat gtc acg tgg ctt 550Cys Phe Ile Asp Lys Phe Thr Pro Pro Val Val Asn Val Thr Trp Leu 135 140 145 cga aat gga aaa cct gtc acc aca gga gtg tca gag aca gtc ttc ctg 598Arg Asn Gly Lys Pro Val Thr Thr Gly Val Ser Glu Thr Val Phe Leu 150 155 160 ccc agg gaa gac cac ctt ttc cgc aag ttc cac tat ctc ccc ttc ctg 646Pro Arg Glu Asp His Leu Phe Arg Lys Phe His Tyr Leu Pro Phe Leu 165 170 175 ccc tca act gag gac gtt tac gac tgc agg gtg gag cac tgg ggc ttg 694Pro Ser Thr Glu Asp Val Tyr Asp Cys Arg Val Glu His Trp Gly Leu 180 185 190 195 gat gag cct ctt ctc aag cac tgg gag ttt gat gct cca agc cct ctc 742Asp Glu Pro Leu Leu Lys His Trp Glu Phe Asp Ala Pro Ser Pro Leu 200 205 210 cca gag act aca gag aac gtg gtg tgt gcc ctg ggc ctg act gtg ggt 790Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu Gly Leu Thr Val Gly 215 220 225 ctg gtg ggc atc att att ggg acc atc ttc atc atc aag gga ttg cgc 838Leu Val Gly Ile Ile Ile Gly Thr Ile Phe Ile Ile Lys Gly Leu Arg 230 235 240 aaa agc aat gca gca gaa cgc agg ggg cct ctg taa ggcacatgga 884Lys Ser Asn Ala Ala Glu Arg Arg Gly Pro Leu 245 250 ggtgatggtg tttcttagag agaagatcac tgaagaaact tctgctttaa tggctttaca 944aagctggcaa tattacaatc cttgacctca gtgaaagcag tcatcttcag cattttccag 1004ccctatagcc accccaagtg tggatatgcc tcttcgattg ctccgtactc taacatctag 1064ctggcttccc tgtctattgc cttttcctgt atctattttc ctctatttcc tatcatttta 1124ttatcaccat gcaatgcctc tggaataaaa catacaggag tctgtctctg ctatggaatg 1184ccccatgggg catctcttgt gtacttattg tttaaggttt cctcaaactg tgatttttct 1244gaacacaata aactattttg atgatcttgg gtggaaaaaa aaaaaaaaaa aaaaaaaaaa 1304aaaaaaaa 131245254PRTHomo sapiens 45Met Ala Ile Ser Gly Val Pro Val Leu Gly Phe Phe Ile Ile Ala Val 1 5 10 15 Leu Met Ser Ala Gln Glu Ser Trp Ala Ile Lys Glu Glu His Val Ile 20 25 30 Ile Gln Ala Glu Phe Tyr Leu Asn Pro Asp Gln Ser Gly Glu Phe Met 35 40 45 Phe Asp Phe Asp Gly Asp Glu Ile Phe His Val Asp Met Ala Lys Lys 50 55 60 Glu Thr Val Trp Arg Leu Glu Glu Phe Gly Arg Phe Ala Ser Phe Glu 65 70 75 80 Ala Gln Gly Ala Leu Ala Asn Ile Ala Val Asp Lys Ala Asn Leu Glu 85 90 95 Ile Met Thr Lys Arg Ser Asn Tyr Thr Pro Ile Thr Asn Val Pro Pro 100 105 110 Glu Val Thr Val Leu Thr Asn Ser Pro Val Glu Leu Arg Glu Pro Asn 115 120 125 Val Leu Ile Cys Phe Ile Asp Lys Phe Thr Pro Pro Val Val Asn Val 130 135 140 Thr Trp Leu Arg Asn Gly Lys Pro Val Thr Thr Gly Val Ser Glu Thr 145 150 155 160 Val Phe Leu Pro Arg Glu Asp His Leu Phe Arg Lys Phe His Tyr Leu 165 170 175 Pro Phe Leu Pro Ser Thr Glu Asp Val Tyr Asp Cys Arg Val Glu His 180 185 190 Trp Gly Leu Asp Glu Pro Leu Leu Lys His Trp Glu Phe Asp Ala Pro 195 200 205 Ser Pro Leu Pro Glu Thr Thr Glu Asn Val Val Cys Ala Leu Gly Leu 210 215 220 Thr Val Gly Leu Val Gly Ile Ile Ile Gly Thr Ile Phe Ile Ile Lys 225 230 235 240 Gly Leu Arg Lys Ser Asn Ala Ala Glu Arg Arg Gly Pro Leu 245 250 46801DNAHomo sapiensCDS(1)..(801) 46atg gtg tgt ctg aag ctc cct gga ggc tcc tgc atg aca gcg ctg aca 48Met Val Cys Leu Lys Leu Pro Gly Gly Ser Cys Met Thr Ala Leu Thr 1 5 10 15 gtg aca ctg atg gtg ctg agc tcc cca ctg gct ttg gct ggg gac acc 96Val Thr Leu Met Val Leu Ser Ser Pro Leu Ala Leu Ala Gly Asp Thr 20 25 30 cga cca cgt ttc ttg tgg cag ctt aag ttt gaa tgt cat ttc ttc aat 144Arg Pro Arg Phe Leu Trp Gln Leu Lys Phe Glu Cys His Phe Phe Asn 35 40 45 ggg acg gag cgg gtg cgg ttg ctg gaa aga tgc atc tat aac caa gag 192Gly Thr Glu Arg Val Arg Leu Leu Glu Arg Cys Ile Tyr Asn Gln Glu 50 55 60 gag tcc gtg cgc ttc gac agc gac gtg ggg gag tac cgg gcg gtg acg 240Glu Ser Val Arg Phe Asp Ser Asp Val Gly Glu Tyr Arg Ala Val Thr 65 70 75 80 gag ctg ggg cgg cct gat gcc gag tac tgg aac agc cag aag gac ctc 288Glu Leu Gly Arg Pro Asp Ala Glu Tyr Trp Asn Ser Gln Lys Asp Leu 85 90 95 ctg gag cag agg cgg gcc gcg gtg gac acc tac tgc aga cac aac tac 336Leu Glu Gln Arg Arg Ala Ala Val Asp Thr Tyr Cys Arg His Asn Tyr 100 105 110 ggg gtt ggt gag agc ttc aca gtg cag cgg cga gtt gag cct aag gtg 384Gly Val Gly Glu Ser Phe Thr Val Gln Arg Arg Val Glu Pro Lys Val 115 120 125 act gtg tat cct tca aag acc cag ccc ctg cag cac cac aac ctc ctg 432Thr Val Tyr Pro Ser Lys Thr Gln Pro Leu Gln His His Asn Leu Leu 130 135 140 gtc tgc tct gtg agt ggt ttc tat cca ggc agc att gaa gtc agg tgg 480Val Cys Ser Val Ser Gly Phe Tyr Pro Gly Ser Ile Glu Val Arg Trp 145 150 155 160 ttc cgg aac ggc cag gaa gag aag gct ggg gtg gtg tcc aca ggc ctg 528Phe Arg Asn Gly Gln Glu Glu Lys Ala Gly Val Val Ser Thr Gly Leu 165 170 175 atc cag aat gga gat tgg acc ttc cag acc ctg gtg atg ctg gaa aca 576Ile Gln Asn Gly Asp Trp Thr Phe Gln Thr Leu Val Met Leu Glu Thr 180 185 190 gtt cct cgg agt gga gag gtt tac acc tgc caa gtg gag cac cca agt 624Val Pro Arg Ser Gly Glu Val Tyr Thr Cys Gln Val Glu His Pro Ser 195 200 205 gtg acg agc cct ctc aca gtg gaa tgg aga gca cgg tct gaa tct gca 672Val Thr Ser Pro Leu Thr Val Glu Trp Arg Ala Arg Ser Glu Ser Ala 210 215 220 cag agc aag atg ctg agt gga gtc ggg ggc ttc gtg ctg ggc ctg ctc 720Gln Ser Lys Met Leu Ser Gly Val Gly Gly Phe Val Leu Gly Leu Leu 225 230 235 240 ttc ctt ggg gcc ggg ctg ttc atc tac ttc agg aat cag aaa gga cac 768Phe Leu Gly Ala Gly Leu Phe Ile Tyr Phe Arg Asn Gln Lys Gly His 245 250 255 tct gga ctt cag cca aca gga ttc ctg agc tga 801Ser Gly Leu Gln Pro Thr Gly Phe Leu Ser 260 265 47266PRTHomo sapiens 47Met Val Cys Leu Lys Leu Pro Gly Gly Ser Cys Met Thr Ala Leu Thr 1 5 10 15 Val Thr Leu Met Val Leu Ser Ser Pro Leu Ala Leu Ala Gly Asp Thr 20 25 30 Arg Pro Arg Phe Leu Trp Gln Leu Lys Phe Glu Cys His Phe Phe Asn 35 40 45 Gly Thr Glu Arg Val Arg Leu Leu Glu Arg Cys Ile Tyr Asn Gln Glu 50 55 60 Glu Ser Val Arg Phe Asp Ser Asp Val Gly Glu Tyr Arg Ala Val Thr 65 70 75 80 Glu Leu Gly Arg Pro Asp Ala Glu Tyr Trp Asn Ser Gln Lys Asp Leu 85 90 95 Leu Glu Gln Arg Arg Ala Ala Val Asp Thr Tyr Cys Arg His Asn Tyr 100 105 110 Gly Val Gly Glu Ser Phe Thr Val Gln Arg Arg Val Glu Pro Lys Val 115 120 125 Thr Val Tyr Pro Ser Lys Thr Gln Pro Leu Gln His His Asn Leu Leu 130 135 140 Val Cys Ser Val Ser Gly Phe Tyr Pro Gly Ser Ile Glu Val Arg Trp 145 150 155 160 Phe Arg Asn Gly Gln Glu Glu Lys Ala Gly Val Val Ser Thr Gly Leu 165 170 175 Ile Gln Asn Gly Asp Trp Thr Phe Gln Thr Leu Val Met Leu Glu Thr 180 185 190 Val Pro Arg Ser Gly Glu Val Tyr Thr Cys Gln Val Glu His Pro Ser 195 200 205 Val Thr Ser Pro Leu Thr Val Glu Trp Arg Ala Arg Ser Glu Ser Ala 210 215 220 Gln Ser Lys Met Leu Ser Gly Val Gly Gly Phe Val Leu Gly Leu Leu 225 230 235 240 Phe Leu Gly Ala Gly Leu Phe Ile Tyr Phe Arg Asn Gln Lys Gly His 245 250 255 Ser Gly Leu Gln Pro Thr Gly Phe Leu Ser 260 265 481122DNAHomo sapiensCDS(87)..(872) 48gatctaaggc caccctctcg gggagggagt tggggaagct gggttggctg ggttggtagc 60tcctacctac tgtgtggcaa gaaggt atg ggt cat gaa cag aac caa gga gct 113 Met Gly His Glu Gln Asn Gln Gly Ala 1 5 gcg ctg cta cag atg tta cca ctt ctg tgg ctg cta ccc cac tcc tgg 161Ala Leu Leu Gln Met Leu Pro Leu Leu Trp Leu Leu Pro His Ser Trp 10 15 20 25 gcc gtc cct gaa gct cct act cca atg tgg cca gat gac ctg caa aac 209Ala Val Pro Glu Ala Pro Thr Pro Met Trp Pro Asp Asp Leu Gln Asn 30 35 40 cac aca ttc ctg cac aca gtg tac tgc cag gat ggg agt ccc agt gtg 257His Thr Phe Leu His Thr Val Tyr Cys Gln Asp Gly Ser Pro Ser Val 45 50 55 gga ctc tct gag gcc tac gac gag gac cag ctt ttc ttc ttc gac ttt 305Gly Leu Ser Glu Ala Tyr Asp Glu Asp Gln Leu Phe Phe Phe Asp Phe 60 65 70 tcc cag aac act cgg gtg cct cgc ctg ccc gaa ttt gct gac tgg gct 353Ser Gln Asn Thr Arg Val Pro Arg Leu Pro Glu Phe Ala Asp Trp Ala 75 80 85 cag gaa cag gga gat gct cct gcc att tta ttt gac aaa gag ttc tgc 401Gln Glu Gln Gly Asp Ala Pro Ala Ile Leu Phe Asp Lys Glu Phe Cys 90 95 100 105 gag tgg atg atc cag caa ata ggg cca aaa ctt gat ggg aaa atc ccg 449Glu Trp Met Ile Gln Gln Ile Gly Pro Lys Leu Asp Gly Lys Ile Pro 110 115 120 gtg tcc aga ggg ttt cct atc gct gaa gtg ttc acg ctg aag ccc ctg 497Val Ser Arg Gly Phe Pro Ile Ala Glu Val Phe Thr Leu Lys Pro Leu 125 130 135 gag ttt ggc aag ccc aac act ttg gtc tgt ttt gtc agt aat ctc ttc 545Glu Phe Gly Lys Pro Asn Thr Leu Val Cys Phe Val Ser Asn Leu Phe 140 145 150 cca ccc atg ctg aca gtg aac tgg cag cat cat tcc gtc cct gtg gaa 593Pro Pro Met Leu Thr Val Asn Trp Gln His His Ser Val Pro Val Glu 155 160 165 gga ttt ggg cct act ttt gtc tca gct gtc gat gga ctc agc ttc cag 641Gly Phe Gly Pro Thr Phe Val Ser Ala Val Asp Gly Leu Ser Phe Gln 170 175 180 185 gcc ttt tct tac tta aac ttc aca cca gaa cct tct gac att ttc tcc 689Ala Phe Ser Tyr Leu Asn Phe Thr Pro Glu Pro Ser Asp Ile Phe Ser 190 195 200 tgc att gtg act cac gaa att gac cgc tac aca gca att gcc tat tgg 737Cys Ile Val Thr His Glu Ile Asp Arg Tyr Thr Ala Ile Ala Tyr Trp 205 210 215 gta ccc cgg aac gca ctg ccc tca gat ctg ctg gag aat gtg ctg tgt 785Val Pro Arg Asn Ala Leu Pro Ser Asp Leu Leu Glu Asn Val Leu Cys 220 225 230 ggc gtg gcc ttt ggc ctg ggt gtg ctg ggc atc atc gtg ggc

att gtt 833Gly Val Ala Phe Gly Leu Gly Val Leu Gly Ile Ile Val Gly Ile Val 235 240 245 ctc atc atc tac ttc cgg aag cct tgc tca ggt gac tga ttcttccaga 882Leu Ile Ile Tyr Phe Arg Lys Pro Cys Ser Gly Asp 250 255 260 ccagagtttg atgccagcag cttcggccat ccaaacagag gatgctcaga tttctcacat 942cctgcccagg atctcctctt agggtagaag tctctgggac atccctgggg tgtgtgtgta 1002gatttcccac ctggggactc tgctgtccct gggcttgcat cccagggatc ccagagtggc 1062ctgcctatca caaccacatc ccttcccccc acaaggcaat aaatctcatt tctttatatc 112249261PRTHomo sapiens 49Met Gly His Glu Gln Asn Gln Gly Ala Ala Leu Leu Gln Met Leu Pro 1 5 10 15 Leu Leu Trp Leu Leu Pro His Ser Trp Ala Val Pro Glu Ala Pro Thr 20 25 30 Pro Met Trp Pro Asp Asp Leu Gln Asn His Thr Phe Leu His Thr Val 35 40 45 Tyr Cys Gln Asp Gly Ser Pro Ser Val Gly Leu Ser Glu Ala Tyr Asp 50 55 60 Glu Asp Gln Leu Phe Phe Phe Asp Phe Ser Gln Asn Thr Arg Val Pro 65 70 75 80 Arg Leu Pro Glu Phe Ala Asp Trp Ala Gln Glu Gln Gly Asp Ala Pro 85 90 95 Ala Ile Leu Phe Asp Lys Glu Phe Cys Glu Trp Met Ile Gln Gln Ile 100 105 110 Gly Pro Lys Leu Asp Gly Lys Ile Pro Val Ser Arg Gly Phe Pro Ile 115 120 125 Ala Glu Val Phe Thr Leu Lys Pro Leu Glu Phe Gly Lys Pro Asn Thr 130 135 140 Leu Val Cys Phe Val Ser Asn Leu Phe Pro Pro Met Leu Thr Val Asn 145 150 155 160 Trp Gln His His Ser Val Pro Val Glu Gly Phe Gly Pro Thr Phe Val 165 170 175 Ser Ala Val Asp Gly Leu Ser Phe Gln Ala Phe Ser Tyr Leu Asn Phe 180 185 190 Thr Pro Glu Pro Ser Asp Ile Phe Ser Cys Ile Val Thr His Glu Ile 195 200 205 Asp Arg Tyr Thr Ala Ile Ala Tyr Trp Val Pro Arg Asn Ala Leu Pro 210 215 220 Ser Asp Leu Leu Glu Asn Val Leu Cys Gly Val Ala Phe Gly Leu Gly 225 230 235 240 Val Leu Gly Ile Ile Val Gly Ile Val Leu Ile Ile Tyr Phe Arg Lys 245 250 255 Pro Cys Ser Gly Asp 260 501412DNAHomo sapiensCDS(264)..(1055) 50atttgtccct gcctacctag ccaatctgtc cctgtttggg acactggact cccgtgagct 60ggaaggaaca gatttaatat ctaggggctg ggtatcccca catcactcat ttggggggtc 120aagggacccg ggcaatatag tattctgctc agtgtctgga gatcatctac ccaggctggg 180gcttctggga caggcgagga cccacggacc ctggaagagc tggtccaggg gactgaactc 240ccggcatctt tacagagcag agc atg atc aca ttc ctg ccg ctg ctg ctg ggg 293 Met Ile Thr Phe Leu Pro Leu Leu Leu Gly 1 5 10 ctc agc ctg ggc tgc aca gga gca ggt ggc ttc gtg gcc cat gtg gaa 341Leu Ser Leu Gly Cys Thr Gly Ala Gly Gly Phe Val Ala His Val Glu 15 20 25 agc acc tgt ctg ttg gat gat gct ggg act cca aag gat ttc aca tac 389Ser Thr Cys Leu Leu Asp Asp Ala Gly Thr Pro Lys Asp Phe Thr Tyr 30 35 40 tgc atc tcc ttc aac aag gat ctg ctg acc tgc tgg gat cca gag gag 437Cys Ile Ser Phe Asn Lys Asp Leu Leu Thr Cys Trp Asp Pro Glu Glu 45 50 55 aat aag atg gcc cct tgc gaa ttt ggg gtg ctg aat agc ttg gcg aat 485Asn Lys Met Ala Pro Cys Glu Phe Gly Val Leu Asn Ser Leu Ala Asn 60 65 70 gtc ctc tca cag cac ctc aac caa aaa gac acc ctg atg cag cgc ttg 533Val Leu Ser Gln His Leu Asn Gln Lys Asp Thr Leu Met Gln Arg Leu 75 80 85 90 cgc aat ggg ctt cag aat tgt gcc aca cac acc cag ccc ttc tgg gga 581Arg Asn Gly Leu Gln Asn Cys Ala Thr His Thr Gln Pro Phe Trp Gly 95 100 105 tca ctg acc aac agg aca cgg cca cca tct gtg caa gta gcc aaa acc 629Ser Leu Thr Asn Arg Thr Arg Pro Pro Ser Val Gln Val Ala Lys Thr 110 115 120 act cct ttt aac acg agg gag cct gtg atg ctg gcc tgc tat gtg tgg 677Thr Pro Phe Asn Thr Arg Glu Pro Val Met Leu Ala Cys Tyr Val Trp 125 130 135 ggc ttc tat cca gca gaa gtg act atc acg tgg agg aag aac ggg aag 725Gly Phe Tyr Pro Ala Glu Val Thr Ile Thr Trp Arg Lys Asn Gly Lys 140 145 150 ctt gtc atg cct cac agc agt gcg cac aag act gcc cag ccc aat gga 773Leu Val Met Pro His Ser Ser Ala His Lys Thr Ala Gln Pro Asn Gly 155 160 165 170 gac tgg aca tac cag acc ctc tcc cat tta gcc tta acc ccc tct tac 821Asp Trp Thr Tyr Gln Thr Leu Ser His Leu Ala Leu Thr Pro Ser Tyr 175 180 185 ggg gac act tac acc tgt gtg gta gag cac act ggg gct cct gag ccc 869Gly Asp Thr Tyr Thr Cys Val Val Glu His Thr Gly Ala Pro Glu Pro 190 195 200 atc ctt cgg gac tgg aca cct ggg ctg tcc ccc atg cag acc ctg aag 917Ile Leu Arg Asp Trp Thr Pro Gly Leu Ser Pro Met Gln Thr Leu Lys 205 210 215 gtt tct gtg tct gca gtg act ctg ggc ctg ggc ctc atc atc ttc tct 965Val Ser Val Ser Ala Val Thr Leu Gly Leu Gly Leu Ile Ile Phe Ser 220 225 230 ctt ggt gtg atc agc tgg cgg aga gct ggc cac tct agt tac act cct 1013Leu Gly Val Ile Ser Trp Arg Arg Ala Gly His Ser Ser Tyr Thr Pro 235 240 245 250 ctt cct ggg tcc aat tat tca gaa gga tgg cac att tcc tag 1055Leu Pro Gly Ser Asn Tyr Ser Glu Gly Trp His Ile Ser 255 260 aggcagaatc ctacaacttc cactccaagt gagaaggaga ttcaaactca atgatgctac 1115catgcctctc caacatcttc aaccccctga cattatcttg gatcctatgg tttctccatc 1175caattctttg aatttcccag tctcccctat gtaaaactta gcaacttggg ggacctcatt 1235cctgggacta tgctgtaacc aaattattgt ccaaggctat atttctggga tgaatataat 1295ctgaggaagg gagttaaaga ccctcctggg gctctcagtg tgccatagag gacagcaact 1355ggtgattgtt tcagagaaat aaactttggt ggaaatattg ttaaaaaaaa aaaaaaa 141251263PRTHomo sapiens 51Met Ile Thr Phe Leu Pro Leu Leu Leu Gly Leu Ser Leu Gly Cys Thr 1 5 10 15 Gly Ala Gly Gly Phe Val Ala His Val Glu Ser Thr Cys Leu Leu Asp 20 25 30 Asp Ala Gly Thr Pro Lys Asp Phe Thr Tyr Cys Ile Ser Phe Asn Lys 35 40 45 Asp Leu Leu Thr Cys Trp Asp Pro Glu Glu Asn Lys Met Ala Pro Cys 50 55 60 Glu Phe Gly Val Leu Asn Ser Leu Ala Asn Val Leu Ser Gln His Leu 65 70 75 80 Asn Gln Lys Asp Thr Leu Met Gln Arg Leu Arg Asn Gly Leu Gln Asn 85 90 95 Cys Ala Thr His Thr Gln Pro Phe Trp Gly Ser Leu Thr Asn Arg Thr 100 105 110 Arg Pro Pro Ser Val Gln Val Ala Lys Thr Thr Pro Phe Asn Thr Arg 115 120 125 Glu Pro Val Met Leu Ala Cys Tyr Val Trp Gly Phe Tyr Pro Ala Glu 130 135 140 Val Thr Ile Thr Trp Arg Lys Asn Gly Lys Leu Val Met Pro His Ser 145 150 155 160 Ser Ala His Lys Thr Ala Gln Pro Asn Gly Asp Trp Thr Tyr Gln Thr 165 170 175 Leu Ser His Leu Ala Leu Thr Pro Ser Tyr Gly Asp Thr Tyr Thr Cys 180 185 190 Val Val Glu His Thr Gly Ala Pro Glu Pro Ile Leu Arg Asp Trp Thr 195 200 205 Pro Gly Leu Ser Pro Met Gln Thr Leu Lys Val Ser Val Ser Ala Val 210 215 220 Thr Leu Gly Leu Gly Leu Ile Ile Phe Ser Leu Gly Val Ile Ser Trp 225 230 235 240 Arg Arg Ala Gly His Ser Ser Tyr Thr Pro Leu Pro Gly Ser Asn Tyr 245 250 255 Ser Glu Gly Trp His Ile Ser 260 523485DNAHomo sapiensCDS(77)..(829) 52cttcttcttt acctccgcct tgttcctgtc ctcaccacac ggactgagac tgatttgatt 60aaagcaccag agtgta atg gcc ctc aga gca ggg ctg gtc ctg ggg ttc cac 112 Met Ala Leu Arg Ala Gly Leu Val Leu Gly Phe His 1 5 10 acc ctg atg acc ctc ctg agc ccg cag gag gca ggg gcc acc aag gct 160Thr Leu Met Thr Leu Leu Ser Pro Gln Glu Ala Gly Ala Thr Lys Ala 15 20 25 gac cac atg ggc tcc tac gga ccc gcc ttc tac cag tct tac ggc gcc 208Asp His Met Gly Ser Tyr Gly Pro Ala Phe Tyr Gln Ser Tyr Gly Ala 30 35 40 tcg ggc cag ttc acc cat gaa ttt gat gag gaa cag ctg ttc tct gtg 256Ser Gly Gln Phe Thr His Glu Phe Asp Glu Glu Gln Leu Phe Ser Val 45 50 55 60 gac ctg aag aaa agc gag gcc gtg tgg cgt ctg cct gag ttt ggt gac 304Asp Leu Lys Lys Ser Glu Ala Val Trp Arg Leu Pro Glu Phe Gly Asp 65 70 75 ttt gcc cgc ttt gac ccg cag ggc ggg ctg gcc ggc atc gcc gca atc 352Phe Ala Arg Phe Asp Pro Gln Gly Gly Leu Ala Gly Ile Ala Ala Ile 80 85 90 aaa gcc cat ctg gac atc ctg gtg gag cgc tcc aac cgc agc aga gcc 400Lys Ala His Leu Asp Ile Leu Val Glu Arg Ser Asn Arg Ser Arg Ala 95 100 105 atc aac gtg cct cca cgg gtg acc gtg ctc ccc aag tct cgg gtg gag 448Ile Asn Val Pro Pro Arg Val Thr Val Leu Pro Lys Ser Arg Val Glu 110 115 120 ctg ggc cag ccc aac atc ctc atc tgc atc gtg gac aac atc ttc ccc 496Leu Gly Gln Pro Asn Ile Leu Ile Cys Ile Val Asp Asn Ile Phe Pro 125 130 135 140 cct gtg atc aat atc acc tgg ctg cgc aac ggc caa act gtc act gag 544Pro Val Ile Asn Ile Thr Trp Leu Arg Asn Gly Gln Thr Val Thr Glu 145 150 155 gga gtg gcc cag acc agc ttc tat tcc cag cct gac cat ttg ttc cgc 592Gly Val Ala Gln Thr Ser Phe Tyr Ser Gln Pro Asp His Leu Phe Arg 160 165 170 aag ttc cac tac ctg ccc ttc gtg ccc tca gcc gag gac gtc tat gac 640Lys Phe His Tyr Leu Pro Phe Val Pro Ser Ala Glu Asp Val Tyr Asp 175 180 185 tgc cag gtg gag cac tgg ggc ctg gat gcg cca ctc ctc agg cat tgg 688Cys Gln Val Glu His Trp Gly Leu Asp Ala Pro Leu Leu Arg His Trp 190 195 200 gag ctc cag gtg cct att cca cca cca gat gcc atg gag acc ctg gtc 736Glu Leu Gln Val Pro Ile Pro Pro Pro Asp Ala Met Glu Thr Leu Val 205 210 215 220 tgt gcc ctg ggc ctg gcc atc ggc ctg gtg ggc ttc ctc gtg ggc acc 784Cys Ala Leu Gly Leu Ala Ile Gly Leu Val Gly Phe Leu Val Gly Thr 225 230 235 gtc ctc atc atc atg ggc aca tat gtg tcc agt gtc ccc agg taa 829Val Leu Ile Ile Met Gly Thr Tyr Val Ser Ser Val Pro Arg 240 245 250 tgatccttct gagagaaatg acttgtggga gacaccctgc agatcctcat gggtttgtga 889cagcccctgc gtgctcagtg ccctttaagt gcatcccgct gtgctgactt tgagtgggat 949caacatctgt cctacgggtc ccctcttttt tggccccagt attcatggca gggtttgttg 1009gacacctact agcttccctt cccattcaac acacacacac attcttgctc tacccaaagc 1069tctggctggc agcactaaat gctttggtgg tgtttgcact gtgtcctttc caggccttgg 1129ccagttcttc caggggtgag gcatgtggtg ctggggattg gcagccatcc tggggcccac 1189acaggtgtgt cttgctccat ttggcccatt gtgtgttact ttgtgaatga gccatttcac 1249atggacttca tgaaatttgc ctcctgagtt caggtttacc ctgaaaggga tgcagattat 1309cctgttcctc acgaccccct cagctaacaa cagttctgaa gggtgctggg acaggacagg 1369ctcatgggga ctccactcct gcctgggttt actctgtatg aagaggccac tggtatcctg 1429ccatgatgtt atctcctttt tctacttttc cctagagtcc catgcatgat aaagagaggc 1489ccaaggcttg gataaggtgg ccacttccct cagtggagtc agtcatgtta ggtaggaggt 1549ggtagagtcg gtctgcgagg tatctcgtaa gaggggaggt ccacctagac acactctaaa 1609tatgtggcct agaagatttt ggtctacttt tctgtgaaca gaatttaaaa catacaaaga 1669gataaatcac cataccacat agtttatgtc aggaccaaaa tgagcaatac agattacggt 1729tttcaaacca gaatgcacat aagaactgct tgggatcctt ttaaaagtac aggcattggc 1789ctggtgcagt ggctcattcc tgtaatccca gcactttggg aggccaaggg gacaggactg 1849cttgaggcca agaggtggaa accatcttgg gctacataga gagaccccat ctctacaaag 1909aaagatttaa aaattaacca ggcatggtgg ctcgcacctg tattcccagc cactggggag 1969gctgaggccg gaggagtgct tgagcccagg agttcaaggc tgcagtgagc caagattgcg 2029ccactgcact ccagcctagg tgacagagtg agaccctgtc tctaaataaa taaataaata 2089aaatataaaa ataacagtca tcacccagac ctactgaatt agaatctcgg gagtgcaggg 2149ggcagcaaca gggaggctgt cttttctgag atggggtctc actctgtcac caggctggag 2209tgccatggca tgatctcagc tcactgcaac ctccacctcc tgagttcaag ccattctcct 2269gcctcagcct cctgagtagc tgggactaca ggtgtgcgcc actacactca gctaattttt 2329gtattttaag tagagacggg gtttcatcat gttggccagg atggcctcca tctcttgacc 2389tcgtgatcca cccaccttcc ctcccaaagt actggaatta caggcattag ccactgtgcc 2449cagccgaggc tgtcattttt aaccggctct ggatgactct gatgcagcca tcctggacct 2509tggctgtggt ctggtaactg gaacccagtg acgtaatcag gtgccatcgg gggtcatggg 2569aaagggggat ccccaaggtc tgaggtggac taggaaggct ttctgaagaa cctgggtctg 2629ttagggcatc agccaatcaa ggtacaagta aatagaggca aaatgagggt ttgaactgtg 2689agcagttggt cctggaaaag aaagaaacca agagattatg gggactcaat gggcttctta 2749agagagaata agttgaaatc aatgaccaga agaccctgat ggaagtggag gagaatcatc 2809tcaggcaaac tttttgtgtg ccagtaacag aaaccctctt tgtgtgatca catgcaaagt 2869ataggatatt tgcaatatag ccatggggag gagtgcaggg cccaagggta gattttagcc 2929aggcctccca ggaacagaac tcggatccga aaagcccaga gaagctagag ctgcccctcc 2989aacactctcg gatccacatg gtctgtgttc tctagacccc cctgcatgtt agcggtgttc 3049tctctctgtg gactgactgt ccttctcagt gaacatgtcc acccgacagc tcctgagttt 3109atatcatctc aaccctcaca acccacagag gctgtgtctc ctagtcacag ctttaaatta 3169ctggaaaaat aaatgactgg ccaaacttgg agcaggtgtc catcccagcc ctgtgtagtt 3229agagcaggaa tcaagatctc aacacaaatg tggctgccaa gcactcagcc ccggggcgag 3289gggtcaagtt cttctcagag aaagaggaat aagttggttc tcagaagaca tcacaagata 3349cgtgtgtacc caacaatctc tgatctctgc tgatcttttg cttagacgtt aacttgatgc 3409atcattggaa aggtgtttct ctcatctctg tcctaaggct tgataaagtc attaaaattg 3469tgttcttttg actaaa 348553250PRTHomo sapiens 53Met Ala Leu Arg Ala Gly Leu Val Leu Gly Phe His Thr Leu Met Thr 1 5 10 15 Leu Leu Ser Pro Gln Glu Ala Gly Ala Thr Lys Ala Asp His Met Gly 20 25 30 Ser Tyr Gly Pro Ala Phe Tyr Gln Ser Tyr Gly Ala Ser Gly Gln Phe 35 40 45 Thr His Glu Phe Asp Glu Glu Gln Leu Phe Ser Val Asp Leu Lys Lys 50 55 60 Ser Glu Ala Val Trp Arg Leu Pro Glu Phe Gly Asp Phe Ala Arg Phe 65 70 75 80 Asp Pro Gln Gly Gly Leu Ala Gly Ile Ala Ala Ile Lys Ala His Leu 85 90 95 Asp Ile Leu Val Glu Arg Ser Asn Arg Ser Arg Ala Ile Asn Val Pro 100 105 110 Pro Arg Val Thr Val Leu Pro Lys Ser Arg Val Glu Leu Gly Gln Pro 115 120 125 Asn Ile Leu Ile Cys Ile Val Asp Asn Ile Phe Pro Pro Val Ile Asn 130 135 140 Ile Thr Trp Leu Arg Asn Gly Gln Thr Val Thr Glu Gly Val Ala Gln 145 150 155 160 Thr Ser Phe Tyr Ser Gln Pro Asp His Leu Phe Arg Lys Phe His Tyr 165 170 175 Leu Pro Phe Val Pro Ser Ala Glu Asp Val Tyr Asp Cys Gln Val Glu 180 185 190 His Trp Gly Leu Asp Ala Pro Leu Leu Arg His Trp Glu Leu Gln Val 195 200 205 Pro Ile Pro Pro Pro Asp Ala Met Glu Thr Leu Val Cys Ala Leu Gly 210 215 220 Leu Ala Ile Gly Leu Val Gly Phe Leu Val Gly Thr Val Leu Ile Ile 225 230 235 240 Met Gly Thr Tyr Val Ser Ser Val Pro Arg 245 250 541388DNAHomo sapiensCDS(98)..(919) 54gatttatact cttaatgggt actttctgac tgaattttat

gagctcattc tgaagaggct 60gacgatttta ctatctcatt tttttccttt ctccaga atg ggt tct ggg tgg gtc 115 Met Gly Ser Gly Trp Val 1 5 ccc tgg gtg gtg gct ctg cta gtg aat ctg acc cga ctg gat tcc tcc 163Pro Trp Val Val Ala Leu Leu Val Asn Leu Thr Arg Leu Asp Ser Ser 10 15 20 atg act caa ggc aca gac tct cca gaa gat ttt gtg att cag gca aag 211Met Thr Gln Gly Thr Asp Ser Pro Glu Asp Phe Val Ile Gln Ala Lys 25 30 35 gct gac tgt tac ttc acc aac ggg aca gaa aag gtg cag ttt gtg gtc 259Ala Asp Cys Tyr Phe Thr Asn Gly Thr Glu Lys Val Gln Phe Val Val 40 45 50 aga ttc atc ttt aac ttg gag gag tat gta cgt ttc gac agt gat gtg 307Arg Phe Ile Phe Asn Leu Glu Glu Tyr Val Arg Phe Asp Ser Asp Val 55 60 65 70 ggg atg ttt gtg gca ttg acc aag ctg ggg cag cca gat gct gag cag 355Gly Met Phe Val Ala Leu Thr Lys Leu Gly Gln Pro Asp Ala Glu Gln 75 80 85 tgg aac agc cgg ctg gat ctc ttg gag agg agc aga cag gcc gtg gat 403Trp Asn Ser Arg Leu Asp Leu Leu Glu Arg Ser Arg Gln Ala Val Asp 90 95 100 ggg gtc tgt aga cac aac tac agg ctg ggc gca ccc ttc act gtg ggg 451Gly Val Cys Arg His Asn Tyr Arg Leu Gly Ala Pro Phe Thr Val Gly 105 110 115 aga aaa gtg caa cca gag gtg aca gtg tac cca gag agg acc cca ctc 499Arg Lys Val Gln Pro Glu Val Thr Val Tyr Pro Glu Arg Thr Pro Leu 120 125 130 ctg cac cag cat aat ctg ctg cac tgc tct gtg aca ggc ttc tat cca 547Leu His Gln His Asn Leu Leu His Cys Ser Val Thr Gly Phe Tyr Pro 135 140 145 150 ggg gat atc aag atc aag tgg ttc ctg aat ggg cag gag gag aga gct 595Gly Asp Ile Lys Ile Lys Trp Phe Leu Asn Gly Gln Glu Glu Arg Ala 155 160 165 ggg gtc atg tcc act ggc cct atc agg aat gga gac tgg acc ttt cag 643Gly Val Met Ser Thr Gly Pro Ile Arg Asn Gly Asp Trp Thr Phe Gln 170 175 180 act gtg gtg atg cta gaa atg act cct gaa ctt gga cat gtc tac acc 691Thr Val Val Met Leu Glu Met Thr Pro Glu Leu Gly His Val Tyr Thr 185 190 195 tgc ctt gtc gat cac tcc agc ctg ctg agc cct gtt tct gtg gag tgg 739Cys Leu Val Asp His Ser Ser Leu Leu Ser Pro Val Ser Val Glu Trp 200 205 210 aga gct cag tct gaa tat tct tgg aga aag atg ctg agt ggc att gca 787Arg Ala Gln Ser Glu Tyr Ser Trp Arg Lys Met Leu Ser Gly Ile Ala 215 220 225 230 gcc ttc cta ctt ggg cta atc ttc ctt ctg gtg gga atc gtc atc cag 835Ala Phe Leu Leu Gly Leu Ile Phe Leu Leu Val Gly Ile Val Ile Gln 235 240 245 cta agg gct cag aaa gga tat gtg agg acg cag atg tct ggt aat gag 883Leu Arg Ala Gln Lys Gly Tyr Val Arg Thr Gln Met Ser Gly Asn Glu 250 255 260 gtc tca aga gct gtt ctg ctc cct cag tca tgc taa ggtcctcact 929Val Ser Arg Ala Val Leu Leu Pro Gln Ser Cys 265 270 gaagcttctc tctctggagc ctgaagtagt gatgagtagt ctgggccctg ggtgaggtaa 989aggacattca tgaggtcaat gttctgggaa taactctctt ccctgatcct tggaggagcc 1049cgaactgatt ctggagctct gtgttctgag atcatgcatc tcccacccat ctgcccttct 1109cccttctacg tgtacatcat taatccccat tgccaagggc attgtccaga aactcccctg 1169agaccttact ccttccagcc ccaaatcatt tacttttctg tggtccagcc ctactcctat 1229aagtcatgat ctccaaagct ttctgtcttc caactgcagt ctccacagtc ttcagaagac 1289aaatgctcag gtagtcactg tttccttttc actgttttta aaaacctttt attgtcaaat 1349aaaatggaga tacaaaaaat gtaaaaaaaa aaaaaaaaa 138855273PRTHomo sapiens 55Met Gly Ser Gly Trp Val Pro Trp Val Val Ala Leu Leu Val Asn Leu 1 5 10 15 Thr Arg Leu Asp Ser Ser Met Thr Gln Gly Thr Asp Ser Pro Glu Asp 20 25 30 Phe Val Ile Gln Ala Lys Ala Asp Cys Tyr Phe Thr Asn Gly Thr Glu 35 40 45 Lys Val Gln Phe Val Val Arg Phe Ile Phe Asn Leu Glu Glu Tyr Val 50 55 60 Arg Phe Asp Ser Asp Val Gly Met Phe Val Ala Leu Thr Lys Leu Gly 65 70 75 80 Gln Pro Asp Ala Glu Gln Trp Asn Ser Arg Leu Asp Leu Leu Glu Arg 85 90 95 Ser Arg Gln Ala Val Asp Gly Val Cys Arg His Asn Tyr Arg Leu Gly 100 105 110 Ala Pro Phe Thr Val Gly Arg Lys Val Gln Pro Glu Val Thr Val Tyr 115 120 125 Pro Glu Arg Thr Pro Leu Leu His Gln His Asn Leu Leu His Cys Ser 130 135 140 Val Thr Gly Phe Tyr Pro Gly Asp Ile Lys Ile Lys Trp Phe Leu Asn 145 150 155 160 Gly Gln Glu Glu Arg Ala Gly Val Met Ser Thr Gly Pro Ile Arg Asn 165 170 175 Gly Asp Trp Thr Phe Gln Thr Val Val Met Leu Glu Met Thr Pro Glu 180 185 190 Leu Gly His Val Tyr Thr Cys Leu Val Asp His Ser Ser Leu Leu Ser 195 200 205 Pro Val Ser Val Glu Trp Arg Ala Gln Ser Glu Tyr Ser Trp Arg Lys 210 215 220 Met Leu Ser Gly Ile Ala Ala Phe Leu Leu Gly Leu Ile Phe Leu Leu 225 230 235 240 Val Gly Ile Val Ile Gln Leu Arg Ala Gln Lys Gly Tyr Val Arg Thr 245 250 255 Gln Met Ser Gly Asn Glu Val Ser Arg Ala Val Leu Leu Pro Gln Ser 260 265 270 Cys 564507DNAArtificial SequenceSynthetic 56ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120aggggttcct gcggccgcgg tcgagtatca agttgctttc tgtcccggca gaggaagcca 180gatcgctgag ggtccggtct ccagtttgcc tcctgctata tccattggaa gagaaaagtt 240tgtgacttgg gcccccaagt tttgagagaa ctgggctttc ggcgcggggg gacagaggag 300gctcgtgggg aggtgagtgg acctcctgga tcgatttagg aggctcgggt gggactggga 360ccaatcgcac ctttgttgag ccgtcactca ttatggggag cccctcccaa caaccatagc 420gaatatttat tgagctccac gcttagcaga tcccccgata agctatgtac agacataatt 480cgttgtaggt ctcatttcca cattttgtcg tggaggaaac tgaggctcaa aggttaagtc 540acgtgcccaa gttctcacgg cctataaatt gagggattcg aacccagaca gctgacccca 600gagccccggc ttttttttcc tttctttttt tttttttttt ttttttttga gacagagtct 660tgctctgtcg ccccagctac agtgcagtgg tgcgatctct gctcaccgca acctccacct 720cccgagttca agcaattctg cctcagcctc ccgagtagct gggatcacag gcgcccgcca 780ccgcgcttgg ctaatttttg tatttttagt acagatgggg tttcaccatg gtggccagcc 840tggtctcgaa ctcctgacct catgatccac cctcctcggc ctcccaaagt gctgggatta 900cagccgtgag ccactgtgcc ctgccagagc ccaggctctt aaacattgca cattgtaggt 960gctttggtgg tggggaatgg tagacctcga aagcagttgg actctggttt tcatttccct 1020ggctctggta attaacctgg acctcagttt acccaccctc acagtgcaag gctaggtatg 1080cagtcggtgc ctactttatt ataactgttg ataattattg tcatctctcc ccttctgaca 1140cctccgccag ctttccccat ctagataact tcgtataatg tatgctatac gaagttatgg 1200atccatcgat tctgcgatcg ctccggtgcc cgtcagtggg cagagcgcac atcgcccaca 1260gtccccgaga agttgggggg aggggtcggc aattgaaccg gtgcctagag aaggtggcgc 1320ggggtaaact gggaaagtga tgtcgtgtac tggctccgcc tttttcccga gggtggggga 1380gaaccgtata taagtgcagt agtcgccgtg aacgttcttt ttcgcaacgg gtttgccgcc 1440agaacacagc tgaagcttcc accatgccca cgctactgcg ggtttatata gacggtcccc 1500acgggatggg gaaaaccacc accacgcaac tgctggtggc cctgggttcg cgcgacgata 1560tcgtctacgt acccgagccg atgacttact ggcgggtgct gggggcttcc gagacaatcg 1620cgaacatcta caccacacaa caccgcctcg accagggtga gatatcggcc ggggacgcgg 1680cggtggtaat gacaagcgcc cagataacaa tgggcatgcc ttatgccgtg accgacgccg 1740ttctggctcc tcatatcggg ggggaggctg ggagctcaca tgccccgccc ccggccctca 1800ccctcatctt cgaccgccat cccatcgccg ccctcctgtg ctacccggcc gcgcggtacc 1860ttatgggcag catgaccccc caggccgtgc tggcgttcgt ggccctcatc ccgccgacct 1920tgcccggcac caacatcgtg cttggggccc ttccggagga cagacacatc gaccgcctgg 1980ccaaacgcca gcgccccggc gagcggctgg acctggctat gctggctgcg attcgccgcg 2040tttacgggct acttgccaat acggtgcggt atctgcagtg cggcgggtcg tggcgggagg 2100actggggaca gctttcgggg acggccgtgc cgccccaggg tgccgagccc cagagcaacg 2160cgggcccacg accccatatc ggggacacgt tatttaccct gtttcgggcc cccgagttgc 2220tggcccccaa cggcgacctg tataacgtgt ttgcctgggc cttggacgtc ttggccaaac 2280gcctccgttc catgcacgtc tttatcctgg attacgacca atcgcccgcc ggctgccggg 2340acgccctgct gcaacttacc tccgggatgg tccagaccca cgtcaccacc cccggctcca 2400taccgacgat atgcgacctg gcgcgcacgt ttgcccggga gatgggatcg gccattgaac 2460aagatggatt gcacgcaggt tctccggccg cttgggtgga gaggctattc ggctatgact 2520gggcacaaca gacaatcggc tgctctgatg ccgccgtgtt ccggctgtca gcgcaggggc 2580gcccggttct ttttgtcaag accgacctgt ccggtgccct gaatgaactg caggacgagg 2640cagcgcggct atcgtggctg gccacgacgg gcgttccttg cgcagctgtg ctcgacgttg 2700tcactgaagc gggaagggac tggctgctat tgggcgaagt gccggggcag gatctcctgt 2760catctcacct tgctcctgcc gagaaagtat ccatcatggc tgatgcaatg cggcggctgc 2820atacgcttga tccggctacc tgcccattcg accaccaagc gaaacatcgc atcgagcgag 2880cacgtactcg gatggaagcc ggtcttgtcg atcaggatga tctggacgaa gagcatcagg 2940ggctcgcgcc agccgaactg ttcgccaggc tcaaggcgcg catgcccgac ggcgaggatc 3000tcgtcgtgac ccatggcgat gcctgcttgc cgaatatcat ggtggaaaat ggccgctttt 3060ctggattcat cgactgtggc cggctgggtg tggcggaccg ctatcaggac atagcgttgg 3120ctacccgtga tattgctgaa gagcttggcg gcgaatgggc tgaccgcttc ctcgtgcttt 3180acggtatcgc cgctcccgat tcgcagcgca tcgccttcta tcgccttctt gacgagttct 3240tctgagggtc tctagcataa cttcgtataa tgtatgctat acgaagttat aataaaagat 3300ccttattttc attggatctg tgtgttggtt ttttgtgtgg gatccgttga ctgagtcgac 3360ggagcttacc cagcctgcag aagacctcat ccagacccag cagacccctg cctcagaact 3420tggggaccct gaagaccccg gagaggaggc tgcagatggc tcagacactg tggtcctcag 3480tctctttccc tgcacccctg agcctgtgaa tcctgaaccg gatgccagtg tttcctctcc 3540acagggtagg atacctcctc tgggattagc cctctgggat tccatgatga tggaatgtca 3600ggcctcacat ggaacctgtg tcttgctttc gtttttgttt tgttttgttt tgttgttttt 3660tgagatggag ttttgctctt gttgcccatg ctggagtgca atggcgtgat ctcagctcac 3720tgcaacctct gcctcctggg ttcaactgat tctcctgtct cagcctcctg agtagctggg 3780attacaggct tccgccacta cgcccagcta attttttggg tatttttagt agagacgggg 3840tttcaccatg ttggccaggc tggtcttgaa ctcctgacct caggtgatcc gcccacctcg 3900gcctcccaaa gtgctgggat tacaggcatg agccactgtg cccggcctgt ttttgttttt 3960tgatacaggg tctcgctctg ttactaaggc tggagtgcag tgatgcaatc atagttcact 4020gcagcctcaa cttcctgggc tgaagccatc actcagcctc cctaggagct gggactatag 4080gcatgcaacc acacctggct aatttttttt ttttttttgg gaggctggtc tccacctcct 4140gggctcaagt gatctgcagg cctccacttc cgaaagtgct gggattacag gtgtgagcca 4200cagtgcccgg cccttcacac ctgtttttaa ctctttgagg gtagatagct aggagtgaaa 4260ttactgggtc agatggtcat cctgttttac ttactgagga actgaggatt tatttttgat 4320tggagtccaa gaatatgcct aatttaggcg gccgatcact agtgaattcg cggccgcagg 4380aacccctagt gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg 4440ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag 4500cgcgcag 4507

Claims

1. An isolated cell comprising a genetically engineered disruption in a human leukocyte antigen (HLA) class II-related gene, wherein the cell is a primate cell.

2. The cell of claim 1, wherein the HLA class II-related gene is selected from the group consisting of regulatory factor X-associated ankyrin-containing protein (RFXANK) (SEQ ID NO: 24-27), regulatory factor 5 (RFX5) (SEQ ID NO: 28-31), regulatory factor X-associated protein (RFXAP) (SEQ ID NO: 32-33), class II transactivator (CIITA) (SEQ ID NO: 34-35), HLA-DPA (α chain) (SEQ ID NO: 36-37), HLA-DPB (β chain) (SEQ ID NO: 38-39), HLA-DQA (SEQ ID NO: 40-41), HLA-DQB (SEQ ID NO: 42-43), HLA-DRA (SEQ ID NO: 44-45), HLA-DRB (SEQ ID NO: 46-47), HLA-DMA (SEQ ID NO: 48-49), HLA-DMB (SEQ ID NO: 50-51), HLA-DOA (SEQ ID NO: 52-53) and HLA-DOB (SEQ ID NO: 54-55).

3. The cell of claim 2, wherein the cell comprises genetically engineered disruptions in at least two, at least three, or in all four of the HLA class II-related genes.

4. The cell of claim 1, wherein the HLA class II-related gene is regulatory factor X-associated ankyrin-containing protein (RFXANK) (SEQ ID NO: 24-27).

5. The cell of claim 1, wherein the cell comprises genetically engineered disruptions in all copies of the HLA class II-related gene.

6. The cell of claim 1, wherein the cell further comprises one or more recombinant immunomodulatory genes, each capable of expressing an immunomodulatory polypeptide in the human cell.

7. The cell of claim 6, wherein the one or more immunomodulatory genes comprise a polynucleotide capable of encoding a single chain fusion HLA class II protein, or an HLA class II protein.

8. The cell of claim 1, wherein the cell further comprises a genetically engineered disruption in the β2-microglobulin (B2M) gene (SEQ ID NO: 1).

9. An isolated cell comprising (a) a genetically engineered disruption in a beta-2 microglobulin (B2M) gene (SEQ ID NO: 1); and (b) one or more polynucleotides capable of encoding a single chain fusion HLA class II protein or an HLA class II protein; wherein the cell is a primate cell.

10. (canceled)

11. The cell of claim 7, wherein the one or more immunomodulatory genes comprise a polynucleotide capable of encoding one or more single chain fusion HLA class II proteins, and wherein the one or more single chain fusion HLA class II proteins comprises at least a portion of an HLA class II gene α chain covalently linked to at least a portion of an HLA class II gene β chain, wherein the HLA class II gene is selected from the group consisting of HLA-DP (SEQ ID NO: 36-39), HLA-DQ (SEQ ID NO: 40-43), HLA-DR (SEQ ID NO: 44-47), HLA-DM (SEQ ID NO: 48-51), and HLA-DO (SEQ ID NO: 52-55).

12. The cell of claim 11, wherein the single chain fusion HLA class II protein comprises a plurality of different single chain fusion HLA class II proteins

13. The cell of claim 11, wherein the single chain fusion HLA class II protein comprises one or more of: a. at least a portion of HLA-DQ α chain (SEQ ID NO: 41) and at least a portion of HLA-DQ (3 chain (SEQ ID NO: 43); and b. at least a portion of HLA-DQ α chain allele HLA-DQA1*01 (SEQ ID NO: 41) and at least a portion of HLA-DQ β chain allele HLA-DQB1*02 (SEQ ID NO: 43).

14. (canceled)

15. The cell of claim 11 wherein the single chain fusion HLA class II protein presents a first target peptide antigen on the cell surface.

16. The cell of claim 15 wherein the first target peptide antigen is covalently linked to the single chain fusion HLA class II protein.

17. (canceled)

18. The cell of claim 8, wherein the cell further comprises a polynucleotide capable of encoding a single chain fusion HLA class I protein.

19. The cell of claim 18, wherein the single chain fusion HLA class I protein comprises one or more of: a. at least a portion of B2M (SEQ ID NO: 2) covalently linked to at least a portion of an HLA class I α chain selected from the group consisting of HLA-A (SEQ ID NO: 4), HLA-B (SEQ ID NO: 6), HLA-C (SEQ ID NO: 8), HLA-E (SEQ ID NO: 10), HLA-F (SEQ ID NO: 12) and HLA-G (SEQ ID NO: 14); b. at least a portion of B2M (SEQ ID NO: 2) covalently linked to at least a portion of HLA-A (SEQ ID NO: 3); and c. at least a portion of B2M covalently linked to at least a portion of HLA-A0201 (SEQ ID NO: 4).

20.-27. (canceled)

28. The cell of any claim 1, wherein the cell is a stem cell.

29-32. (canceled)

33. The cell of claim 1, wherein the cell is a human cell.

34. A vaccine comprising the cell of claim 16, wherein the vaccine is capable of eliciting in a primate an immune response specific for the first and/or second target peptide antigen.

35. (canceled)

36. A method of transplantation in a patient in need thereof comprising the step of administering to the patient an effective amount of the cell of claim 1.

37-39. (canceled)

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