Multifunctional Aptamer-Nucleic Acid Nanostructures for Tumor-Targeted Killing

Abstract

The present invention provides compositions comprising a ligand-nucleic acid nanostructure that promote tumor cell-specific killing and methods of using the compositions. Specially, the invention provides aptamer-nucleic acid nanostructures for treating tumors in a mammal. The methods of making the compositions are also provided.

Description

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. Provisional Application No. 61/253,389 filed Oct. 20, 2009, which is incorporated by reference in its entirety.

[0002] The sequence listing submitted herewith is incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0003] The present invention relates to the fields of cell biology, tumor biology, nucleic acid-based tiling arrays, nanotechnology, and related fields.

BACKGROUND OF THE INVENTION

[0004] Despite decades of research efforts, cancer remains today's most pressing health concerns. Current cancer therapies primarily focus on surgical resection, radiotherapy, and chemotherapy. Radiation therapy and many chemotherapeutic compounds trigger the intrinsic apoptotic pathway by inducing DNA damage and cellular stress, which block DNA replication and inhibit tumor cell division. These conventional therapies, however, often cause systemic toxicity and become ineffective when resistant tumors emerge.

[0005] Recently, attention has been focused on a new generation of drugs targeting tumor-related biological molecules, such as Traztuzumab, a monoclonal antibody that targets the human epidermal growth factor receptor (HER-2) in breast cancer. In addition, induction of extrinsic apoptotic pathway has been noted as a promising approach of tumor therapy. Tumor necrosis factor (TNF) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) are recently discovered targeted therapeutics. TRAIL is a member of the tumor necrosis factor (TNF) cytokine family that induces apoptosis upon binding to its death domain containing receptors TNF receptor (TNFR), TRAIL receptor 1 (TRAIL-R1, also known as death receptor 4 or DR4) and TRAIL receptor 2 (TRAIL-R2, also known as death receptor 5 or DRS). TRAIL binds to TRAIL-R1 and TRAIL-R2 and triggers TRAIL-induced apoptosis. Upon binding to their respective receptors, TNF and TRAIL trigger trimerization of the death receptors and recruitment of death domain-containing mediator proteins. The cascade of protein activation leads to the activation of the initiator caspase, caspase 8, and subsequently the effector caspases, which act on the death substrate in apoptosis.

[0006] So far, five TRAIL receptors have been discovered: two are agonist receptors TRAIL-R1 and TRAIL-R2 and three are antagonistic receptors TRAIL-R3 (also known as decoy receptor 1, DcR1), TRAIL-R4 (DcR2) and osteoprotegerin. DcR1 and DcR2 as decoy membrane receptors can bind to TRAIL, but cannot transmit the apoptotic signal because they do not contain functional intracellular death domains. Osteoprotegerin is a secreted TNF receptor family member and may be a soluble antagonist receptor for TRAIL.

[0007] Tumor therapy using purified recombinant TRAIL has entered clinical trials. The prospects of recombinant TRAIL anti-cancer therapy, however, have been dampened by reports of hepatotoxicity and tumor resistance. Although TRAIL preferentially induces apoptosis in cancerous cells than normal cells, not all tumor cells are sensitive to TRAIL. The basis for the resistance may be multifaceted, ranging from the competition of decoy receptors for TRAIL binding to up-regulation of NF-.kappa.B, an anti-apoptosis factor induced by TRAIL signaling. Though it has been proposed that combination of recombinant TRAIL therapy with traditional chemotherapy or radiation therapy may overcome TRAIL resistance, the non-selective nature of the conventional therapies may cause damages to normal cells.

[0008] TRAIL-R1 and TRAIL-R2 agonistic antibodies have been developed and under clinical trials with the hope that the specificity for death receptors may eliminate tumor resistance resulted from decoy receptor competition. The generation of antibodies or humanized antibodies, however, is time consuming and cumbersome. In addition, tumor resistance caused by death receptor mutations that abolish antibody binding to the receptors has been reported. See Lee et al. 1999, Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers, Cancer Research 59(22):5683-6, and Dechant et al., 2004, Mutation analysis of the apoptotic "death-receptors" and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines, Int. J. Cancer 109:661-667.

[0009] Thus, there exists a need in the art for a more effective and adaptable anti-tumor therapy based on the death receptors induced extrinsic apoptosis pathway.

SUMMARY OF THE INVENTION

[0010] In one aspect, the present invention provides compositions comprising a first ligand that is specific for binding to a tumor cell, and a second ligand that is specific for binding to a death receptor on the tumor cell, wherein the first and second ligands are bound to a nucleic acid nanostructure. In certain preferred embodiments, the first ligand is a first aptamer, and the second ligand is a second aptamer. In certain preferred embodiments, the first and second aptamers are linked by one or more linker oligonucleotides to form one or more multispecific aptamers wherein the first and second aptamers are separated by 15-45 nucleotides, more preferably 30-45 nucleotides (or 5-15 nm, more preferably 10-15 nm in spacing) in the multispecific aptamer. In certain preferred embodiments, the first aptamer is specific for binding to a tumor antigen on the surface of the tumor cell. In certain other preferred embodiments, the tumor antigen is CD.sub.20 (GenBank Accession No. NM.sub.--152866, SEQ ID NO:1, and NP.sub.--690605.1, SEQ ID NO:2) for B cell lymphoma, Her2/Neu for breast cancer (NM.sub.--001005862, SEQ ID NO:3, and NP.sub.--001005862, SEQ ID NO:4), PSMA for prostate cancer (NM.sub.--001014986, SEQ ID NO:5, and NP.sub.--001014986, SEQ ID NO:6), and Mud1 (NM.sub.--002456, SEQ ID NO:7, and NP 002447, SEQ ID NO:8) for many different cancers, including cancers derived from breast, lung, prostate, colon and bladder tissues. In addition, any newly identified tumor-associated antigens can be targeted for the selection of tumor-specific aptamers. In yet other preferred embodiments, the death receptor is TRAIL Receptor 1 (TRAIL-R1) (NM.sub.--003844, DNA and protein sequences are shown in SEQ ID NO:9 and SEQ ID NO:10, respectively), TRAIL Receptor 2 (TRAIL-R2) (NM.sub.--003842, DNA and protein sequences are shown in SEQ ID NO:11 and SEQ ID NO:12, respectively), Fas (NM.sub.--080685, DNA and protein sequences are shown in SEQ ID NO:13 and SEQ ID NO:14, respectively), tumor necrosis factor receptor I (TNFRI or CD120a, NM.sub.--001065, DNA and protein sequences are shown in SEQ ID NO:15 and SEQ ID NO:16, respectively), TNFRII (CD120b, NM.sub.--001066, DNA and protein sequences are shown in SEQ ID NO:17 and SEQ ID NO:18, respectively), or TNFRIII (LTBR or CD 18, NM.sub.--002342, DNA and protein sequences are shown in SEQ ID NO:19 and SEQ ID NO:20, respectively). In certain preferred embodiments of this aspect, the distance between the first aptamer and the second aptamer on the nucleic acid nanostructure is about 5 nm to about 15 nm, preferably about 10 nm to about 15 nm.

[0011] In further preferred embodiments of this aspect, the first aptamer comprises a plurality of first aptamers, and the second aptamer comprises a plurality of second aptamers. Each aptamer of the plurality of aptamers can bind to the same or different binding sites on the target protein. In certain preferred embodiments, the plurality of first aptamers is present on the nucleic acid nanostructure at a density of 5-10 aptamers per nucleic acid nanostructure, and the plurality of second aptamers is present on the nucleic acid nanostructure at a density of 5-10 aptamers per nucleic acid nanostructure. In certain other preferred embodiments, the distance between each aptamer of the plurality of first aptamers and the distance between each aptamer of the plurality of second aptamers on the nucleic acid nanostructure is about 5 nm to about 15 nm, and more preferably, 5-8 nm. In certain preferred embodiments, the distribution of the first and second aptamers on the nucleic acid nanostructure is not uniform. In certain preferred embodiments, the distance between two of the first aptamers of the plurality of the first aptamers and/or the distance between two of the second aptamers of the plurality of the second aptamers is about 5-8 nm in some portions, and the distance is about 8-10 nm in other portions, of the nucleic acid nanostructure. In certain other preferred embodiments, the distance between a first aptamer and a second aptamer is from about 10 to about 12 nm in some portions, and the distance is from about 13 to about 15 nm in other portions, of the nucleic acid nanostructure. The spacing can be varied depending on the distribution or density of the target molecules on the surface of the cells. Methods for determining the distribution or density of a target molecule on the cell surface are within the knowledge of one of ordinary skill in the art, including without limitation immuno-fluorescence staining and flow cytometry, wherein stronger surface fluorescence staining indicates higher density of the target molecule on the cell surface. In certain preferred embodiments, the ratio of first aptamers to second aptamers on the nucleic acid nanostructure is 1:1.

[0012] In certain preferred embodiments of this aspect, the first aptamer comprises a dimer, trimer, tetramer, or pentamer of an aptamer that is specific for a tumor cell. In certain other preferred embodiments, the second aptamer comprises a dimer, trimer, tetramer, or pentamer of an aptamer that is specific for binding to the death receptor. In other preferred embodiments, the first aptamer comprises a plurality of first aptamers, and/or the second aptamer comprises a plurality of second aptamers. In certain preferred embodiments, the plurality of first aptamers is present on the nucleic acid nanostructure at a density of 5-10 aptamers per nucleic acid nanostructure, and the plurality of second aptamers is present on the nucleic acid nanostructure at a density of 5-10 aptamers per nucleic acid nanostructure. In yet other preferred embodiments, the distance between each aptamer of the plurality of first aptamers and the distance between each aptamer of the plurality of second aptamers on the nucleic acid nanostructure is about 10 nm to about 15 nm. And in certain particular preferred embodiments, the ratio of first aptamers to second aptamers on the nucleic acid nanostructure is 1:1. Further, in certain preferred embodiments, the first aptamer comprises a plurality of first aptamers that is specific for binding to at least two different tumor antigens on the surface of the tumor cell; in certain other preferred embodiments, the second aptamer comprises a plurality of second aptamers that is specific for binding to at least two different death receptors on the tumor cell.

[0013] In other preferred embodiments of this invention, the composition further comprises one or more apoptosis inducers that are bound to the nucleic acid nanostructure. Suitable apoptosis inducers include without limitation an siRNA molecule, an antisense oligonucleotide or a decoy oligonucleotide against anti-apoptosis proteins including without limitation NF-.kappa.B (NM.sub.--003998.3, DNA and protein sequences are shown in SEQ ID NO:21 and SEQ ID NO:22, respectively), STAT 3 (NM.sub.--139276, DNA and protein sequences are shown in SEQ ID NO:23 and SEQ ID NO:24, respectively), survivin (NM.sub.--001168, DNA and protein sequences are shown in SEQ ID NO:25 and SEQ ID NO:26, respectively), bcl-2 (NM.sub.--000633, DNA and protein sequences are shown in SEQ ID NO:27 and SEQ ID NO:28, respectively), and cFLIP (NM.sub.--001127183, DNA and protein sequences are shown in SEQ ID NO:29 and SEQ ID NO:30, respectively).

[0014] Exemplary siRNA sequences for NF-.kappa.B and STAT 3 include without limitation 5'-AGU CCA GGA UUA UAG CCC CdTdT for NF-.kappa.B (SEQ ID NO:31) and 5'-AAC AUC UGC CUA GAU CGG CUA dTdT-3' for STAT 3 (SEQ ID NO:32).

[0015] In certain preferred embodiments, the apoptosis inducer is an NF-.kappa.B inhibitor. In certain other preferred embodiments, the NF-.kappa.B inhibitor is a decoy oligonucleotide having the sequence 5'-GGATTTCCC-3'. In certain other preferred embodiments, the apoptosis inducer is a STAT3 inhibitor; in yet other preferred embodiments, the STAT3 inhibitor is a STAT3 decoy oligonucleotide having the sequence 5'-CATTTCCCGTAAATC-3' as identified by SEQ ID NO:33.

[0016] In certain preferred embodiments, the nucleic acid nanostructure comprises 4-10 copies of one type of apoptosis inducer; while in other preferred embodiments, the nucleic acid nanostructure comprises 4-10 copies of each of more than one type of apoptosis inducers. In certain preferred embodiments, the nucleic acid nanostructure comprises both NF-kB decoy oligonucleotides and STAT 3 decoy oligonucleotides at a ratio of 1:1.

[0017] In certain further preferred embodiments, the nucleic acid nanostructure comprises a nucleic acid tile. In certain preferred embodiments, the nucleic acid nanostructure comprises a plurality of nucleic acid tiles; in certain other preferred embodiments, the plurality of nucleic acid tiles forms a nucleic acid tiling array. In certain particular preferred embodiments, the aptamer-nucleic acid nanostructure is between about 10 nm and about 2000 nm in length. In certain preferred embodiments, the aptamer-nucleic acid nanostructure is 100 nm in length; while in other preferred embodiments, the aptamer-nucleic acid nanostructure is 100-2000 nm in length. In certain other preferred embodiments, the composition of this aspect of the invention further comprises a pharmaceutically acceptable carrier.

[0018] In another aspect, the invention provides methods of treating a tumor in a mammal comprising administering to a mammal in need thereof an amount effective to treat the tumor of a composition that comprises a first ligand that is specific for a tumor cell, and a second ligand that is specific for a death receptor on the tumor cell, wherein the first and second ligands are bound to a nucleic acid nanostructure. In certain preferred embodiments, the first ligand is a first aptamer and the second ligand is a second aptamer. In certain other preferred embodiments, the tumor cell is selected from the group consisting of lymphoma cell, breast cancer cell, melanoma cell, plasmacytoma cell, sarcoma cell, glioma cell, thymoma cell, leukemia cell, prostate cancer cell, colon cancer cell, esophageal cancer cell, lung cancer cell, ovarian cancer cell, cervical cancer cell, hepatoma cell, and gastric cancer cell. In certain other preferred embodiments, the invention provides methods of treating a tumor in a mammal comprising administering to a mammal in need thereof an amount effective to treat the tumor a composition according to any embodiments of the first aspect of the invention.

[0019] In yet another aspect, the invention provides methods of making the composition of the first aspect, comprising contacting a first aptamer, a second aptamer, and at least one polynucleotide under conditions suitable for binding of the first and second aptamers to the at least one polynucleotide to form an aptamer-nucleic acid nanostructure, wherein the first aptamer is specific for a tumor cell and the second aptamer is specific for binding to a death receptor on the tumor cell. In certain preferred embodiments, the at least one polynucleotide comprises a plurality of polynucleotides, and wherein the contacting is done under conditions suitable to promote hybridization of the plurality of polynucleotides into at least one nucleic acid tile. In certain other preferred embodiments, the at least one nucleic acid tile comprises a plurality of nucleic acid tiles, and wherein the plurality of nucleic acid tiles forms at least one nucleic acid tiling array.

[0020] Specific embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.

BRIEF DESCRIPTION OF THE FIGURES

[0021] FIG. 1A shows a diagram illustrating the structure and function of an exemplary aptamer-nucleic acid nanostructure for tumor-specific induction of apoptosis where the nucleic acid nanostructure is represented by a DNA tile or tiling array. FIG. 1B provides the diagram legend for FIG. 1A.

[0022] FIG. 2 shows a diagram illustrating apoptosis induction induced by the engagement of TRAIL-receptors by TRAIL-receptor agonists, such as TRAIL, antibodies or aptamers, the engagement of which causes cross-linking of the TRAIL-receptors.

[0023] FIG. 3 shows multivalent binding of two aptamers against thrombin. a) Two thrombin aptamers are positioned on a five-helix DNA scaffold at optimized distance to improve the binding efficiency. b) Single molecule visualization of the bivalent aptamer-protein binding using AFM. In this case, aptamers are displayed in lines on a rectangular shaped DNA tile. The dual aptamer line possesses stronger binding affinity with protein than each individual aptamer lines.

[0024] FIG. 4 shows results of competitive inhibition of fluorescently-labeled, monomeric aptamers to B cell leukemia Ramos cells by unlabeled mono- or multi-valent aptamer-nucleic acid nanostructure. A. Illustration of exemplary monomeric, flexible dimeric and flexible tetrameric aptamers specific to a B cell line. B. Fluorescence intensity assessed by flow cytometry (y-axis) of the cells after incubation with labeled monomer in the presence of various concentrations of unlabeled monomeric, rigid dimeric, or rigid tetrameric aptamers at the indicated concentrations (x-axis). Rigid dimeric and tetrameric aptamers differ from their flexible counterparts in that the rigid multimers do not contain dT in the linker oligonucleotide.

[0025] FIG. 5 shows a photograph of image of native gel electrophoresis of M1 dimeric aptamer incubated with or without cells at different temperatures. M1 and M2 are input dimeric and monomeric DNA aptamers, respectively, as illustrated on the right.

[0026] FIG. 6 presents a diagram illustrating synergized apoptosis of tumor cells by a multifunctional aptamer-nucleic acid nanostructure containing tumor-specific aptamers, agonistic aptamers to TRAIL-Rs and apoptosis-inducers, such as NF-.kappa.B inhibitors (illustrated in stars).

DETAILED DESCRIPTION OF THE INVENTION

[0027] All publications, patents and patent applications cited herein are hereby expressly incorporated by reference for all purposes.

[0028] 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) and PCR Protocols: A Guide to Methods and Applications (Innis, et al. 1990. Academic Press, San Diego, Calif.).

[0029] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to a "nucleic acid" means one or more nucleic acids.

[0030] As used herein, the terms "polynucleotide", "nucleotide", "oligonucleotide", and "nucleic acid" may be used interchangeably to refer to nucleic acid comprising DNA, RNA, derivative thereof, or combination thereof.

[0031] As used herein, "nucleic acid" means DNA, RNA, peptide nucleic acids ("PNA"), and locked nucleic acids ("LNA"), nucleic acid-like structures, as well as combinations thereof and analogues thereof, unless specifically indicated. Nucleic acid analogues include known analogues of natural nucleotides which have similar or improved binding properties. The term also encompasses nucleic-acid-like structures with synthetic backbones. DNA backbone analogues provided by the invention include phosphodiester, phosphorothioate, phosphorodithioate, methylphosphonate, phosphoramidate, alkyl phosphotriester, sulfamate, 3'-thioacetal, methylene(methylimino), 3'-N-carbamate, morpholino carbamate, and peptide nucleic acids (PNAs), methylphosphonate linkages or alternating methylphosphonate and phosphodiester linkages (Strauss-Soukup (1997) Biochemistry 36:8692-8698), and benzylphosphonate linkages, as discussed in U.S. Pat. No. 6,664,057; see also Oligonucleotides and Analogues, a Practical Approach, edited by F. Eckstein, IRL Press at Oxford University Press (1991); Antisense Strategies, Annals of the New York Academy of Sciences, Volume 600, Eds. Baserga and Denhardt (NYAS 1992); Milligan (1993) J. Med. Chem. 36:1923-1937; Antisense Research and Applications (1993, CRC Press).

[0032] As used herein, the term "binding to" or "bound to" refers to any of direct binding, indirect binding, covalent binding, or non-covalent binding, unless otherwise specifically indicated.

[0033] As used herein, the term "ligand" is any molecule capable of binding to a target. Such ligands include, but are not limited to, proteins, lipids, carbohydrates, nucleic acids (including, but not limited to, aptamers), and other molecules. In certain preferred embodiments, the ligand refers to a binding partner that binds to a cell surface molecule or receptor. In certain preferred embodiments of the invention, the ligand is a monovalent ligand; in other preferred embodiments, the ligand is a multivalent ligand, which can be without limitation a homomultimeric or heteromultimeric ligand. In certain other preferred embodiments, a ligand is an aptamer or an agonistic antibody.

[0034] In a first aspect, the invention provides compositions comprising a first ligand that is specific for binding to a tumor cell, and a second ligand that is specific for binding to a death receptor on the tumor cell, wherein the first and second ligands are bound to a nucleic acid nanostructure. In certain preferred embodiments, the first ligand is a first aptamer and the second ligand is a second aptamer. In certain preferred embodiments, the first aptamer binds to a tumor antigen on the surface of a tumor cell.

[0035] As used herein, the term "specific binding" of "specific for binding" to a target molecule is used consistently with the term used in the art of immunology and ligand/receptor interaction in general. For example, a second aptamer specific for binding to a death receptor on the tumor cell indicates that the second aptamer specifically binds to a target death receptor under stringent binding conditions and that the aptamer's binding, if any, to other non-target death receptor or other molecules that do not have the same binding site under the same binding conditions is insubstantial or undetectable as determined by methods commonly used in the immunology or ligand/receptor art. Stringent binding conditions can be determined by one of ordinary skill in the art further aided by the disclosure of the instant application and knowledge known in the art. See Sambrook et al. supra. Specific binding can also be determined by competition; for example, a specific binding between a labeled ligand and its receptor under stringent binding conditions can be competed by the unlabeled ligand, but not by other unlabeled irrelevant molecules that are present at equal molar concentration with the labeled ligand.

[0036] As used herein the term "tumor antigen" refers to a molecule that is present on a tumor cell, especially on the surface of a tumor cell, and not present to a detectable level on the corresponding non-tumor or normal cell. Alternatively, the term "tumor antigen" refers to a molecule that is present in at least a 10-fold higher level on the surface of a tumor cell than on the corresponding non-tumor or normal cell. Thus, the tumor antigen offers tumor-specific recognition. Known tumor antigens suitable for use in the instant application to provide tumor-specific targeting include without limitation CD20 for B cell lymphoma, Her2/neu (human epidermal growth receptor 2) for breast cancer, PSMA (prostate-specific membrane antigen) for prostate cancer, Muc1 (mucin 1) for many different cancers, including cancers derived from breast, lung, prostate, colon and bladder tissues. Tumor antigens are not limited to protein or peptide molecules; any molecule, such as lipid or carbohydrate that is present predominantly on tumor cells verses normal cells is suitable for use as a tumor antigen in the instant invention. In advantageous embodiments, tumor-specific targeting by the binding of the first aptamer to a tumor antigen greatly reduces non-specific cell killing and cytotoxicity that is currently encountered in existing TRAIL-centered anti-cancer therapies.

[0037] The present invention also provides methods for identifying previously unknown tumor antigens. An aptamer that binds to a tumor cell but not to a corresponding normal or non-tumor cell recognizes a tumor antigen on the surface of the tumor cell. The molecule on the tumor cell surface bound by the aptamer can be purified by methods known in the art, such as affinity purification and the identity of the molecule can be analyzed. However, the identity of the tumor antigen is not necessary for using the tumor antigen in the instant application: a cell surface molecule that is present on the tumor cell but not on the corresponding non-tumor or normal cell offers tumor-specific targeting.

[0038] As used herein the term "death receptor" refers to a receptor to a ligand belonging to the tumor necrosis factor family. Tumor necrosis factor (TNF) family refers to a group of cytokines, including TNF-.alpha. (NM.sub.--000594, DNA and protein sequences are shown in SEQ ID NO:34 and SEQ ID NO:35, respectively), TNF-.beta. (NM.sub.--000595, DNA and protein sequences are shown in SEQ ID NO:36 and SEQ ID NO:37, respectively), TRAIL (NM.sub.--003810, DNA and protein sequences are shown in SEQ ID NO:38 and SEQ ID NO:39, respectively), and FAS ligand (NM.sub.--000639, DNA and protein sequences are shown in SEQ ID NO:40 and SEQ ID NO:41, respectively), which binds to its respective receptor and can cause cell death. A death receptor contains one or more functional death domains. Newly discovered death receptors can be identified by the presence of signature TNFR domains, which consist of three tandem repeats of cysteine-rich domains (CRDs). The binding of a ligand, an agonistic antibody or aptamer to a death receptor triggers oligomerization of the death receptor and death domain-induced activation of caspases and cell death. In certain preferred embodiments, the death receptors include without limitation TNFRI, TNFRII, TNFRIII, FAS, TRAIL-R1, and TRAIL-R2.

[0039] The term "aptamer" as used herein refers to single-stranded nucleic acid molecules with secondary structures that facilitate high-affinity binding to a target molecule. In certain preferred embodiments, the single-stranded nucleic acid is ssDNA, RNA or derivatives thereof. The aptamer comprises nucleic acid sequence that does not participate in base-pairing with other polynucleotides within the nucleic acid nanostructure.

[0040] Aptamers can be synthesized and screened by any suitable methods in the art. For example, aptamers can be screened and identified from a random aptamer library by SELEX (systematic evolution of ligands by exponential enrichment). In certain preferred embodiments, aptamers that bind to a cell surface target molecule can be suitably screened and selected by a modified selection method herein referred to as cell-SELEX or cellular-SELEX, even if the identity of the cell surface target molecule is unknown (Phillips et al., 2008, Anal Chim Acta 621:101-108; Shamah et al., 2008, Acc Chem Res 41:130-138). In certain other preferred embodiments, aptamers that bind to a cell surface target molecule can be screened by capillary electrophoresis and enriched by SELEX based on the observation that aptamer-target molecule complexes exhibited retarded migration rate in native polyacrylamide gel electrophoresis as compared to unbound aptamers.

[0041] In certain preferred embodiments, a random aptamer library can be created that contains monomeric, dimeric, trimeric, tetrameric or other higher multimeric aptamers. A random aptamer library (either ssDNA or RNA) can be modified by including oligonucleotide linkers to link individual aptamer monomers to form multimeric aptamer fusion molecules. In certain preferred embodiments, a random oligonucleotide library is synthesized with randomized 45 nt sequences flanked by defined 20 nt sequences both upstream and downstream of the random sequence, i.e., known as 5'-arm and 3'-arm, which are used for the amplification of selected aptamers. A linking oligonucleotide (i.e., linker) is designed to contain sequences complementary to both 5'-arm and 3'-arm regions of random aptamers to form dimeric aptamers. For trimeric or tetrameric aptamers, a small trimeric or tetrameric (i.e., a Holiday junction-like) DNA nanostructure will be engineered to include sequences complementary to the 3'-arm region of the random aptamers, therefore creating multimeric aptamer fusion through hybridization. In addition, 3 to 5 or 5 to 10 dT rich nucleotides can be engineered into the linker polynucleotides as a single stranded region between the aptamer-binding motifs, which offers flexibility and freedom of multiple aptamers to coordinate and synergize multivalent interactions with cellular ligands or receptors. Alternatively, multimeric aptamers can also be formed by mixing biotinylated aptamers with streptavidin.

[0042] A modified cellular SELEX procedure can be employed to select target-binding aptamers. Multimeric aptamers may have multivalent but single binding specificity, or multivalent and multi-specific binding activity. Both types of these aptamer molecules are desirable as long as they display high binding avidity to target cells. For example, if aptamers with multiple specificities are selected by cellular binding, their corresponding cellular receptors likely reside in close vicinity on the cell surface or are different binding sties of one surface molecule. These types of aptamers are most likely present in the initial random library or during the early stage of cellular SELEX selection. If the multi-specific aptamers can survive rounds of selection, they may have advantage of targeting several co-receptors and therefore triggering multiple signaling pathways for cellular activation. On the other hand, multivalent but single target-binding aptamers are expected to be more readily selected by the cellular SELEX because of their intrinsic high binding avidity. This type of aptamer molecules can be used to target both tumor cells and effector cells.

[0043] In certain other preferred embodiments, for the selection of target specific RNA-aptamers, a well-established RNA-aptamer selection protocol (Ohuchi et al., 2006. Biochimie 88:897-904) is applied with some modification. The dsDNA after PCR amplification of the random DNA library is transcribed to generate a RNA pool using T7-RNA polymerase. This RNA library is optionally incubated with linkers to form multivalent aptamer library. The aptamers from the library are incubated with target tumor cells and counter-selected against normal cells or other non-target tumor cells. The selected RNA aptamers are reversely transcribed into cDNA and amplified by PCR, which will then be transcribed into RNA. These RNA molecules can be incubated with linkers to form multivalent aptamers for the next round of selection and amplification. Aptamers of ssDNA or RNA aptamers labeled with fluorophore can be used to reveal aptamer-specific cell binding by flow cytometry. Furthermore, the aptamers specific for a tumor antigen or death receptor can also be enriched through FACS-based cell sorting. After 20-30 cycles of positive/negative selection, the selected aptamers can be cloned and sequenced. The binding valence and specificity of selected multimeric aptamer can be further characterized. For example, the binding aptamers can be eluted from the cells and analyzed by gel electrophoresis for the size and species, some of which will be analyzed by sequence analyses.

[0044] Aptamers are known as "chemical antibodies" in that it shares the specificity of antibodies but enjoys the advantages of adaptability. Development of antibodies is a process that takes time. A random sequence aptamer library, on the other hand, can be efficiently synthesized and screened for suitable binders to a target molecule with desirable affinity. One of the concerns over TRAIL-R agonist antibody-based therapy is the emerging of resistant tumors caused by the occurrence of mutations in the TRAIL-R proteins that abolish antibody binding. In the aptamer-based therapy, on the other hand, new aptamers that are capable of specific binding to the mutant TRAIL-Rs can be quickly screened and identified. Such aptamers can be used to overcome tumor resistance.

[0045] Further, humanized antibody is preferred for administering to a human subject. The development and production of a suitable humanized TRAIL-R antibody is a time consuming and cumbersome process. As compared to antibodies developed in non-human animals, aptamers are immunogenically inert. Thus, in certain advantageous embodiments, the invention provides aptamer-nucleic acid nanostructure that induces minimal or no immune response when administered into a human subject.

[0046] In certain preferred embodiments, a suitable nucleotide length for an aptamer ranges from about 25 to about 100 nucleotide (nt), and in various other preferred embodiments, 30-100 nt, 30-60 nt, 25-70 nt, 25-60 nt, 40-60 nt, or 40-70 nt in length. In certain preferred embodiments, the length of an aptamer is about 2-20 nm, in various other preferred embodiments, 2-15 nm, 5-15 nm, 5-10 nm, or less than 10 nm in size. In certain preferred embodiments, the monomeric aptamer contains a predetermined sequence that is about 8-10 nm in length (25-30 nt in length). However, the sequence can be designed with sufficient flexibility such that it can accommodate interactions of aptamers with two targets at the distances described herein.

[0047] Individual aptamers generally have lower binding affinity than antibodies. In certain preferred embodiments, the aptamer has affinity at the range of 10-100 nM, which, after binding of the aptamer to a tumor cell surface molecule, permits dissociation of the aptamer from the target molecule, which leads to the release and recycle of the aptamer nucleic acid nanostructure to target other tumor cells. In certain other preferred embodiments, the affinity of individual aptamers can be increased by 4-50 fold by constructing multimeric aptamers linked together by covalent or non-covalent linkages. Thus, in certain preferred embodiments, the desirable affinity of an aptamer to a target death receptor can be fine-tuned by adjusting the multiplexity of the monomeric aptamer binding units on the nucleic acid nanostructure.

[0048] In certain embodiment of this aspect of the invention, the composition comprises multimeric first and/or second aptamers. As used herein, the term "multimeric aptamer" or "multivalent aptamer" refers to an aptamer that comprises multiple monomeric binding units, wherein each of the monomeric binding unit can be an aptamer on its own. Similarly, in certain preferred embodiments of this aspect, the first aptamer comprises a dimer, trimer, tetramer, or pentamer of an aptamer or a monomeric binding unit, wherein the first aptamer is capable of binding to one or more cell surface proteins of a tumor cell, and/or the second aptamers comprises a dimer, trimer, tetramer, or pentamer of an aptamer or a monomeric binding unit wherein the second aptamer is capable of binding to one or more death receptors.

[0049] A multimeric aptamer can be a homomultimer or a heteromultimer. The term "homomultimer" refers to a multimeric aptamer that comprises multiple binding units of the same kind, i.e., each binding unit binds to the same binding site of the same target molecule. The term `heteromultimer" refers to a multimeric aptamer that comprises multiple binding units of different kinds, i.e., each binding unit binds to a different binding site of the same target molecule, or each binding unit binds to a binding site on different target molecule. Thus, a heteromultimer can refer to a multimeric aptamer that binds to one target molecule at different binding sties or a multimeric aptamer that binds to different target molecules. A heteromultimer that binds to different target molecules can also be referred to as a multi-specific multimer. In certain preferred embodiments, the invention provides compositions that comprise multi-specific multimeric first aptamers that bind to different tumor antigens on the tumor cell and/or multi-specific multimeric second aptamers that bind to different death receptors on the tumor cells. In certain preferred embodiments, the multi-specific multimeric second aptamers bind to TRAIL-R1 and TRAIL-R2 on the tumor cell.

[0050] Multimeric aptamers with monomeric binding units that each bind to the same target molecule acquire higher binding avidity than their monomeric counterparts and therefore are likely to be preferentially selected by cellular SELEX. On the other hand, multimeric aptamers with monomeric binding units that each bind to different target molecules may also possess binding advantages if two or three aptamer binding motifs happen to interact with their ligands located at close vicinity on the cell surface. Interactions among these different receptor/ligand pairs can also synergize the binding activity as well. Multimers of aptamer binding unit can be covalently linked to each other. Alternatively, multimers of aptamer binding units can be linked to each other by direct base pairing with each other or with a linker polynucleotide, or other non-covalent linkage including without limitation, biotin-streptavidin interaction. Multimeric aptamers provide multivalent binding capacity either for one type of target molecule or receptor, or for multiple types of target molecules or receptors.

[0051] In certain preferred embodiments, the linker polynucleotide has a length between about 5 nucleotides (nt) and about 100 nt; in various other preferred embodiments, 10-30 nt, 20-30 nt, 25-35 nt, 30-50 nt, 40-50 nt, 50-60 nt, 55-65 nt, 50-80 nt, or 80-100 nt. It is within the ability of one of skill in the art to adjust the length of the linker polynucleotide to accommodate each monomeric ligand present on the nucleic acid nanostructure.

[0052] In certain preferred embodiments, the multimeric aptamers can be identified and screened from a random multimeric aptamer library as described herein. In other preferred embodiments, the monomeric aptamers are linked to each other by one or a plurality of linker polynucleotides to form multimeric aptamers. Monomeric aptamers can be linked to form multimeric aptamers by any suitable means and in any configurations. Exemplary multimeric aptamers are illustrated in FIG. 4A. In certain preferred embodiments, the monomeric aptamer comprises a first portion of a randomized sequence that is about 25 to 100 nucleotide (nt) in length, and in various other preferred embodiments, 30-100 nt, 30-60 nt, 25-70 nt, 25-60 nt, 40-60 nt, or 40-70 nt in length. In certain preferred embodiments, the randomized sequence is 45 nt in length.

[0053] In other preferred embodiments, the randomized sequence is flanked by at least one, preferably two, predetermined sequences of about 10-50 nt in length, and in various other embodiments, 15-40 nt, 15-30 nt, 20-40 nt, 25-30 nt, or 20-30 nt in length. In certain preferred embodiments, the predetermined sequence is 20 nt in length. In certain preferred embodiments, each monomeric aptamer comprises a randomized 45 nt sequence flanked by defined 20 nt sequences both upstream and downstream of the random sequence, i.e., the 5'-arm and 3'-arm, respectively. Computer programs are available to assist in designing the suitable predetermined sequence of the 5'-arm and 3'-arm regions to facilitate hybridization with the linker polynucleotide and to minimize potential secondary structure in the 5'-arm and 3'-arm regions. Exemplary computer program includes without limitation Mfold available at web site mobyle.pasteur.fr/cgi-bin/MobylePortal/portal.py?form=mfold.

[0054] In certain preferred embodiments of this aspect, randomized dimeric aptamers are formed wherein a linker polynucleotide comprises sequences complementary to both 5'-arm and/or 3'-arm region of random aptamers to form dimeric aptamers. In other preferred embodiments, trimeric or tetrameric aptamers are formed when a plurality of linker polynucleotides that hybridize to the 3'-arm and 5'-arm regions are introduced. In other preferred embodiments, the linker polynucleotide further comprises a single stranded hinge region situated in between the aptamer-binding motifs. In certain preferred embodiments, the hinge region is 3-10 nt in length; in various other preferred embodiments, the hinge region is 3-8 nt, 3-6 nt or 3-5 nt in length. In other preferred embodiments, the hinge region comprises sequence that is rich in As and Ts. The additional single stranded hinge region offers flexibility to allow the multimeric aptamers to coordinate and synergize multivalent interactions with target molecules or receptors.

[0055] As used herein, the term "randomized sequence" refers to an undefined nucleic acid molecule that contains degenerative nucleotide residues at some or all positions. Nucleic acid containing randomized sequence can be chemically synthesized by various methods known in the art and described herein.

[0056] As used herein, the term "predetermined sequence" refers to a defined nucleic acid molecule for which the nucleotide sequence is known. Nucleic acid containing randomized sequence can be chemically synthesized by methods known in the art and described herein or produced recombinantly in a cell.

[0057] In certain preferred embodiments, the predetermined sequence is complementary to at least 10 nt of sequence of the linker polynucleotide; in various other preferred embodiments, at least 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt or 50 nt of the sequence of the linker polynucleotide.

[0058] in certain preferred embodiments, the aptamers are further modified to protect the aptamers from nuclease and other enzymatic activities. The aptamer sequence can be modified by any suitable methods known in the art. For example, phosphorothioate can be incorporated into the backbone, and 5'-modified pyrimidine can be included in 5' end of ssDNA for DNA aptamer. For RNA aptamers, modified nucleotides such as substitutions of the 2'-OH groups of the ribose backbone, e.g., with 2'-deoxy-NTP or 2'-fluoro-NTP, can be incorporated into the RNA molecule using T7 RNA polymerase mutants (Epicentre Biotech, Madison, Wis.). The resistance of these modified aptamers to nuclease can be tested by incubating them with either purified nucleases or nuclease from mouse serum, and the integrity of aptamers can be analyzed by gel electrophoresis.

[0059] In certain preferred embodiments of this aspect of the invention, the aptamer, either monomeric or multimeric, can be covalently or non-covalently bound to one or more polynucleotides in the nucleic acid nanostructure; in other preferred embodiments, the aptamer binds to a connector polynucleotide that is directly or indirectly bound to the one or more polynucleotides in the nucleic acid nanostructure. Non-covalent binding includes without limitation nucleic acid base pairing of the aptamer directly with the polynucleotide of the nucleic acid nanostructure (one that remains partially unbound after formation of the nucleic acid nanostructure) or by way of a connector polynucleotide, or via biotin-streptavidin interaction.

[0060] The integrity of cell binding activities of the aptamers after binding to the nucleic acid nanostructure and/or after being modified to achieve nuclease resistance as described above can be tested by any suitable methods in the art, including without limitation flow cytometry and confocal fluorescent microscopy imaging to ensure that the binding to the nucleic acid nanostructure and/or modification does not compromise the cell binding activity.

[0061] In other preferred embodiments of this aspect, the first aptamer comprises a plurality of first aptamers, and/or the second aptamer comprises a plurality of second aptamers. Each of the first aptamer of the plurality of first aptamers and/or each of the second aptamer of the plurality of second aptamers can be a monomer or a multimer, such as a homo-multimer or hetero-multimer. It was shown that aptamers positioned in close vicinity facilitate binding to the target molecule (see FIG. 3B). Suitable distance between each aptamer of the plurality of first aptamers and between each aptamer of the plurality of second aptamers on the nucleic acid nanostructure is determined by the distance that allows cross-linking of molecules, and coincides with the distance that promotes cooperative binding. In certain particular preferred embodiments, the distance of each second aptamer in the plurality of second aptamers is determined at a distance that facilitates trimerization of the death receptors upon aptamer binding. The suitable distance can be determined by any suitable methods in the art, including without limitation the method described herein. In certain embodiment, the distance between each aptamer of the plurality of first aptamers or between each aptamer of the plurality of second aptamers is from about 5 nm to about 15 nm; in various other preferred embodiments, between 5 nm and 8 nm; 6 nm and 8 nm; 10 nm and 13 nm; 10 nm and 15 nm; or 8 nm and 15 nm. Further, in certain other preferred embodiments, the distance between each first aptamer and second aptamer is from about 5 nm to about 15 nm; in various other preferred embodiments, between 5 nm and 8 nm; 6 nm and 8 nm; 10 nm and 13 nm; 10 nm and 15 nm; or 8 nm and 15 nm.

[0062] The distance between each aptamer of the plurality of aptamers on the nucleic acid nanostructure can be adjusted by changing the length of the aptamer nucleic acid or a connector polynucleotide by which the aptamer is bound to the nucleic acid nanostructure. In certain preferred embodiments, the adjustment of spacing is based on known parameters of B-DNA. For example, it is known that B-DNA is 3.4 angstrom per base pair rise, and 2 nm in diameter. In other preferred embodiments, the spacing can be adjusted by lengthening or shortening the aptamer sequences or the connector sequences. The spacing can be determined and verified by any suitable methods in the art, including without limitation atomic force microscopy (AFM) and Fluorescent Resonant Energy Transfer (FRET).

[0063] In certain preferred embodiments, the binding affinity for each aptamer-nucleic acid nanostructure with a defined spatial arrangement of aptamers is determined. In one embodiment, fluorophore-labeled aptamer-nucleic acid nanostructures are incubated with target cells and their binding activity is examined by flow cytometry. The binding affinity will be determined by the mean fluorescence intensity of target cells bound with fluorophore-labeled aptamers, as described by Tang et al., 2007, Anal. Chem. 79:4900. In certain preferred embodiments, the spacing between each aptamers of the same type or different types on the nucleic acid nanostructure can be adjusted to modulate binding affinity of the aptamers to the cell surface molecules or receptors.

[0064] In certain preferred embodiments, the distance between the first aptamer and the second aptamer on the aptamer-nucleic acid nanostructure is between about 5-15 nm; in various further preferred embodiments, between about 5-8 nm; 5-10 nm; 10-12 nm; 13-15 nm; 10-15 nm; or 8-15 nm.

[0065] In certain further preferred embodiments, the first aptamer comprises heteromultimeric aptamers that recognize at least two different binding sites on the same tumor cell; in certain other preferred embodiments, the second aptamer comprises heteromultimeric aptamers that recognize at least two different binding sites on the same death receptor.

[0066] In certain other preferred embodiments of this aspect, the first aptamer comprises a plurality of first aptamers that is specific for binding to at least two different tumor antigens on the surface of tumor cells; in certain other preferred embodiments, the second aptamer comprises a plurality of second aptamers that is specific for binding to at least two different death receptors. The multi-specific nature of the first aptamers allows better targeting and binding to one or multiple types of tumor cells, and the multi-specific nature of the second aptamers can achieve more efficient tumor cell killing and help circumvent the emergence of resistant tumor cells.

[0067] In certain preferred embodiments of this aspect, both the first aptamer and the second aptamer are each present on the nucleic acid nanostructure at a density of 2-20 aptamers per nucleic acid nanostructure; in various other preferred embodiments, between 2-15; 2-10; 4-20; 5-10; 4-15; 4-10; 2-9; 4-9; 4-8; 2-8; 4-6; or 2-6 aptamers per nucleic acid nanostructure. In certain preferred embodiments, the first aptamer is present on the nucleic acid nanostructure at a density of 5-10 aptamers per nucleic acid nanostructure, and the second aptamer is present at a density of 5-10 aptamers per nucleic acid nanostructure.

[0068] The density refers to the number of aptamers present on each nanostructure, where each aptamer is positioned in relation to other aptamer at a predetermined distance. For example, in certain preferred embodiments, the nucleic acid nanostructure contains 5-10 first aptamers, and each first aptamer is 5-8 nm away from any other first aptamers and 10-15 nm from any other second aptamers.

[0069] In certain particular preferred embodiments of this aspect, the ratio of first aptamers to second aptamers on the nucleic acid nanostructure is 1:1. In alternative preferred embodiments, the ratio of first aptamers to second aptamers on the nucleic acid nanostructure is 1:2, 1:3 or 1:4 to further enhance death-induction. In certain other preferred embodiments, the ratio of first aptamers to second aptamers on the nucleic acid nanostructure is 2:1, 3:1 or 4:1 to further enhance target tumor cell recognition.

[0070] In various further preferred embodiments, the composition comprises further aptamers (third, fourth, fifth, etc.) as may be suitable for a given intended use. All embodiments of the first and second aptamers apply to further aptamers.

[0071] Synthesis of polynucleotides is well known in the art. See, for example, Yan, H. et al., Science 2003, 301, 1882-1884; U.S. Pat. No. 6,255,469; WO 97/41142; Seeman, N. C., Chem Biol, 2003. 10: p. 1151-9; Seeman, N. C. Nature, 2003. 421: p. 427-431; Winfree, E. et al., Nature, 1998. 394: p. 539-44; Fu, T. J. and N. C. Seeman, Biochemistry, 1993. 32: p. 3211-20; Seeman, N. C., J Theor Biol, 1982. 99: p. 237-47; Storhoff, J. J. and C. A. Mirkin, Chem. Rev., 1999. 99: p. 1849-1862; Yan et al., PNAS 100, Jul. 8, 2003 pp 8103-8108); and WO2006/124089. It is highly desirable, but not essential, in making the polynucleotides for the nucleic acid nanostructures to appropriately design sequences to minimize undesired base pairing and undesired secondary structure formation. Computer programs for such purposes are well known in the art. (See, for example, Seeman, N. C., J Biomol Struct Dyn, 1990. 8: p. 573-81). It is further preferred that the polynucleotides are purified prior to nucleic acid tile assembly. Purification can be by any appropriate means, such as by gel electrophoretic techniques.

[0072] As used herein, the term "nucleic acid nanostructure" or "nanostructure" refers to a nucleic acid structure that includes at least one nanoscale dimension, wherein the nucleic acid structure comprises one or more single stranded nucleic acids, which hybridize to form at least a partially double-stranded structure with defined features and geometry. The nucleic acid nanostructure presents ligands bound thereto to the target cell surface molecules, including a death receptor, on a tumor cell, and the resulting binding promotes death-receptor mediated tumor cell death. In some preferred embodiments, the nucleic acid nanostructure comprises a double-stranded DNA linker molecule. In preferred embodiments, the nucleic acid nanostructure comprises a DNA nanostructure. In certain preferred embodiments, the nucleic acid nanostructure comprises a DNA tile; in certain other preferred embodiments, the nucleic acid nanostructure comprises a DNA tiling array.

[0073] A variety of suitable nucleic acid nanostructures are known in the art. See for example, WO2008/033848 and WO2006/124089, and Ke et al., 2008, Science 319: 180-183, the disclosures of which are incorporated herein by reference in their entireties. In certain preferred embodiments, the nucleic acid nanostructure comprises a spiral DNA scaffold, a DNA origami, or a DNA tile or tiling array. Such nucleic acid nanostructures are formed by base pairing of single stranded DNA or derivatives thereof or by other non-covalent linkage, such as biotin-streptavidin interaction.

[0074] In certain preferred embodiments of this aspect, the nucleic acid nanostructure comprises a multi-helical bundle to display ligands. In certain preferred embodiments, the ligands are aptamers. The multi-helical bundle comprises 2-20 double stranded helices; in various other preferred embodiments, the multi-helical bundle comprises 2-15, 2-12, 2-10, 3-20, 3-12, 3-10, 4-20, 4-10, 4-8 double stranded helices. It is within the skill of one of ordinary skill in the art to determine the suitable number of double stranded helices suitable for use as nucleic acid nanostructure in the present invention. In certain preferred embodiments, the nucleic acid nanostructure is 50-2000 nm (i.e., 50.times.50 nm.sup.2 to 2000.times.2000 nm.sup.2); in other preferred embodiments, 10-200 nm; 25-200 nm; 25-100 nm; 50-200 nm; 50-150 nm; 50-100 nm; 100-200 nm; 100-300 nm; 300-500 nm; 300-800 nm; 800-1000 nm; 1000-1500 nm; 1300-1800; or 1500-2000 nm in length. In certain preferred embodiments, the nucleic acid nanostructure is 100 nm in length (i.e.: 100.times.100 nm.sup.2) or 100-2000 nm in length.

[0075] In certain preferred embodiments of the invention, the nucleic acid nanostructure comprises one or more nucleic acid tiles, preferably DNA tiles. In certain other preferred embodiments, the nucleic acid nanostructure comprises a DNA tiling array. Self-assembling nucleic acid tiling lattices represent a versatile system for nanoscale construction. Structure formation using nucleic acid `smart tiles` begins with the chemical synthesis of single-stranded polynucleotides, which when properly annealed, self-assemble into nucleic acid tile building blocks through Watson-Crick base pairing. DNA tiles bearing complementary sticky ends are then able to further self-assemble into larger arrays with distinct topological and geometric features. A self-assembling, finite nucleic acid-based nanoarray allows a wide variety of discrete molecules to be placed at specific locations with nm-scale accuracy. Various nucleic acid tiles and tiling array have been described in the art. See for example WO2008/033848 and WO2006/124089, the disclosures of which are incorporated herein by reference in their entireties.

[0076] The dimensions of a given nucleic acid tile can be programmed, based on the length of the polynucleotides of the nucleic acid nanostructure (i.e., those polynucleotides that are integrally involved in the structure of the nucleic acid tile) and their programmed shape and size, the length of the sticky ends (when used), and other design elements. Based on the teachings provided herein and known in the art, those of skill in the art can prepare nucleic acid tiles of any desired size. In various preferred embodiments the length and width of individual nucleic acid tiles are between 3 nm and 100 nm; in various other preferred embodiments, widths range from 4 nm to 60 nm and lengths range from 10 nm to 90 nm. In certain preferred embodiments, the nucleic acid nanostructure comprises a singe nucleic acid tile or a nucleic acid tiling array that has a dimension consistent with the dimension of a nucleic acid nanostructure as described above suitable for use in the present invention.

[0077] The dimensions of nucleic acid tiling arrays can also be programmed with the use of boundary tiles (i.e., tiles designed to terminate further assembly of the array), depending on the size of the individual nucleic acid tiles, the number of nucleic acid tiles, the length of the sticky ends (when used), the desired spacing between individual nucleic acid tiles, and other design elements. In embodiments that do not incorporate boundary tiles, the size of the arrays depends on the purity of the DNA strands, the stoichiometry of the different polynucleotides, and the kinetics (how slow the annealing process is). Based on the teachings herein and known in the art, those of skill in the art can prepare nucleic acid tiling arrays of any desired size. In certain preferred embodiments, the nucleic acid tiling array is within a size limit that does not induce internalization of the tiling array by way of phagocytosis of the cell. In certain preferred embodiments, the nucleic acid tile or tiling array is not more than 100 nm in length (i.e.: 100.times.100 nm.sup.2).

[0078] In certain particular preferred embodiments, the aptamer-nucleic acid nanostructure is of a size sufficient to trigger passive phagocytosis of the ligand-nucleic acid nanostructure by the cells. In certain preferred embodiments, the composition comprises an aptamer-nucleic acid nanostructure that is between about 100 nm and about 2 .mu.m in length (i.e., 100.times.100 nm.sup.2 to 2000.times.2000 nm.sup.2); in various other preferred embodiments, 100-200 nm, 100-300 nm, 300-500 nm, 300-800 nm, 800-1000 nm, 1000-1500 nm, 1300-1800, or 1500-2000 nm in length.

[0079] In certain embodiments, the aptamer-nucleic acid nanostructure further comprises a transduction domain. As used herein, the term "transduction domain" means one or more amino acid sequence or any other molecule that can carry the intracellular nucleic acid nanostructure across cellular membranes. (See, for example, Cell 55: 1179-1188, 1988; Cell 55: 1189-1193, 1988; Proc Natl Acad Sci USA 91: 664-668, 1994; Science 285: 1569-1572, 1999; J Biol Chem 276: 3254-3261, 2001; and Cancer Res 61: 474-477, 2001). Any transduction domains that can lead a molecule across cellular membranes are suitable for use in the present invention. In further embodiments, the nucleic acid nanostructure comprises at least one transduction domain selected from the group consisting of (R).sub.4-9 (SEQ ID NO:43); GRKKRRQRRRPPQ (SEQ ID NO:44); AYARAAARQARA (SEQ ID NO:45); DAATATRGRSAASRPTERPRAP ARSASRPRRPVE (SEQ ID NO:46); GWTLNSAGYLLGLINLKALAALAKKIL (SEQ ID NO:47); PLSSIFSRIGDP (SEQ ID NO:48); AAVALLPAVLLALLAP (SEQ ID NO:49); AAVLLPVLLAAP (SEQ ID NO:50); VTVLALGALAGVGVG (SEQ ID NO:51); GALFLGWLGAAGSTMGAWSQP (SEQ ID NO:52); GWTLNSAGYLLGLINLKALAALAKKIL (SEQ ID NO:53); KLALKLALKALKAALKLA (SEQ ID NO:54); KETWWETWWTEWSQPKKKRKV (SEQ ID NO:55); KAFAKLAARLYRKAGC (SEQ ID NO:56); KAFAKLAARLYRAAGC (SEQ ID NO:57); AAFAKLAARLYRKAGC (SEQ ID NO:58); KAFAALAARLYRKAGC (SEQ ID NO:59); KAFAKLAAQLYRKAGC (SEQ ID NO:60), and AGGGGYGRKKRRQRRR (SEQ ID NO:61). In certain embodiments, the aptamer-nucleic acid nanostructure comprising a transduction domain further comprises one or more modifications to the nucleic acid that facilitate phagocytosis as described above.

[0080] In one preferred embodiment, the nucleic acid nanostructure comprises or consists of a nucleic acid tiling array, comprising a plurality of nucleic acid tiles joined to one another via sticky ends, wherein each nucleic acid tile comprises one or more sticky ends, and wherein a sticky end for a given nucleic acid tile is complementary to a single sticky end of another nucleic acid tile in the nucleic acid tiling array; wherein the nucleic acid tiles are present at predetermined positions within the nucleic acid tiling array as a result of programmed base pairing between the sticky ends of the nucleic acid tiles. In this embodiment, one or more tiles in the array comprise nucleic acid probes for binding the ligands to the nanostructure.

[0081] As used herein, "programmed base pairing" means that the sticky ends for the different nucleic acid tiles are designed to ensure interactions of specific nucleic acid tiles through their complementary sticky ends, thus programming the position of the nucleic acid tile within the nucleic acid tiling array. As used herein, "predetermined positions" means that the ultimate position of each nucleic acid tile in the self-assembled nucleic acid tiling array is based on the sequence and position of its sticky ends and the sequence and position of the sticky ends of the other nucleic acid tiles in the nucleic acid tiling array, such that the plurality of nucleic acid tiles can only assemble in one specific way.

[0082] Since the position of all nucleic acid tiles in the array is predetermined, the boundary tiles are also predetermined, and thus the nucleic acid tiling arrays of the present invention have defined boundaries (i.e.: "finite" nucleic acid tiling arrays).

[0083] Each "nucleic acid tile" comprises (a) a structural element (also referred to herein as the polynucleotide "core") constructed from a plurality of nucleic acid polynucleotides; and (b) 1 or more "sticky ends" per nucleic acid tile attached to the polynucleotide core. Those of skill in the art are well aware of the wide range of such polynucleotide cores, including but not limited to 4 arm branch junctions, 3 arm branch junctions, double crossovers, triple crossovers, parallelograms, 8 helix bundles, 6-tube formations, and structures assembled using one or more long strands of nucleic acid that are folded with the help of smaller `helper` strands (See, for example, Yan, H. et al., Science 2003, 301, 1882-1884; U.S. Pat. No. 6,255,469; WO 97/41142; Seeman, N. C., Chem Biol, 2003. 10: p. 1151-9; Seeman, N. C. Nature, 2003. 421: p. 427-431; Winfree, E. et al., Nature, 1998. 394: p. 539-44; Fu, T. J. and N. C. Seeman, Biochemistry, 1993. 32: p. 3211-20; Seeman, N. C., J Theor Biol, 1982. 99: p. 237-47; Storhoff, J. J. and C. A. Mirkin, Chem. Rev., 1999. 99: p. 1849-1862; Yan et al., Proceedings of the National Academy of Sciences 100, Jul. 8, 2003 pp 8103-8108.)

[0084] Self-assembly of a plurality of nucleic acid tiles results in programmed base-pairing interactions between sticky ends on different nucleic acid tiles to form the nucleic acid tiling arrays.

[0085] As used herein, a "plurality" of nucleic acid tiles means 4 or more nucleic acid tiles. In various preferred embodiments, the nucleic acid tiling array contains at least 6, 9, 16, 25, 36, 49, 64, 81, 100, 121, 144, 169, 206, 225, 256, 289, 324, 361, or 400 nucleic acid tiles.

[0086] As used herein, the term "nucleic acid probe" refers to a nucleic acid sequence synthesized as part of one or more core polynucleotide structure in the nucleic acid tile that does not participate in base pairing with other core polynucleotide structures or adjacent nucleic acid tiles. Thus, the nucleic acid probe is available for interactions with various "targets" to which it binds directly or indirectly.

[0087] As used herein, a "nucleic acid tiling array" is the assembled array of nucleic acid tiles of the invention based on specific Watson-Crick base pairing between sticky ends of different nucleic acid tiles. Each nucleic acid tile within the nucleic acid tiling array is located at a pre-determined position in the array, based on the complementarity of its "sticky ends" to sticky ends on a different nucleic acid tile. As will be apparent to those of skill in the art, a given nucleic acid tile may specifically bind to only one other nucleic acid tile in the nucleic acid tiling array (if the given nucleic acid tile is programmed with only a single sticky end), or it may interact with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more other nucleic acid tiles in the nucleic acid tiling array if the given nucleic acid tile has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more sticky ends, respectively. For example, closely packed arrays typically utilize 2-12 sticky ends, but more sticky ends might be used in an array that branched from a central point, as in a dendrimeric nucleic acid tiling array.

[0088] As discussed above, the nucleic acid tiles in the tiling array include "boundary tiles", nucleic acid tiles that are programmed for self-assembly at the edge of the nucleic acid tiling array based on their sticky end composition. As a result, the nucleic acid tiling array is finite. In a preferred embodiment, one or more boundary tiles in the nucleic acid tiling array further comprise modification of one or more polynucleotides that terminate further self-assembly. In a non-limiting example, the modification comprises addition of "TTT" (or some other sequence that has no complement within the array) overhangs at the parts of each tile that lies at the edge of the array (or adjacent to holes in it) such that the array must not be continued beyond those points. Alternatively, no sticky ends are placed on those sections of the tiles that lie at the edges of the arrays, terminating them instead with blunt-ended nucleic acid, such as double helical DNA (and thus these boundary tiles only have sticky ends to tie into the existing array, but not to extend it).

[0089] In a further embodiment, sticky-ends can be added to the edge of the finite size arrays, thus allowing hierarchical assembly of larger arrays with defined dimensions. In this embodiment, sticky ends that are not complementary to any of the stick ends on the nucleic acid tiling array, are added to the edge of the array to permit complementary binding to any other structure of interest, such as a second finite array.

[0090] In a further preferred embodiment, the nucleic acid tiling array comprises an indexing feature to orient the tiling array and thus facilitate identification of each individual nucleic acid tile in the array. Any indexing feature can be used, so long as it is located at some spot on the array that has a lower symmetry than the array itself. Examples of such indexing features include, but are not limited to: (1) including one or more tiles that impart(s) an asymmetry to the array; (2) including one or more tiles that is/are differentially distinguishable from the other tiles (for example, by a detectable label); for example, a biotin molecule that could later be marked by exposing the array to streptavidin; (3) including any protrusion on an edge of the array that is offset from two edges by unequal amounts, which will serve to index the array even if it is imaged upside down; (4) including a high point on the array that is detectable; (5) introducing one or more gaps in the tiling array that introduce a detectable asymmetry; and (6) making the nucleic acid tiling array of low enough symmetry with respect to rotations and inversions that locations on it could be identified unambiguously; for example, a nucleic acid tiling array in the shape of a letter "L" with unequal sized arms would serve such a purpose.

[0091] As used herein, a "sticky end" is a single stranded base sequence attached to the polynucleotide core of a nucleic acid tile. For each sticky end, there is a complementary sticky end on a different nucleic acid tile with which it is designed to bind, via base pairing, within the nucleic acid tiling array. Each nucleic acid tile must contain at least one sticky end (for example, in a boundary nucleic acid tile of certain embodiments), but may contain 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more sticky ends, depending on the design of the nucleic acid tiling array.

[0092] The sticky ends are incorporated into the nucleic acid tile as a portion of one or more of the core polynucleotides. Such incorporation can be carried out in a variety of ways, in part depending on the type of polynucleotide core used.

[0093] The length of the sticky ends for each nucleic acid tile can vary, depending on the desired spacing between nucleic acid tiles, the number of nucleic acid tiles in the nucleic acid tiling array, the desired dimensions of the nucleic acid tiling array, and any other design parameters such as the desired distance between ligands attached to the array. The sticky ends do not have to be of identical length for a given nucleic acid tile or relative to other nucleic acid tiles in the nucleic acid tiling array, so long as a complementary sticky end of an identical length is present on the nucleic acid tile to which it is designed to base pair. Alternatively, the sticky ends on all of the nucleic acid tiles can be of identical length. Particularly preferred lengths of the sticky ends are 4, 5, 6, 7, 8, 9, or 10 nucleotides.

[0094] In one preferred embodiment, each sticky end for a given nucleic acid tile is (a) different than the other sticky ends for that nucleic acid tile; (b) unique to that nucleic acid tile with respect to all other nucleic acid tiles in the array; and (c) complementary to a single sticky end of one other nucleic acid tile in the nucleic acid tiling array. As will be apparent to those of skill in the art, the polynucleotide structural element of each nucleic acid tile can be identical in this embodiment, so long as the sticky ends are unique. Thus, in this embodiment, a nucleic acid tiling array with "N" tiles is made by synthesizing "N" different tiles, each containing unique sticky-ends to connect to its neighboring tiles, so that each tile takes up a unique and well defined position in the array.

[0095] In a preferred embodiment, the nucleic acid tiles are not all unique (i.e.: some of the nucleic acid tiles may contain the same sticky ends). The nucleic acid tiling strategy in this embodiment takes advantage of the geometric symmetry of the nucleic acid tiling array. In general, to use a total of N tiles to construct a fixed size 2D nucleic acid tiling array with C.sub.m, symmetry, where m=2, 3, 4, or 6, the number of unique tiles the fixed size array requires is N/m, if N/m is an integral number, or Int (N/m)+1, if N/m is an non-integral number. This strategy is cost-effective in material, particularly when combined with embodiments where the polynucleotide structural element for each nucleic acid tile is identical. This embodiment minimizes polynucleotide design time and the sample preparation time dramatically. In these embodiments, the total number of unique sticky end pairs is preferably N*(N-1)/2.

[0096] In a preferred embodiment of each of the above embodiments, each nucleic acid tile comprises an identical polynucleotide structural element, which limits the number of different polynucleotides that must be synthesized and assembled. In this embodiment, the nucleic acid tiles differ in their sticky ends, which program the predetermined position of each nucleic acid tile in the nucleic acid tiling array. As disclosed below, the nucleic acid tiles in this and all other embodiments may contain further components in addition to the polynucleotide structural element and the sticky ends, and these further components may differ between different nucleic acid tiles.

[0097] In a preferred embodiment, the resulting nucleic acid tiling array is "non-periodic," meaning that the array does not include simple repetitive nucleic acid tile "patterns," such as ABABAB; ABCDABCD; ABABDCDCABABDCDC. This does not require that all of the tiles in the array be unique.

[0098] In another preferred embodiment, the nucleic acid nanostructure comprises or consists of a nucleic acid thread strand-based tile, comprises: (a) a nucleic acid thread strand; (b) a plurality of helper nucleic acid strands that are complementary to parts of the nucleic acid thread strand; wherein a plurality of the helper nucleic acid strands further comprises a nucleic acid probe; and wherein the nucleic acid thread strand is folded into a desired shape by hybridization to the helper strands; wherein the nucleic acid thread strand is not complementary to any of the nucleic acid probes, and wherein the predetermined size of the array is determined by the length and shape of the nucleic acid thread strand as folded by helper strands.

[0099] As used herein, "the nucleic acid thread strand is not complementary to any of the nucleic acid probes" means that the nucleic acid probes do not base pair with the thread strand over the length of the nucleic acid probe under the conditions used, and thus the helper strands are available for interactions with a target. In this embodiment, no sticky ends are required for self-assembly.

[0100] The nucleic acid thread strand can be any suitable polynucleotide of appropriate length and sequence for the desired nucleic acid tile. In one embodiment, the nucleic acid thread strand is a genomic nucleic acid strand, or suitable fragments thereof, such as from a virus, bacterium, or indeed any organism from which long DNA can be extracted. The only caveat is that the chosen section of genomic nucleic acid should not have sequences that are complementary to the probe sequences, and they should not contain significant amounts of repeated sequences or other sequences that might form structures that interfere with assembly of the array (such the G-rich regions that might form quadruplexes as in telomere DNA).

[0101] In a preferred embodiment, genomic nucleic acid, or fragments thereof, is used as the nucleic acid thread for lengths above about 50 bp where synthetic nucleic acid becomes expensive and difficult to make. Lengths up to the full length of an organism's genome (ca. 10.sup.9 bp) are feasible if they met the sequence criteria described above.

[0102] The nucleic acid helper strands are complementary to regions of the nucleic acid thread and not to each other, and are designed to hybridize to the nucleic acid thread strand so as to constrain the nucleic acid thread strand into a desired shape. A plurality of the nucleic acid helper strands comprises nucleic acid probes. In one embodiment, helper strands are between 10 and 50 nucleotides, not including any DNA probe that is part of the helper strand.

[0103] In a further embodiment, the nucleic acid thread-based tile further comprises nucleic acid filler strands that hybridize to the nucleic acid thread strand. These strands are not involved in shaping the nucleic acid thread strand, but add further structural integrity to the resulting nucleic acid tile. It is further preferred that a plurality of the nucleic acid filler strands further comprises a nucleic acid probe.

[0104] In another embodiment, one or more of the helper strands can be part of a larger nucleic acid structure. In one example, one or more helper strands protrude from one or more nucleic acid tiles. The helper strands fold the thread strand into place, and the nucleic acid tiles (and their nucleic acid probes) comprising the helper strands are thus precisely positioned on the thread strand.

[0105] In another embodiment, one or more of the helper strands may protrude from one or more nucleic acid arrays (formed by combining two or more nucleic acid tiles). In this embodiment, one or more helper strands protrude from one or more tiling arrays and fold the thread strand into place, and the tiling arrays (and the nucleic acid tiles they are composed of, including nucleic acid probes) comprising the helper strands are thus precisely positioned on the thread strand. In this embodiment, it is possible, for example, to provide unlimited hierarchies of nucleic acid tiling arrays.

[0106] The dimensions of a given nucleic acid thread strand-based tile can be programmed, based on the available length and sequence of thread strand nucleic acid, and other design elements. For example, a 10,000 base thread strand nucleic acid could be formed into a nucleic acid tile covering an area of approximately 2 nm.times.10,000.times.0.3 nm or 6.times.10.sup.-15 m.sup.2. This would correspond to a square of about 0.1 .mu.m on each side. Depending upon the design of the thread strand-based nucleic acid tile, the size of the nucleic acid probe, the specific target, and other design feature, the density of target molecules on the nucleic acid tile can be as high as 10.sup.12 per square cm.

[0107] In this most preferred embodiment, the nucleic acid thread-based tile can be assembled in one step. A long template strand of nucleic acid is mixed with shorter `helper` strands, usually in a large molar excess of the shorter strands. The strand sequences are chosen to fold the long template strand into the desired shape, as described by Yan et al. (Proceedings of the National Academy of Sciences 100, Jul. 8, 2003 pp 8103-8108.) The probe array is then achieved by using one or more helper strands with nucleic acid probes that are not complementary to any part of the template strand or the other helper strands. These will then protrude from the array, forming single stranded probe strands at known locations if the array contains an index feature. General conditions for such hybridization are known in the art.

[0108] The scalable feature of the aptamer-nucleic acid nanostructure makes it easy to assemble additional immune modulating ligands to synergize the cell-death pathways and maximize cancer cell killing. In certain advantageous embodiments, the aptamer nucleic acid nanostructure of the invention further comprises an apoptosis inducer that is bound to the nucleic acid nanostructure. Suitable apoptosis inducers for use in the instant invention include without limitation shRNA, siRNA, decoy oligonucleotides for STAT3 or NF-.kappa.B. Exemplary decoy oligonucleotides include double stranded deoxyoligonucleotides with a hairpin end containing single or multiple copies of NF-.kappa.B binding site (GGATTTCCC) or STAT3 binding site (CATTTCCCGTAAATC, SEQ ID NO:33), such that these oligonucleotides can bind to NF-.kappa.B or STAT3, blocking the NF-.kappa.B- or STAT3-mediated anti-apoptotic responses in the cells. NF-.kappa.B activation is known to protect cells from apoptosis and NF-.kappa.B inhibitors can sensitize tumor cells to targeted apoptosis by TRAIL-R agonists (Franco et al., 2001. J Immunol 166:5337-5345). Thus, in certain preferred embodiments, the apoptosis inducer is an NF-.kappa.B inhibitor; in certain other preferred embodiments, the NF-.kappa.B inhibitor is a NF-.kappa.B decoy oligonucleotide as illustrated in FIG. 6. Without being limited to certain specific mechanisms, in certain preferred embodiments, once the aptamer-nucleic acid nanostructure is internalized inside the tumor cell, the apoptosis inducer can trigger and activate the intrinsic apoptosis pathway to facilitate tumor cell killing. The assembled aptamer nucleic acid nanostructure is analogous to a "Trojan Horse" in the sense that it carries an array of arsenals of predetermined amounts to the target tumor cells to induce apoptosis.

[0109] In certain other preferred embodiments, alternative or additional apoptosis-sensitizing molecules can be included in the aptamer-nucleic acid nanostructure. For example, interfering RNA (RNAi), which can down-regulate the expression of several anti-apoptotic genes, such as survivin, bcl-2 and cFLIP, can be readily inserted into the aptamer-nucleic acid nanostructure. In certain preferred embodiments, the RNAi becomes dissociated from the nanostructure and enters the nucleus after the aptamer-nucleic acid nanostructure is internalized into the tumor cell.

[0110] In certain preferred embodiments the nucleic acid nanostructure comprises one type of apoptosis inducers present at a density of 2-10, 2-5, 4-10, 4-8, 5-10, 8-10 per nucleic acid nanostructure. In other preferred embodiments, the apoptosis inducers are present at a density of 4-10 per nucleic acid nanostructure. In certain other preferred embodiments, the nucleic acid nanostructure comprises at least two types of apoptosis inducers each present at a density of 2-10, 2-5, 4-10, 4-8, 5-10, 8-10 per nucleic acid nanostructure. In certain preferred embodiments, each type of apoptosis inducers is present at a density of 4-10 per nucleic acid nanostructure. In certain other preferred embodiments, the two types of apoptosis inducers are present at a ratio of 1:1, 1:2, or 1:3. In certain preferred embodiments, the nucleic acid nanostructure comprises NF-kB and STAT3 decoy oligonucleotides. In certain preferred embodiments, these two types of apoptosis inducers are present at a ratio of 1:1.

[0111] Such multi-functional aptamer-nucleic acid nanostructures described herein comprising tumor-targeting and tumor-killing activities are advantageous for target-specific cancer treatment. Attempts have been made to develop nanocarriers as delivery platforms to assemble multi-functional molecules, such as drugs, genes and vaccines, in liposomes or virus-like particles (VLPs) for treating cancer or immunodisorders (Jabr-Milane et al., 2008, J Control Release 130:121-128; Peek et al., 2008, Adv Drug Deliv Rev 60:915-928). The inventive aptamer-nucleic acid nanostructure, however, provides the critical spatial arrangement or precise ratio control that is not possible in other systems. TRAIL-induced apoptosis are dependent on the cross-linking and/or oligomerization of their cognate receptors, which is greatly facilitated by the adjustable structural configurations of the aptamers on the nucleic acid nanostructure as described herein.

[0112] The inventive nucleic acid nanostructure can be designed by incorporating 5-10 nucleotides single-stranded oligo-dT to increase flexibility--incorporation of longer single-stranded oligo-dT increases flexibility and reduces rigidity of the nucleic acid nanostructure. See Hasegawa et al., 2008. Sensors 8:1090-1098. The rigidity and well-defined geometry of nucleic acid nanostructures provide superb spatial and orientational control of the ligands on the array. The spacing of the ligands and their positioning with respect to, for example, a tiling array surface can be precisely controlled to the sub-nanometer scale. This not only allows optimization of geometry for fast kinetics, it also allows efficient rebinding of the receptor to nearby ligands and leads to improved binding efficiency. The well separated positioning of the ligands/aptamers on the array also allows efficient binding of different receptors to bind corresponding ligands or aptamers on the tiling array.

[0113] As will be apparent to those of skill in the art, in this embodiment, not all of the nucleic acid tiles in a nucleic acid tiling array are required to possess an aptamer. Thus, one or more of the nucleic acid tiles in the nucleic acid tiling array comprises an aptamer; preferably a majority of the nucleic acid tiles in the array comprise an aptamer; more preferably all of the nucleic acid tiles comprise an aptamer.

[0114] All embodiments of aptamers, linkers, etc. described herein are applicable to this aspect of the invention as well. All embodiments of this aspect can be applied to any other aspects of the invention.

[0115] In yet another aspect, the invention provides methods of making an aptamer-nucleic acid nanostructure, the method comprising contacting a first aptamer, a second aptamer, and at least one polynucleotide under conditions suitable for binding of the first and second aptamers to the polynucleotide to form an aptamer-DNA nanostructure, wherein the first aptamer is specific for binding to a tumor cell and the second aptamer is specific for binding to a death receptor on the tumor cell, and wherein the polynucleotide forms a nucleic acid nanostructure. In certain preferred embodiments, the first and second aptamers directly bind to the polynucleotide, or indirectly through a connector polynucleotide or a nucleic acid probe that is bound to the polynucleotide. In various other preferred embodiments, the first and second aptamers bind to the polynucleotide non-covalently by ways of, including without limitation, base pairing and biotin-streptavidin interaction. In certain preferred embodiments of this aspect, the polynucleotide is part of a nucleic acid tile.

[0116] In another embodiment, the aptamer-nucleic acid nanostructure comprises a plurality of polynucleotides, and wherein the contacting is done under conditions suitable to promote hybridization of the plurality of polynucleotides into at least one nucleic acid tile. In yet further preferred embodiments, the plurality of polynucleotides forms a plurality of nucleic acid tiles, and wherein the plurality of nucleic acid tiles forms at least one nucleic acid tiling array.

[0117] The particular hybridization buffers and other conditions employed can vary depending on the polynucleotide lengths and sequences, and are well within the level of skill in the art based on the teachings herein. Any suitable hybridization conditions known in the art can be adopted. Exemplary hybridization conditions are provided as follows. The nucleic acid nanostructures carry a considerable negative charge at low salt, and therefore hybridization in the presence of a significant amount of salt (e.g., 10 mM MgCl.sub.2 or 600 mM or greater monovalent salt like NaCl) is preferred. Other typical annealing conditions include 1 M NaCl, 10 mM NaHPO.sub.4 (pH7). Aptamers (when included as ligands) typically require 10 mM MgCl.sub.2 to fold properly. General parameters for hybridization conditions for nucleic acids are described in Sambrook et al., supra, and in Ausubel et al., 1987, Current Protocols in Molecular Biology, Greene Publishing and Wiley-Interscience, New York.

[0118] In certain preferred embodiments, the stoichiometric amount of each polynucleotide in a nucleic acid nanostructure is combined under denaturing conditions, such as between 90.degree. C. and 99.degree. C., followed by cooling to between 25.degree. C. and 50.degree. C. in appropriate hybridization buffer, as can be determined by those of skill in the art. In a preferred embodiment, annealing protocols involve a high temperature and low salt denaturing step, followed by a low temperature high salt annealing step. In this embodiment, the high salt concentrations are not added to the reaction until the polynucleotides are removed from the heat and placed on ice.

[0119] The polynucleotide concentration used can vary, and those of skill in the art, based on the teachings provided herein and known in the art, can determine appropriate concentrations. In one embodiment, polynucleotide concentration is between 1 nm and 10 .mu.M.

[0120] In certain preferred embodiments, the nucleic acid nanostructure comprises a plurality of nucleic acid tiles that is combined under conditions suitable to promote hybridization of the sticky ends between different nucleic acid tiles. In a preferred embodiment, such suitable conditions include incubation in appropriate hybridization solution at a beginning temperature of between 25.degree. C. and 45.degree. C., followed by cooling in the same hybridization buffer to between 5.degree. C. and 25.degree. C. over 1 hour to 24 hours. The specific condition chosen need to balance the needs between avoiding disassembly of the tiles, which generally have melting temperatures in the range of 50-65.degree. C., and to eliminate the possible mismatches among the different sticky ends of the tiles. In a preferred embodiment, the buffer condition used comprises 40 mM Tris, 20 mM acetic acid, 2 mM EDTA, and 12.5 mM magnesium acetate, pH 8.0.

[0121] In a preferred embodiment, synthesis of the nucleic acid tiling arrays comprises separating free nucleic acid tiles and/or incompletely hybridized nucleic acid tiles from completely formed nucleic acid tiling arrays. Any appropriate separation method can be used, including but not limited to size exclusion chromatography, sucrose gradient centrifugation, and affinity based separation techniques. In a preferred embodiment, the nucleic acid tiling arrays are chemically modified so as to permit affinity-based separation techniques. Any chemical modification that permits such affinity-based separation techniques can be used, including but not limited to, chemically modifying the nucleic acid tiling array to contain one or more biotin residues, which can then be used for streptavidin-based affinity separation of the nucleic acid tiles.

[0122] The aptamer-nucleic acid nanostructures of the invention can be made and stored as described herein. In various preferred embodiments, the aptamer-nucleic acid nanostructures may be present in solution, or in lyophilized form. All the preferred embodiments of this aspect of methods of making an aptamer-nucleic acid nanostructure can be used in conjunction with in any other aspects of the invention.

[0123] In yet another aspect, the invention provides a method of treating a tumor in a mammal comprising administering to a mammal in need thereof an amount effective to treat the tumor of a composition comprising a first ligand that is specific for a tumor cell, and a second ligand that is specific for a death receptor on the tumor cell, wherein the first and second ligands are bound to a nucleic acid nanostructure. In certain preferred embodiments, the first ligand is a first aptamer and the second ligand is a second aptamer.

[0124] Without being bound or limited to a particular mechanism, in certain preferred embodiments, the first aptamer binds to tumor antigen on a tumor cell and the second aptamer binds to a TRAIL receptor on the tumor cell, wherein the aptamer nucleic acid nanostructure targets specifically to tumor cells by the binding of the first aptamer with the tumor antigen, and triggers TRAIL receptor oligomerization and apoptosis of the tumor cell by the binding of the second aptamer to the TRAIL receptor.

[0125] As used herein, the terms "treatment" and "treating" means (i) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, such as preventing tumor growth and/or metastasis; (ii) limiting the disease; for example, limiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; for example, limiting tumor growth and/or metastasis, or limiting the rate of tumor growth and/or metastasis, or extending patient survival relative to untreated patents; and (iii) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease, such as decreasing tumor size and/or incidence of metastasis. Suitable tumor cells include without limitation lymphoma cell, breast cancer cell, melanoma cell, plasmacytoma cell, sarcoma cell, glioma cell, thymoma cell, leukemia cell, prostate cancer cell, colon cancer cell, esophageal cancer cell, lung cancer cell, ovarian cancer cell, cervical cancer cell and hepatoma cell.

[0126] In a further aspect, the invention provides methods of treating tumor in a mammal comprising administering to a mammal in need thereof an amount effective to treat the tumor of a composition that comprises a first ligand that is specific for a tumor cell, and a second ligand that is specific for a death receptor on the tumor cell, wherein the first and second ligands are bound to a nucleic acid nanostructure. In certain preferred embodiments, the first ligand is a first aptamer and the second ligand is a second aptamer. All preferred embodiments applicable to the other aspect of the invention with regard to the inventive aptamer-nucleic acid nanostructures also apply to this aspect of the invention.

[0127] In certain preferred embodiments, the inventive composition is injected into a subject in conjunction with a pharmaceutical acceptable carrier, diluent or excipient known to one of skill in the art for modifying, maintaining, or preserving, in a manner that does not hinder the activities of the inventive composition described herein, for example, pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobial compounds, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite), buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, betacyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as serum albumin, gelatin, or immunoglobulins), coloring, flavoring and diluting agents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), solvents (such as glycerin, propylene glycol, or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants or wetting agents (such as pluronics; PEG; sorbitan esters; polysorbates such as polysorbate 20 or polysorbate 80; Triton; trimethamine; lecithin; cholesterol or tyloxapal), stability enhancing agents (such as sucrose or sorbitol), tonicity enhancing agents (such as alkali metal halides--preferably sodium or potassium chloride--or mannitol sorbitol), delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants. See REMINGTON'S PHARMACEUTICAL SCIENCES (18th Ed., A. R. Gennaro, ed., Mack Publishing Company 1990).

[0128] As used herein, the term "subject" refers to an animal or a mammal and in particular preferred embodiments, a human, in need of the tumor therapy using the inventive compositions.

[0129] The primary vehicle or carrier in a pharmaceutical composition may be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier for injection may be physiological saline solution, or artificial cerebrospinal fluid. Optimal pharmaceutical compositions can be determined by a skilled artisan depending upon, for example, the intended route of administration, delivery format, desired dosage and recipient tissue. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, supra. Such compositions may influence the physical state, stability, and effectiveness of the composition.

[0130] The pharmaceutical composition to be used for in vivo administration typically is sterile and pyrogen-free. In certain preferred embodiments, this may be accomplished by filtration through sterile filtration membranes. In certain preferred embodiments, where the composition is lyophilized, sterilization using this method may be conducted either prior to or following lyophilization and reconstitution. In certain preferred embodiments, the composition for parenteral administration may be stored in lyophilized form or in a solution. In certain preferred embodiments, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0131] Once the pharmaceutical composition of the invention has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form or in a form (e.g., lyophilized) that is reconstituted prior to administration.

[0132] The effective amount of a pharmaceutical composition of the invention to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment, according to certain preferred embodiments, will thus vary depending, in part, upon the molecule delivered, the indication for which the pharmaceutical composition is being used, the route of administration, and the size (body weight, body surface or organ size) and/or condition (the age and general health) of the patient. A clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect. Aptamers delivered at 40-400 .mu.g/kg have been shown to be effective in vivo (McNamara wt al., 2008. J Clin Invest 118:376-386).

[0133] The dosing frequency will depend upon the pharmacokinetic parameters of an aptamer-nucleic acid nanostructure in the formulation. For example, a clinician administers the composition until a dosage is reached that achieves the desired effect. The composition may therefore be administered as a single dose or as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages may be ascertained through use of appropriate dose-response data.

[0134] Administration routes for the pharmaceutical compositions of the invention include topically, orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, subcutaneous, or intralesional routes; by sustained release systems or by implantation devices. The pharmaceutical compositions may be administered by bolus injection or continuously by infusion, or by implantation device. The pharmaceutical composition also can be administered locally via implantation of a membrane, sponge or another appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device may be implanted into any suitable tissue or organ, and delivery of the desired molecule may be via diffusion, timed-release bolus, or continuous administration.

[0135] One of skill in the art would understand that all embodiments described herein in any aspect of the invention can be applied in any other aspects of the invention.

[0136] The Examples, which follow, are illustrative of specific embodiments of the invention, and various uses thereof. They are set forth for explanatory purposes only, and are not to be taken as limiting the invention.

EXAMPLES

Example 1

Selection of Aptamers

[0137] Aptamers having desirable binding affinity to a tumor antigen on B leukemia Ramos cells are selected from a random aptamer library. Because the Ramos cells express primarily TRAIL-R1, aptamers that specifically bind to TRAIL-R1 are also selected from the random aptamer library. Specifically, TRAIL-R1-Fc fusion protein (catalog No. D9438, Sigma, St. Louis, Mo.), as well as decoy receptors-Fc fusion proteins (catalog No. 630-TR-100, R & D Systems, Minneapolis, Minn.) are incubated with the aptamer library. Candidate aptamers having binding affinity to the TRAIL-R1-Fc fusion protein but not to the decoy receptor-Fc fusion proteins are identified by capillary electrophoresis. Aptamer-fusion protein complexes are detected by the retardation of migration rate in electrophoresis. Candidate aptamers are amplified by the SELEX procedure as known in the art and described in this application.

Example 2

Construction of Bi-Specific Aptamer-Nucleic Acid Nanostructure for Tumor-Specific Killing

[0138] Although TRAIL-Rs are primarily expressed in tumor cells, they are also found present in normal cells and have been suggested to account for TRAIL-induced toxicity (Zheng et al., 2004, J Clin Invest 113:58-64). To achieve tumor-specific targeting, bi-specific aptamer-nucleic acid nanostructures containing tumor-specific aptamers and death receptor-specific aptamers on a DNA-nanostructure are generated. The aptamer M2 as previously reported that is specific to Ramos cells, and does not bind to T-cell leukemia cells has been reported (Shangguan et al., 2006, Proc Natl Acad Sci USA 103:11838-11843) (M2 aptamer: 5'-TAGGCAGTGGTTTGACGTCCGCATG TTGGGAATAGCCACGCCT-3', SEQ ID NO:42). The tumor-specific aptamers M2 are assembled onto a DNA-nanostructure along with the death-inducible aptamers, in which various configurations will be constructed, in terms of position and copy numbers of aptamers, as well as ratio of the tumor-specific and death receptor-specific aptamers as described throughout this application. The optimal configuration is selected based on their ability to induce tumor-specific apoptosis.

[0139] Multimerization further improves the binding avidity of aptamers. The bi-specific aptamer nucleic acid nanostructures contain not only multiple copies of aptamers, but also multivalent aptamers. Competitive inhibition assays were performed where Ramos cells were incubated with fluorescence-labeled monomeric aptamers in the presence of different concentrations of non-labeled monomeric, dimeric or tetrameric aptamers. As shown in FIG. 4, the tetramers most efficiently competed with the labeled monomers for binding to Ramos cells.

[0140] The multimeric aptamers are used to construct bi-specific aptamer-DNA nanostructures, which contain the Ramos cell-specific aptamers and aptamers specific for TRAIL-R1 arranged at defined position, as illustrated in FIG. 1. These aptamer-DNA nanostructures are tested for their ability to induce apoptosis in Ramos but not in Jurkat cells because the M2 aptamer is specific for Ramos cells. In addition, aptamer-nucleic acid nanostructures containing other Ramos cell-specific aptamers identified by methods described in this application along with TRAIL-R1-aptamers are constructed and tested for targeted induction of apoptosis in tumor cells as described below.

[0141] Approximately 200,000 human B cell lymphoma Ramos cells are incubated with multimeric aptamer-DNA nanostructures at various concentrations in 0.5 ml culture medium (RPMI supplemented with 10% FBS and antibiotics) at 37.degree. C. Twenty-four hours after the incubation, cells are stained with 1 .mu.g/ml propidium iodide (PI) and analyzed by flow cytometry, where PI-positive cells indicate dead cells. Anti-DR4 or DRS antibodies (for example, catalog Nos. ab8414 and ab47179, respectively, AbCam, Cambridge, Mass.), as well as the DNA damaging agent etoposide are included as a positive control for the induction of apoptosis. Cells cultured in the medium only without the aptamer-DNA nanostructures are served as a negative control, reflecting the background number of dead cells in the culture.

Example 3

Aptamers Remained Stable Under Different Conditions

[0142] The stability of the dimeric aptamers was tested in this experiment. The dimeric B cell-specific aptamer M1, which consisted of monomeric aptamer M2, was incubated in the culture medium (1 mg/ml BSA in PBS) with or without human B cell lymphoma at different temperatures. After incubation, aptamers were recovered from the cell mixture by spinning down the cells. The supernatants were treated with phenol/chloroform to remove proteins, and the aptamers were precipitated by 95% ethanol. The recovered aptamer DNA was dissolved in H.sub.2O and separated by a native polyacrylamide gel (16%) to check the integrity of the aptamers-nanostructure.

[0143] As shown in FIG. 5, the integrity and levels of recovered aptamers were comparable under all conditions tested, including incubating with or without cells in the culture medium at 4.degree. C., room temperature, and 37.degree. C. Thus, this multimeric aptamer-DNA nanostructure was relatively stable in cell culture. Chemical modifications are introduced to further enhance the stability of the aptamer-DNA nanostructure. See Keefe et al., 2008, Curr Opin Chem Biol 12:448-456.

Example 4

Multi-Functional Aptamer-Nucleic Acid Nanostructure is Constructed for Synergized Tumor Cells Killing

[0144] In further experiments, factors promoting apoptosis are included into the aptamer-nucleic acid nanostructures to provided synergized tumor cell killing. An NF-.kappa.B decoy oligonucleotide comprising the sequence 5'-GGATTTCCC-3' that functions as NF-.kappa.B inhibitor is incorporated into the aptamer-nucleic acid nanostructures (see FIG. 6). The number and position as well as the ratio of NF-.kappa.B decoy oligonucleotides to the aptamer molecules are evaluated during the construction of these multifunctional complexes. The levels of apoptosis induction are compared between these multifunctional aptamer-nucleic acid nanostructures containing NF-.kappa.B inhibitor and the bi-specific nanostructures that do not contain an NF-.kappa.B inhibitor.

[0145] It should be understood that the foregoing disclosure emphasizes certain specific embodiments of the invention and that all modifications or alternatives equivalent thereto are within the spirit and scope of the invention as set forth in the appended claims.

Sequence CWU 1

1

6113594DNAHomo sapiensCDS(417)..(1310) 1gtctatcagc gatttcatct tcaggcctgg actacaccac tcaccctccc agtgtgcttg 60agaaacaaac tgcacccact gaactccgca gctagcatcc aaatcagccc ttgagatttg 120aggccttgga gactcagatc ctgaacaaga gagaacaaaa tctctacttt gatggaactt 180ccattctgtg gggaagagac tgacaataag caattaaata aataagaact cagcagtagg 240ccttgcctca gatccaaggt cactcggaag aggccatgtc taccctcaat gacactcatg 300gaggaaatgc tgagagaagc attcagatgc atgacacaag gtaagactgc caaaaatctt 360gttcttgctc tcctcatttt gttatttgtt ttatttttag gagttttgag agcaaa atg 419 Met 1 aca aca ccc aga aat tca gta aat ggg act ttc ccg gca gag cca atg 467Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro Met 5 10 15 aaa ggc cct att gct atg caa tct ggt cca aaa cca ctc ttc agg agg 515Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg Arg 20 25 30 atg tct tca ctg gtg ggc ccc acg caa agc ttc ttc atg agg gaa tct 563Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu Ser 35 40 45 aag act ttg ggg gct gtc cag att atg aat ggg ctc ttc cac att gcc 611Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile Ala 50 55 60 65 ctg ggg ggt ctt ctg atg atc cca gca ggg atc tat gca ccc atc tgt 659Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile Cys 70 75 80 gtg act gtg tgg tac cct ctc tgg gga ggc att atg tat att att tcc 707Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile Ser 85 90 95 gga tca ctc ctg gca gca acg gag aaa aac tcc agg aag tgt ttg gtc 755Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu Val 100 105 110 aaa gga aaa atg ata atg aat tca ttg agc ctc ttt gct gcc att tct 803Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile Ser 115 120 125 gga atg att ctt tca atc atg gac ata ctt aat att aaa att tcc cat 851Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser His 130 135 140 145 ttt tta aaa atg gag agt ctg aat ttt att aga gct cac aca cca tat 899Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro Tyr 150 155 160 att aac ata tac aac tgt gaa cca gct aat ccc tct gag aaa aac tcc 947Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn Ser 165 170 175 cca tct acc caa tac tgt tac agc ata caa tct ctg ttc ttg ggc att 995Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly Ile 180 185 190 ttg tca gtg atg ctg atc ttt gcc ttc ttc cag gaa ctt gta ata gct 1043Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile Ala 195 200 205 ggc atc gtt gag aat gaa tgg aaa aga acg tgc tcc aga ccc aaa tct 1091Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys Ser 210 215 220 225 aac ata gtt ctc ctg tca gca gaa gaa aaa aaa gaa cag act att gaa 1139Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile Glu 230 235 240 ata aaa gaa gaa gtg gtt ggg cta act gaa aca tct tcc caa cca aag 1187Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro Lys 245 250 255 aat gaa gaa gac att gaa att att cca atc caa gaa gag gaa gaa gaa 1235Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu Glu 260 265 270 gaa aca gag acg aac ttt cca gaa cct ccc caa gat cag gaa tcc tca 1283Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser Ser 275 280 285 cca ata gaa aat gac agc tct cct taa gtgatttctt ctgttttctg 1330Pro Ile Glu Asn Asp Ser Ser Pro 290 295 tttccttttt taaacattag tgttcatagc ttccaagaga catgctgact ttcatttctt 1390gaggtactct gcacatacgc accacatctc tatctggcct ttgcatggag tgaccatagc 1450tccttctctc ttacattgaa tgtagagaat gtagccattg tagcagcttg tgttgtcacg 1510cttcttcttt tgagcaactt tcttacactg aagaaaggca gaatgagtgc ttcagaatgt 1570gatttcctac taacctgttc cttggatagg ctttttagta tagtattttt ttttgtcatt 1630ttctccatca acaaccaggg agactgcacc tgatggaaaa gatatatgac tgcttcatga 1690cattcctaaa ctatcttttt tttattccac atctacgttt ttggtggagt cccttttgca 1750tcattgtttt aaggatgata aaaaaaaata acaactaggg acaatacaga acccattcca 1810tttatctttc tacagggctg acattgtggc acattcttag agttaccaca ccccatgagg 1870gaagctctaa atagccaaca cccatctgtt ttttgtaaaa acagcatagc ttatacatgg 1930acatgtctct gccttaactt ttcctaactc ccactctagg ctattgtttg catgtctacc 1990tacttttagc cattatgcga gaaaagaaaa aaatgaccat agaaaatgcc accatgaggt 2050gcccaaattt caaataataa ttaacattta gttatattta taatttccag atgacaaagt 2110atttcatcaa ataacttcat ttgatgttcc atgatcaaga aagaatccct atctctattt 2170tacaagtaat tcaaagaggc caaataactt gtaaacaaga aaaggtaact tgtcaacagt 2230cataactagt aattatgaga gccttgtttc ataaccaggt cttcttactc aaatcctgtg 2290atgtttgaaa taaccaaatt gtctctccaa tgtctgcata aactgtgaga gccaagtcaa 2350cagcttttat caagaattta ctctctgacc agcaataaac aagcactgag agacacagag 2410agccagattc agattttacc catggggata aaaagactca gactttcacc acatttggaa 2470aactacttgc atcataaata tataataact ggtagtttat atgaagcaga cactaagtgc 2530tatagacact ctcagaatat catacttgga aacaatgtaa ttaaaatgcc gaatctgagt 2590caacagctgc cctacttttc aattcagata tactagtacc ttacctagaa ataatgttaa 2650cctagggtga agtcactata atctgtagtc tattatttgg gcatttgcta catgatgagt 2710gctgccagat tgtggcaggt aaagagacaa tgtaatttgc actccctatg atatttctac 2770atttttagcg accactagtg gaagacattc cccaaaatta gaaaaaaagg agatagaaga 2830tttctgtcta tgtaaagttc tcaaaatttg ttctaaatta ataaaactat ctttgtgttc 2890ttttctgcaa cagatgattc caacatgggt gtttgtctat tcttctttac tcttgaaaca 2950ttagaccatg ggaggctctt acagccttga gttgatattt atacaaccca aatctaggtt 3010tgaacggtga ggtgtcaggt catcaaatat tcatgtctat atagtcttac acaggttctc 3070aaaaaaaatg ttcatgggat aggtcattga taatggattc cttattctga gaactccaga 3130cgactgaaat atatgagaga aggaaaagga catagtagga gcaggcctga gaaaaaaatg 3190aaagtcagaa atctttaaaa aaatacaaga tcttatttct atcttatttt ttctcctctt 3250ctgaaatata tatgaggatt cctctccaaa cccatggttt ctctaagaat tttgagtcat 3310ttgtatgacc tcaaataatt agttttagct gacctcacat aactccttat aataggagac 3370atctttaatg tctgctatta aagaaggatg aaaattccta tgaccttctc cccgattatc 3430cctttggcaa tatagagtca aataataaca ttgaccaata gtaaacatgc tttgccaaga 3490agtagaagat atattctcta gccttagttt ttcctcccaa tttgcatttt tgtaaaaata 3550atgttgtatc cacaaaggaa ataaacttta aaaacccaag tgca 35942297PRTHomo sapiens 2Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro 1 5 10 15 Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg 20 25 30 Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu 35 40 45 Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile 50 55 60 Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile 65 70 75 80 Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile 85 90 95 Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu 100 105 110 Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile 115 120 125 Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser 130 135 140 His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro 145 150 155 160 Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn 165 170 175 Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly 180 185 190 Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile 195 200 205 Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys 210 215 220 Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile 225 230 235 240 Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro 245 250 255 Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu 260 265 270 Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser 275 280 285 Ser Pro Ile Glu Asn Asp Ser Ser Pro 290 295 34816DNAHomo sapiensCDS(521)..(4198) 3gttcccggat ttttgtgggc gcctgccccg cccctcgtcc ccctgctgtg tccatatatc 60gaggcgatag ggttaaggga aggcggacgc ctgatgggtt aatgagcaaa ctgaagtgtt 120ttccatgatc ttttttgagt cgcaattgaa gtaccacctc ccgagggtga ttgcttcccc 180atgcggggta gaacctttgc tgtcctgttc accactctac ctccagcaca gaatttggct 240tatgcctact caatgtgaag atgatgagga tgaaaacctt tgtgatgatc cacttccact 300taatgaatgg tggcaaagca aagctatatt caagaccaca tgcaaagcta ctccctgagc 360aaagagtcac agataaaacg ggggcaccag tagaatggcc aggacaaacg cagtgcagca 420cagagactca gaccctggca gccatgcctg cgcaggcagt gatgagagtg acatgtactg 480ttgtggacat gcacaaaagt gagtgtgcac cggcacagac atg aag ctg cgg ctc 535 Met Lys Leu Arg Leu 1 5 cct gcc agt ccc gag acc cac ctg gac atg ctc cgc cac ctc tac cag 583Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His Leu Tyr Gln 10 15 20 ggc tgc cag gtg gtg cag gga aac ctg gaa ctc acc tac ctg ccc acc 631Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr Leu Pro Thr 25 30 35 aat gcc agc ctg tcc ttc ctg cag gat atc cag gag gtg cag ggc tac 679Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val Gln Gly Tyr 40 45 50 gtg ctc atc gct cac aac caa gtg agg cag gtc cca ctg cag agg ctg 727Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu Gln Arg Leu 55 60 65 cgg att gtg cga ggc acc cag ctc ttt gag gac aac tat gcc ctg gcc 775Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr Ala Leu Ala 70 75 80 85 gtg cta gac aat gga gac ccg ctg aac aat acc acc cct gtc aca ggg 823Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro Val Thr Gly 90 95 100 gcc tcc cca gga ggc ctg cgg gag ctg cag ctt cga agc ctc aca gag 871Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser Leu Thr Glu 105 110 115 atc ttg aaa gga ggg gtc ttg atc cag cgg aac ccc cag ctc tgc tac 919Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln Leu Cys Tyr 120 125 130 cag gac acg att ttg tgg aag gac atc ttc cac aag aac aac cag ctg 967Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn Asn Gln Leu 135 140 145 gct ctc aca ctg ata gac acc aac cgc tct cgg gcc tgc cac ccc tgt 1015Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys His Pro Cys 150 155 160 165 tct ccg atg tgt aag ggc tcc cgc tgc tgg gga gag agt tct gag gat 1063Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser Ser Glu Asp 170 175 180 tgt cag agc ctg acg cgc act gtc tgt gcc ggt ggc tgt gcc cgc tgc 1111Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys Ala Arg Cys 185 190 195 aag ggg cca ctg ccc act gac tgc tgc cat gag cag tgt gct gcc ggc 1159Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys Ala Ala Gly 200 205 210 tgc acg ggc ccc aag cac tct gac tgc ctg gcc tgc ctc cac ttc aac 1207Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu His Phe Asn 215 220 225 cac agt ggc atc tgt gag ctg cac tgc cca gcc ctg gtc acc tac aac 1255His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val Thr Tyr Asn 230 235 240 245 aca gac acg ttt gag tcc atg ccc aat ccc gag ggc cgg tat aca ttc 1303Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg Tyr Thr Phe 250 255 260 ggc gcc agc tgt gtg act gcc tgt ccc tac aac tac ctt tct acg gac 1351Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu Ser Thr Asp 265 270 275 gtg gga tcc tgc acc ctc gtc tgc ccc ctg cac aac caa gag gtg aca 1399Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln Glu Val Thr 280 285 290 gca gag gat gga aca cag cgg tgt gag aag tgc agc aag ccc tgt gcc 1447Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys Pro Cys Ala 295 300 305 cga gtg tgc tat ggt ctg ggc atg gag cac ttg cga gag gtg agg gca 1495Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu Val Arg Ala 310 315 320 325 gtt acc agt gcc aat atc cag gag ttt gct ggc tgc aag aag atc ttt 1543Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys Lys Ile Phe 330 335 340 ggg agc ctg gca ttt ctg ccg gag agc ttt gat ggg gac cca gcc tcc 1591Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp Pro Ala Ser 345 350 355 aac act gcc ccg ctc cag cca gag cag ctc caa gtg ttt gag act ctg 1639Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe Glu Thr Leu 360 365 370 gaa gag atc aca ggt tac cta tac atc tca gca tgg ccg gac agc ctg 1687Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro Asp Ser Leu 375 380 385 cct gac ctc agc gtc ttc cag aac ctg caa gta atc cgg gga cga att 1735Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg Gly Arg Ile 390 395 400 405 ctg cac aat ggc gcc tac tcg ctg acc ctg caa ggg ctg ggc atc agc 1783Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu Gly Ile Ser 410 415 420 tgg ctg ggg ctg cgc tca ctg agg gaa ctg ggc agt gga ctg gcc ctc 1831Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly Leu Ala Leu 425 430 435 atc cac cat aac acc cac ctc tgc ttc gtg cac acg gtg ccc tgg gac 1879Ile His His Asn Thr His Leu Cys Phe Val His Thr Val Pro Trp Asp 440 445 450 cag ctc ttt cgg aac ccg cac caa gct ctg ctc cac act gcc aac cgg 1927Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr Ala Asn Arg 455 460 465 cca gag gac gag tgt gtg ggc gag ggc ctg gcc tgc cac cag ctg tgc 1975Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His Gln Leu Cys 470 475 480 485 gcc cga ggg cac tgc tgg ggt cca ggg ccc acc cag tgt gtc aac tgc 2023Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys Val Asn Cys 490 495 500 agc cag ttc ctt cgg ggc cag gag tgc gtg gag gaa tgc cga gta ctg 2071Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys Arg Val Leu 505 510 515 cag ggg ctc ccc agg gag tat gtg aat gcc agg cac tgt ttg ccg tgc 2119Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys Leu Pro Cys 520 525 530 cac cct gag tgt cag ccc cag aat ggc tca gtg acc tgt ttt gga ccg 2167His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys Phe Gly Pro 535 540 545 gag gct gac

cag tgt gtg gcc tgt gcc cac tat aag gac cct ccc ttc 2215Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp Pro Pro Phe 550 555 560 565 tgc gtg gcc cgc tgc ccc agc ggt gtg aaa cct gac ctc tcc tac atg 2263Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu Ser Tyr Met 570 575 580 ccc atc tgg aag ttt cca gat gag gag ggc gca tgc cag cct tgc ccc 2311Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln Pro Cys Pro 585 590 595 atc aac tgc acc cac tcc tgt gtg gac ctg gat gac aag ggc tgc ccc 2359Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys Gly Cys Pro 600 605 610 gcc gag cag aga gcc agc cct ctg acg tcc atc atc tct gcg gtg gtt 2407Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser Ala Val Val 615 620 625 ggc att ctg ctg gtc gtg gtc ttg ggg gtg gtc ttt ggg atc ctc atc 2455Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly Ile Leu Ile 630 635 640 645 aag cga cgg cag cag aag atc cgg aag tac acg atg cgg aga ctg ctg 2503Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg Arg Leu Leu 650 655 660 cag gaa acg gag ctg gtg gag ccg ctg aca cct agc gga gcg atg ccc 2551Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Ala Met Pro 665 670 675 aac cag gcg cag atg cgg atc ctg aaa gag acg gag ctg agg aag gtg 2599Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu Arg Lys Val 680 685 690 aag gtg ctt gga tct ggc gct ttt ggc aca gtc tac aag ggc atc tgg 2647Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Ile Trp 695 700 705 atc cct gat ggg gag aat gtg aaa att cca gtg gcc atc aaa gtg ttg 2695Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile Lys Val Leu 710 715 720 725 agg gaa aac aca tcc ccc aaa gcc aac aaa gaa atc tta gac gaa gca 2743Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala 730 735 740 tac gtg atg gct ggt gtg ggc tcc cca tat gtc tcc cgc ctt ctg ggc 2791Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg Leu Leu Gly 745 750 755 atc tgc ctg aca tcc acg gtg cag ctg gtg aca cag ctt atg ccc tat 2839Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu Met Pro Tyr 760 765 770 ggc tgc ctc tta gac cat gtc cgg gaa aac cgc gga cgc ctg ggc tcc 2887Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg Leu Gly Ser 775 780 785 cag gac ctg ctg aac tgg tgt atg cag att gcc aag ggg atg agc tac 2935Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly Met Ser Tyr 790 795 800 805 ctg gag gat gtg cgg ctc gta cac agg gac ttg gcc gct cgg aac gtg 2983Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val 810 815 820 ctg gtc aag agt ccc aac cat gtc aaa att aca gac ttc ggg ctg gct 3031Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe Gly Leu Ala 825 830 835 cgg ctg ctg gac att gac gag aca gag tac cat gca gat ggg ggc aag 3079Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp Gly Gly Lys 840 845 850 gtg ccc atc aag tgg atg gcg ctg gag tcc att ctc cgc cgg cgg ttc 3127Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg Arg Arg Phe 855 860 865 acc cac cag agt gat gtg tgg agt tat ggt gtg act gtg tgg gag ctg 3175Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu 870 875 880 885 atg act ttt ggg gcc aaa cct tac gat ggg atc cca gcc cgg gag atc 3223Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala Arg Glu Ile 890 895 900 cct gac ctg ctg gaa aag ggg gag cgg ctg ccc cag ccc ccc atc tgc 3271Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys 905 910 915 acc att gat gtc tac atg atc atg gtc aaa tgt tgg atg att gac tct 3319Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ser 920 925 930 gaa tgt cgg cca aga ttc cgg gag ttg gtg tct gaa ttc tcc cgc atg 3367Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe Ser Arg Met 935 940 945 gcc agg gac ccc cag cgc ttt gtg gtc atc cag aat gag gac ttg ggc 3415Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu Asp Leu Gly 950 955 960 965 cca gcc agt ccc ttg gac agc acc ttc tac cgc tca ctg ctg gag gac 3463Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu Leu Glu Asp 970 975 980 gat gac atg ggg gac ctg gtg gat gct gag gag tat ctg gta ccc cag 3511Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr Leu Val Pro Gln 985 990 995 cag ggc ttc ttc tgt cca gac cct gcc ccg ggc gct ggg ggc atg 3556Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly Ala Gly Gly Met 1000 1005 1010 gtc cac cac agg cac cgc agc tca tct acc agg agt ggc ggt ggg 3601Val His His Arg His Arg Ser Ser Ser Thr Arg Ser Gly Gly Gly 1015 1020 1025 gac ctg aca cta ggg ctg gag ccc tct gaa gag gag gcc ccc agg 3646Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu Glu Ala Pro Arg 1030 1035 1040 tct cca ctg gca ccc tcc gaa ggg gct ggc tcc gat gta ttt gat 3691Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser Asp Val Phe Asp 1045 1050 1055 ggt gac ctg gga atg ggg gca gcc aag ggg ctg caa agc ctc ccc 3736Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu Gln Ser Leu Pro 1060 1065 1070 aca cat gac ccc agc cct cta cag cgg tac agt gag gac ccc aca 3781Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser Glu Asp Pro Thr 1075 1080 1085 gta ccc ctg ccc tct gag act gat ggc tac gtt gcc ccc ctg acc 3826Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val Ala Pro Leu Thr 1090 1095 1100 tgc agc ccc cag cct gaa tat gtg aac cag cca gat gtt cgg ccc 3871Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro Asp Val Arg Pro 1105 1110 1115 cag ccc cct tcg ccc cga gag ggc cct ctg cct gct gcc cga cct 3916Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro Ala Ala Arg Pro 1120 1125 1130 gct ggt gcc act ctg gaa agg ccc aag act ctc tcc cca ggg aag 3961Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu Ser Pro Gly Lys 1135 1140 1145 aat ggg gtc gtc aaa gac gtt ttt gcc ttt ggg ggt gcc gtg gag 4006Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly Gly Ala Val Glu 1150 1155 1160 aac ccc gag tac ttg aca ccc cag gga gga gct gcc cct cag ccc 4051Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala Ala Pro Gln Pro 1165 1170 1175 cac cct cct cct gcc ttc agc cca gcc ttc gac aac ctc tat tac 4096His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp Asn Leu Tyr Tyr 1180 1185 1190 tgg gac cag gac cca cca gag cgg ggg gct cca ccc agc acc ttc 4141Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro Pro Ser Thr Phe 1195 1200 1205 aaa ggg aca cct acg gca gag aac cca gag tac ctg ggt ctg gac 4186Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr Leu Gly Leu Asp 1210 1215 1220 gtg cca gtg tga accagaaggc caagtccgca gaagccctga tgtgtcctca 4238Val Pro Val 1225 gggagcaggg aaggcctgac ttctgctggc atcaagaggt gggagggccc tccgaccact 4298tccaggggaa cctgccatgc caggaacctg tcctaaggaa ccttccttcc tgcttgagtt 4358cccagatggc tggaaggggt ccagcctcgt tggaagagga acagcactgg ggagtctttg 4418tggattctga ggccctgccc aatgagactc tagggtccag tggatgccac agcccagctt 4478ggccctttcc ttccagatcc tgggtactga aagccttagg gaagctggcc tgagagggga 4538agcggcccta agggagtgtc taagaacaaa agcgacccat tcagagactg tccctgaaac 4598ctagtactgc cccccatgag gaaggaacag caatggtgtc agtatccagg ctttgtacag 4658agtgcttttc tgtttagttt ttactttttt tgttttgttt ttttaaagat gaaataaaga 4718cccaggggga gaatgggtgt tgtatgggga ggcaagtgtg gggggtcctt ctccacaccc 4778actttgtcca tttgcaaata tattttggaa aacagcta 481641225PRTHomo sapiens 4Met Lys Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu 1 5 10 15 Arg His Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu 20 25 30 Thr Tyr Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln 35 40 45 Glu Val Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val 50 55 60 Pro Leu Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp 65 70 75 80 Asn Tyr Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr 85 90 95 Thr Pro Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu 100 105 110 Arg Ser Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn 115 120 125 Pro Gln Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His 130 135 140 Lys Asn Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg 145 150 155 160 Ala Cys His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly 165 170 175 Glu Ser Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly 180 185 190 Gly Cys Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu 195 200 205 Gln Cys Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala 210 215 220 Cys Leu His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala 225 230 235 240 Leu Val Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu 245 250 255 Gly Arg Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn 260 265 270 Tyr Leu Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His 275 280 285 Asn Gln Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys 290 295 300 Ser Lys Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu 305 310 315 320 Arg Glu Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly 325 330 335 Cys Lys Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp 340 345 350 Gly Asp Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln 355 360 365 Val Phe Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala 370 375 380 Trp Pro Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val 385 390 395 400 Ile Arg Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln 405 410 415 Gly Leu Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly 420 425 430 Ser Gly Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His 435 440 445 Thr Val Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu 450 455 460 His Thr Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala 465 470 475 480 Cys His Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr 485 490 495 Gln Cys Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu 500 505 510 Glu Cys Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg 515 520 525 His Cys Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val 530 535 540 Thr Cys Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr 545 550 555 560 Lys Asp Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro 565 570 575 Asp Leu Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala 580 585 590 Cys Gln Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp 595 600 605 Asp Lys Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile 610 615 620 Ile Ser Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val 625 630 635 640 Phe Gly Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr 645 650 655 Met Arg Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro 660 665 670 Ser Gly Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr 675 680 685 Glu Leu Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val 690 695 700 Tyr Lys Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val 705 710 715 720 Ala Ile Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu 725 730 735 Ile Leu Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val 740 745 750 Ser Arg Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr 755 760 765 Gln Leu Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg 770 775 780 Gly Arg Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala 785 790 795 800 Lys Gly Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu 805 810 815 Ala Ala Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr 820 825 830 Asp Phe Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His 835 840 845 Ala Asp Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile 850 855 860 Leu Arg Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val 865 870 875 880 Thr Val Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile 885 890 895 Pro Ala Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro 900 905 910 Gln Pro Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys 915 920 925 Trp Met Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser 930 935 940 Glu Phe Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln 945 950 955 960 Asn Glu Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg 965 970 975 Ser Leu Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu 980 985 990 Tyr Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly

995 1000 1005 Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg 1010 1015 1020 Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu 1025 1030 1035 Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser 1040 1045 1050 Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu 1055 1060 1065 Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser 1070 1075 1080 Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val 1085 1090 1095 Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro 1100 1105 1110 Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro 1115 1120 1125 Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu 1130 1135 1140 Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly 1145 1150 1155 Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala 1160 1165 1170 Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp 1175 1180 1185 Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro 1190 1195 1200 Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr 1205 1210 1215 Leu Gly Leu Asp Val Pro Val 1220 1225 52560DNAHomo sapiensCDS(262)..(2421) 5ctcaaaaggg gccggatttc cttctcctgg aggcagatgt tgcctctctc tctcgctcgg 60attggttcag tgcactctag aaacactgct gtggtggaga aactggaccc caggtctgga 120gcgaattcca gcctgcaggg ctgataagcg aggcattagt gagattgaga gagactttac 180cccgccgtgg tggttggagg gcgcgcagta gagcagcagc acaggcgcgg gtcccgggag 240gccggctctg ctcgcgccga g atg tgg aat ctc ctt cac gaa acc gac tcg 291 Met Trp Asn Leu Leu His Glu Thr Asp Ser 1 5 10 gct gtg gcc acc gcg cgc cgc ccg cgc tgg ctg tgc gct ggg gcg ctg 339Ala Val Ala Thr Ala Arg Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu 15 20 25 gtg ctg gcg ggt ggc ttc ttt ctc ctc ggc ttc ctc ttc ggg tgg ttt 387Val Leu Ala Gly Gly Phe Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe 30 35 40 ata aaa tcc tcc aat gaa gct act aac att act cca aag cat aat atg 435Ile Lys Ser Ser Asn Glu Ala Thr Asn Ile Thr Pro Lys His Asn Met 45 50 55 aaa gca ttt ttg gat gaa ttg aaa gct gag aac atc aag aag ttc tta 483Lys Ala Phe Leu Asp Glu Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu 60 65 70 tat aat ttt aca cag ata cca cat tta gca gga aca gaa caa aac ttt 531Tyr Asn Phe Thr Gln Ile Pro His Leu Ala Gly Thr Glu Gln Asn Phe 75 80 85 90 cag ctt gca aag caa att caa tcc cag tgg aaa gaa ttt ggc ctg gat 579Gln Leu Ala Lys Gln Ile Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp 95 100 105 tct gtt gag cta gca cat tat gat gtc ctg ttg tcc tac cca aat aag 627Ser Val Glu Leu Ala His Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys 110 115 120 act cat ccc aac tac atc tca ata att aat gaa gat gga aat gag att 675Thr His Pro Asn Tyr Ile Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile 125 130 135 ttc aac aca tca tta ttt gaa cca cct cct cca gga tat gaa aat gtt 723Phe Asn Thr Ser Leu Phe Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val 140 145 150 tcg gat att gta cca cct ttc agt gct ttc tct cct caa gga atg cca 771Ser Asp Ile Val Pro Pro Phe Ser Ala Phe Ser Pro Gln Gly Met Pro 155 160 165 170 gag ggc gat cta gtg tat gtt aac tat gca cga act gaa gac ttc ttt 819Glu Gly Asp Leu Val Tyr Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe 175 180 185 aaa ttg gaa cgg gac atg aaa atc aat tgc tct ggg aaa att gta att 867Lys Leu Glu Arg Asp Met Lys Ile Asn Cys Ser Gly Lys Ile Val Ile 190 195 200 gcc aga tat ggg aaa gtt ttc aga gga aat aag gtt aaa aat gcc cag 915Ala Arg Tyr Gly Lys Val Phe Arg Gly Asn Lys Val Lys Asn Ala Gln 205 210 215 ctg gca ggg gcc aaa gga gtc att ctc tac tcc gac cct gct gac tac 963Leu Ala Gly Ala Lys Gly Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr 220 225 230 ttt gct cct ggg gtg aag tcc tat cca gat ggt tgg aat ctt cct gga 1011Phe Ala Pro Gly Val Lys Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly 235 240 245 250 ggt ggt gtc cag cgt gga aat atc cta aat ctg aat ggt gca gga gac 1059Gly Gly Val Gln Arg Gly Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp 255 260 265 cct ctc aca cca ggt tac cca gca aat gaa tat gct tat agg cgt gga 1107Pro Leu Thr Pro Gly Tyr Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly 270 275 280 att gca gag gct gtt ggt ctt cca agt att cct gtt cat cca att gga 1155Ile Ala Glu Ala Val Gly Leu Pro Ser Ile Pro Val His Pro Ile Gly 285 290 295 tac tat gat gca cag aag ctc cta gaa aaa atg ggt ggc tca gca cca 1203Tyr Tyr Asp Ala Gln Lys Leu Leu Glu Lys Met Gly Gly Ser Ala Pro 300 305 310 cca gat agc agc tgg aga gga agt ctc aaa gtg ccc tac aat gtt gga 1251Pro Asp Ser Ser Trp Arg Gly Ser Leu Lys Val Pro Tyr Asn Val Gly 315 320 325 330 cct ggc ttt act gga aac ttt tct aca caa aaa gtc aag atg cac atc 1299Pro Gly Phe Thr Gly Asn Phe Ser Thr Gln Lys Val Lys Met His Ile 335 340 345 cac tct acc aat gaa gtg aca aga att tac aat gtg ata ggt act ctc 1347His Ser Thr Asn Glu Val Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu 350 355 360 aga gga gca gtg gaa cca gac aga tat gtc att ctg gga ggt cac cgg 1395Arg Gly Ala Val Glu Pro Asp Arg Tyr Val Ile Leu Gly Gly His Arg 365 370 375 gac tca tgg gtg ttt ggt ggt att gac cct cag agt gga gca gct gtt 1443Asp Ser Trp Val Phe Gly Gly Ile Asp Pro Gln Ser Gly Ala Ala Val 380 385 390 gtt cat gaa att gtg agg agc ttt gga aca ctg aaa aag gaa ggg tgg 1491Val His Glu Ile Val Arg Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp 395 400 405 410 aga cct aga aga aca att ttg ttt gca agc tgg gat gca gaa gaa ttt 1539Arg Pro Arg Arg Thr Ile Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe 415 420 425 ggt ctt ctt ggt tct act gag tgg gca gag gag aat tca aga ctc ctt 1587Gly Leu Leu Gly Ser Thr Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu 430 435 440 caa gag cgt ggc gtg gct tat att aat gct gac tca tct ata gaa gga 1635Gln Glu Arg Gly Val Ala Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly 445 450 455 aac tac act ctg aga gtt gat tgt aca ccg ctg atg tac agc ttg gta 1683Asn Tyr Thr Leu Arg Val Asp Cys Thr Pro Leu Met Tyr Ser Leu Val 460 465 470 cac aac cta aca aaa gag ctg aaa agc cct gat gaa ggc ttt gaa ggc 1731His Asn Leu Thr Lys Glu Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly 475 480 485 490 aaa tct ctt tat gaa agt tgg act aaa aaa agt cct tcc cca gag ttc 1779Lys Ser Leu Tyr Glu Ser Trp Thr Lys Lys Ser Pro Ser Pro Glu Phe 495 500 505 agt ggc atg ccc agg ata agc aaa ttg gga tct gga aat gat ttt gag 1827Ser Gly Met Pro Arg Ile Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu 510 515 520 gtg ttc ttc caa cga ctt gga att gct tca ggc aga gca cgg tat act 1875Val Phe Phe Gln Arg Leu Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr 525 530 535 aaa aat tgg gaa aca aac aaa ttc agc ggc tat cca ctg tat cac agt 1923Lys Asn Trp Glu Thr Asn Lys Phe Ser Gly Tyr Pro Leu Tyr His Ser 540 545 550 gtc tat gaa aca tat gag ttg gtg gaa aag ttt tat gat cca atg ttt 1971Val Tyr Glu Thr Tyr Glu Leu Val Glu Lys Phe Tyr Asp Pro Met Phe 555 560 565 570 aaa tat cac ctc act gtg gcc cag gtt cga gga ggg atg gtg ttt gag 2019Lys Tyr His Leu Thr Val Ala Gln Val Arg Gly Gly Met Val Phe Glu 575 580 585 cta gcc aat tcc ata gtg ctc cct ttt gat tgt cga gat tat gct gta 2067Leu Ala Asn Ser Ile Val Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val 590 595 600 gtt tta aga aag tat gct gac aaa atc tac agt att tct atg aaa cat 2115Val Leu Arg Lys Tyr Ala Asp Lys Ile Tyr Ser Ile Ser Met Lys His 605 610 615 cca cag gaa atg aag aca tac agt gta tca ttt gat tca ctt ttt tct 2163Pro Gln Glu Met Lys Thr Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser 620 625 630 gca gta aag aat ttt aca gaa att gct tcc aag ttc agt gag aga ctc 2211Ala Val Lys Asn Phe Thr Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu 635 640 645 650 cag gac ttt gac aaa agc aag cat gtc atc tat gct cca agc agc cac 2259Gln Asp Phe Asp Lys Ser Lys His Val Ile Tyr Ala Pro Ser Ser His 655 660 665 aac aag tat gca ggg gag tca ttc cca gga att tat gat gct ctg ttt 2307Asn Lys Tyr Ala Gly Glu Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe 670 675 680 gat att gaa agc aaa gtg gac cct tcc aag gcc tgg gga gaa gtg aag 2355Asp Ile Glu Ser Lys Val Asp Pro Ser Lys Ala Trp Gly Glu Val Lys 685 690 695 aga cag att tat gtt gca gcc ttc aca gtg cag gca gct gca gag act 2403Arg Gln Ile Tyr Val Ala Ala Phe Thr Val Gln Ala Ala Ala Glu Thr 700 705 710 ttg agt gaa gta gcc taa gaggattctt tagagaatcc gtattgaatt 2451Leu Ser Glu Val Ala 715 tgtgtggtat gtcactcaga aagaatcgta atgggtatat tgataaattt taaaattggt 2511atatttgaaa taaagttgaa tattatatat aaaaaaaaaa aaaaaaaaa 25606719PRTHomo sapiens 6Met Trp Asn Leu Leu His Glu Thr Asp Ser Ala Val Ala Thr Ala Arg 1 5 10 15 Arg Pro Arg Trp Leu Cys Ala Gly Ala Leu Val Leu Ala Gly Gly Phe 20 25 30 Phe Leu Leu Gly Phe Leu Phe Gly Trp Phe Ile Lys Ser Ser Asn Glu 35 40 45 Ala Thr Asn Ile Thr Pro Lys His Asn Met Lys Ala Phe Leu Asp Glu 50 55 60 Leu Lys Ala Glu Asn Ile Lys Lys Phe Leu Tyr Asn Phe Thr Gln Ile 65 70 75 80 Pro His Leu Ala Gly Thr Glu Gln Asn Phe Gln Leu Ala Lys Gln Ile 85 90 95 Gln Ser Gln Trp Lys Glu Phe Gly Leu Asp Ser Val Glu Leu Ala His 100 105 110 Tyr Asp Val Leu Leu Ser Tyr Pro Asn Lys Thr His Pro Asn Tyr Ile 115 120 125 Ser Ile Ile Asn Glu Asp Gly Asn Glu Ile Phe Asn Thr Ser Leu Phe 130 135 140 Glu Pro Pro Pro Pro Gly Tyr Glu Asn Val Ser Asp Ile Val Pro Pro 145 150 155 160 Phe Ser Ala Phe Ser Pro Gln Gly Met Pro Glu Gly Asp Leu Val Tyr 165 170 175 Val Asn Tyr Ala Arg Thr Glu Asp Phe Phe Lys Leu Glu Arg Asp Met 180 185 190 Lys Ile Asn Cys Ser Gly Lys Ile Val Ile Ala Arg Tyr Gly Lys Val 195 200 205 Phe Arg Gly Asn Lys Val Lys Asn Ala Gln Leu Ala Gly Ala Lys Gly 210 215 220 Val Ile Leu Tyr Ser Asp Pro Ala Asp Tyr Phe Ala Pro Gly Val Lys 225 230 235 240 Ser Tyr Pro Asp Gly Trp Asn Leu Pro Gly Gly Gly Val Gln Arg Gly 245 250 255 Asn Ile Leu Asn Leu Asn Gly Ala Gly Asp Pro Leu Thr Pro Gly Tyr 260 265 270 Pro Ala Asn Glu Tyr Ala Tyr Arg Arg Gly Ile Ala Glu Ala Val Gly 275 280 285 Leu Pro Ser Ile Pro Val His Pro Ile Gly Tyr Tyr Asp Ala Gln Lys 290 295 300 Leu Leu Glu Lys Met Gly Gly Ser Ala Pro Pro Asp Ser Ser Trp Arg 305 310 315 320 Gly Ser Leu Lys Val Pro Tyr Asn Val Gly Pro Gly Phe Thr Gly Asn 325 330 335 Phe Ser Thr Gln Lys Val Lys Met His Ile His Ser Thr Asn Glu Val 340 345 350 Thr Arg Ile Tyr Asn Val Ile Gly Thr Leu Arg Gly Ala Val Glu Pro 355 360 365 Asp Arg Tyr Val Ile Leu Gly Gly His Arg Asp Ser Trp Val Phe Gly 370 375 380 Gly Ile Asp Pro Gln Ser Gly Ala Ala Val Val His Glu Ile Val Arg 385 390 395 400 Ser Phe Gly Thr Leu Lys Lys Glu Gly Trp Arg Pro Arg Arg Thr Ile 405 410 415 Leu Phe Ala Ser Trp Asp Ala Glu Glu Phe Gly Leu Leu Gly Ser Thr 420 425 430 Glu Trp Ala Glu Glu Asn Ser Arg Leu Leu Gln Glu Arg Gly Val Ala 435 440 445 Tyr Ile Asn Ala Asp Ser Ser Ile Glu Gly Asn Tyr Thr Leu Arg Val 450 455 460 Asp Cys Thr Pro Leu Met Tyr Ser Leu Val His Asn Leu Thr Lys Glu 465 470 475 480 Leu Lys Ser Pro Asp Glu Gly Phe Glu Gly Lys Ser Leu Tyr Glu Ser 485 490 495 Trp Thr Lys Lys Ser Pro Ser Pro Glu Phe Ser Gly Met Pro Arg Ile 500 505 510 Ser Lys Leu Gly Ser Gly Asn Asp Phe Glu Val Phe Phe Gln Arg Leu 515 520 525 Gly Ile Ala Ser Gly Arg Ala Arg Tyr Thr Lys Asn Trp Glu Thr Asn 530 535 540 Lys Phe Ser Gly Tyr Pro Leu Tyr His Ser Val Tyr Glu Thr Tyr Glu 545 550 555 560 Leu Val Glu Lys Phe Tyr Asp Pro Met Phe Lys Tyr His Leu Thr Val 565 570 575 Ala Gln Val Arg Gly Gly Met Val Phe Glu Leu Ala Asn Ser Ile Val 580 585 590 Leu Pro Phe Asp Cys Arg Asp Tyr Ala Val Val Leu Arg Lys Tyr Ala 595 600 605 Asp Lys Ile Tyr Ser Ile Ser Met Lys His Pro Gln Glu Met Lys Thr 610 615 620 Tyr Ser Val Ser Phe Asp Ser Leu Phe Ser Ala Val Lys Asn Phe Thr 625 630 635 640 Glu Ile Ala Ser Lys Phe Ser Glu Arg Leu Gln Asp Phe Asp Lys Ser 645 650 655 Lys His Val Ile Tyr Ala Pro Ser Ser His Asn Lys Tyr Ala Gly Glu 660 665 670 Ser Phe Pro Gly Ile Tyr Asp Ala Leu Phe Asp Ile Glu Ser Lys Val 675 680 685 Asp Pro Ser Lys Ala Trp Gly Glu Val Lys Arg Gln Ile Tyr Val Ala 690 695 700 Ala Phe Thr Val Gln Ala Ala Ala Glu Thr Leu Ser Glu Val Ala 705 710 715 71209DNAHomo sapiensCDS(67)..(888) 7acctctcaag cagccagcgc ctgcctgaat ctgttctgcc ccctccccac ccatttcacc 60accacc atg aca ccg ggc acc cag tct

cct ttc ttc ctg ctg ctg ctc 108 Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu 1 5 10 ctc aca gtg ctt aca gtt gtt acg ggt tct ggt cat gca agc tct acc 156Leu Thr Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr 15 20 25 30 cca ggt gga gaa aag gag act tcg gct acc cag aga agt tca gtg ccc 204Pro Gly Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro 35 40 45 agc tct act gag aag aat gct ttg tct act ggg gtc tct ttc ttt ttc 252Ser Ser Thr Glu Lys Asn Ala Leu Ser Thr Gly Val Ser Phe Phe Phe 50 55 60 ctg tct ttt cac att tca aac ctc cag ttt aat tcc tct ctg gaa gat 300Leu Ser Phe His Ile Ser Asn Leu Gln Phe Asn Ser Ser Leu Glu Asp 65 70 75 ccc agc acc gac tac tac caa gag ctg cag aga gac att tct gaa atg 348Pro Ser Thr Asp Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met 80 85 90 ttt ttg cag att tat aaa caa ggg ggt ttt ctg ggc ctc tcc aat att 396Phe Leu Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile 95 100 105 110 aag ttc agg cca gga tct gtg gtg gta caa ttg act ctg gcc ttc cga 444Lys Phe Arg Pro Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg 115 120 125 gaa ggt acc atc aat gtc cac gac gtg gag aca cag ttc aat cag tat 492Glu Gly Thr Ile Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr 130 135 140 aaa acg gaa gca gcc tct cga tat aac ctg acg atc tca gac gtc agc 540Lys Thr Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser 145 150 155 gtg agt gat gtg cca ttt cct ttc tct gcc cag tct ggg gct ggg gtg 588Val Ser Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val 160 165 170 cca ggc tgg ggc atc gcg ctg ctg gtg ctg gtc tgt gtt ctg gtt gcg 636Pro Gly Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala 175 180 185 190 ctg gcc att gtc tat ctc att gcc ttg gct gtc tgt cag tgc cgc cga 684Leu Ala Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg 195 200 205 aag aac tac ggg cag ctg gac atc ttt cca gcc cgg gat acc tac cat 732Lys Asn Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His 210 215 220 cct atg agc gag tac ccc acc tac cac acc cat ggg cgc tat gtg ccc 780Pro Met Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro 225 230 235 cct agc agt acc gat cgt agc ccc tat gag aag gtt tct gca ggt aat 828Pro Ser Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn 240 245 250 ggt ggc agc agc ctc tct tac aca aac cca gca gtg gca gcc act tct 876Gly Gly Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser 255 260 265 270 gcc aac ttg tag gggcacgtcg cccgctgagc tgagtggcca gccagtgcca 928Ala Asn Leu ttccactcca ctcaggttct tcagggccag agcccctgca ccctgtttgg gctggtgagc 988tgggagttca ggtgggctgc tcacagcctc cttcagaggc cccaccaatt tctcggacac 1048ttctcagtgt gtggaagctc atgtgggccc ctgagggctc atgcctggga agtgttgtgg 1108tgggggctcc caggaggact ggcccagaga gccctgagat agcggggatc ctgaactgga 1168ctgaataaaa cgtggtctcc cactgcgcca aaaaaaaaaa a 12098273PRTHomo sapiens 8Met Thr Pro Gly Thr Gln Ser Pro Phe Phe Leu Leu Leu Leu Leu Thr 1 5 10 15 Val Leu Thr Val Val Thr Gly Ser Gly His Ala Ser Ser Thr Pro Gly 20 25 30 Gly Glu Lys Glu Thr Ser Ala Thr Gln Arg Ser Ser Val Pro Ser Ser 35 40 45 Thr Glu Lys Asn Ala Leu Ser Thr Gly Val Ser Phe Phe Phe Leu Ser 50 55 60 Phe His Ile Ser Asn Leu Gln Phe Asn Ser Ser Leu Glu Asp Pro Ser 65 70 75 80 Thr Asp Tyr Tyr Gln Glu Leu Gln Arg Asp Ile Ser Glu Met Phe Leu 85 90 95 Gln Ile Tyr Lys Gln Gly Gly Phe Leu Gly Leu Ser Asn Ile Lys Phe 100 105 110 Arg Pro Gly Ser Val Val Val Gln Leu Thr Leu Ala Phe Arg Glu Gly 115 120 125 Thr Ile Asn Val His Asp Val Glu Thr Gln Phe Asn Gln Tyr Lys Thr 130 135 140 Glu Ala Ala Ser Arg Tyr Asn Leu Thr Ile Ser Asp Val Ser Val Ser 145 150 155 160 Asp Val Pro Phe Pro Phe Ser Ala Gln Ser Gly Ala Gly Val Pro Gly 165 170 175 Trp Gly Ile Ala Leu Leu Val Leu Val Cys Val Leu Val Ala Leu Ala 180 185 190 Ile Val Tyr Leu Ile Ala Leu Ala Val Cys Gln Cys Arg Arg Lys Asn 195 200 205 Tyr Gly Gln Leu Asp Ile Phe Pro Ala Arg Asp Thr Tyr His Pro Met 210 215 220 Ser Glu Tyr Pro Thr Tyr His Thr His Gly Arg Tyr Val Pro Pro Ser 225 230 235 240 Ser Thr Asp Arg Ser Pro Tyr Glu Lys Val Ser Ala Gly Asn Gly Gly 245 250 255 Ser Ser Leu Ser Tyr Thr Asn Pro Ala Val Ala Ala Thr Ser Ala Asn 260 265 270 Leu 91764DNAHomo sapiensCDS(107)..(1513) 9gcaggtgccc cgaaaagggg gcggggtcag gggtgccctg aactccgaat gcgaagttct 60gtcttgtcat agccaagcac gctgcttctt ggattgacct ggcagg atg gcg cca 115 Met Ala Pro 1 cca cca gct aga gta cat cta ggt gcg ttc ctg gca gtg act ccg aat 163Pro Pro Ala Arg Val His Leu Gly Ala Phe Leu Ala Val Thr Pro Asn 5 10 15 ccc ggg agc gca gcg agt ggg aca gag gca gcc gcg gcc aca ccc agc 211Pro Gly Ser Ala Ala Ser Gly Thr Glu Ala Ala Ala Ala Thr Pro Ser 20 25 30 35 aaa gtg tgg ggc tct tcc gcg ggg agg att gaa cca cga ggc ggg ggc 259Lys Val Trp Gly Ser Ser Ala Gly Arg Ile Glu Pro Arg Gly Gly Gly 40 45 50 cga gga gcg ctc cct acc tcc atg gga cag cac gga ccc agt gcc cgg 307Arg Gly Ala Leu Pro Thr Ser Met Gly Gln His Gly Pro Ser Ala Arg 55 60 65 gcc cgg gca ggg cgc gcc cca gga ccc agg ccg gcg cgg gaa gcc agc 355Ala Arg Ala Gly Arg Ala Pro Gly Pro Arg Pro Ala Arg Glu Ala Ser 70 75 80 cct cgg ctc cgg gtc cac aag acc ttc aag ttt gtc gtc gtc ggg gtc 403Pro Arg Leu Arg Val His Lys Thr Phe Lys Phe Val Val Val Gly Val 85 90 95 ctg ctg cag gtc gta cct agc tca gct gca acc atc aaa ctt cat gat 451Leu Leu Gln Val Val Pro Ser Ser Ala Ala Thr Ile Lys Leu His Asp 100 105 110 115 caa tca att ggc aca cag caa tgg gaa cat agc cct ttg gga gag ttg 499Gln Ser Ile Gly Thr Gln Gln Trp Glu His Ser Pro Leu Gly Glu Leu 120 125 130 tgt cca cca gga tct cat aga tca gaa cat cct gga gcc tgt aac cgg 547Cys Pro Pro Gly Ser His Arg Ser Glu His Pro Gly Ala Cys Asn Arg 135 140 145 tgc aca gag ggt gtg ggt tac acc aat gct tcc aac aat ttg ttt gct 595Cys Thr Glu Gly Val Gly Tyr Thr Asn Ala Ser Asn Asn Leu Phe Ala 150 155 160 tgc ctc cca tgt aca gct tgt aaa tca gat gaa gaa gag aga agt ccc 643Cys Leu Pro Cys Thr Ala Cys Lys Ser Asp Glu Glu Glu Arg Ser Pro 165 170 175 tgc acc acg acc agg aac aca gca tgt cag tgc aaa cca gga act ttc 691Cys Thr Thr Thr Arg Asn Thr Ala Cys Gln Cys Lys Pro Gly Thr Phe 180 185 190 195 cgg aat gac aat tct gct gag atg tgc cgg aag tgc agc aga ggg tgc 739Arg Asn Asp Asn Ser Ala Glu Met Cys Arg Lys Cys Ser Arg Gly Cys 200 205 210 ccc aga ggg atg gtc aag gtc aag gat tgt acg ccc tgg agt gac atc 787Pro Arg Gly Met Val Lys Val Lys Asp Cys Thr Pro Trp Ser Asp Ile 215 220 225 gag tgt gtc cac aaa gaa tca ggc aat gga cat aat ata tgg gtg att 835Glu Cys Val His Lys Glu Ser Gly Asn Gly His Asn Ile Trp Val Ile 230 235 240 ttg gtt gtg act ttg gtt gtt ccg ttg ctg ttg gtg gct gtg ctg att 883Leu Val Val Thr Leu Val Val Pro Leu Leu Leu Val Ala Val Leu Ile 245 250 255 gtc tgt tgt tgc atc ggc tca ggt tgt gga ggg gac ccc aag tgc atg 931Val Cys Cys Cys Ile Gly Ser Gly Cys Gly Gly Asp Pro Lys Cys Met 260 265 270 275 gac agg gtg tgt ttc tgg cgc ttg ggt ctc cta cga ggg cct ggg gct 979Asp Arg Val Cys Phe Trp Arg Leu Gly Leu Leu Arg Gly Pro Gly Ala 280 285 290 gag gac aat gct cac aac gag att ctg agc aac gca gac tcg ctg tcc 1027Glu Asp Asn Ala His Asn Glu Ile Leu Ser Asn Ala Asp Ser Leu Ser 295 300 305 act ttc gtc tct gag cag caa atg gaa agc cag gag ccg gca gat ttg 1075Thr Phe Val Ser Glu Gln Gln Met Glu Ser Gln Glu Pro Ala Asp Leu 310 315 320 aca ggt gtc act gta cag tcc cca ggg gag gca cag tgt ctg ctg gga 1123Thr Gly Val Thr Val Gln Ser Pro Gly Glu Ala Gln Cys Leu Leu Gly 325 330 335 ccg gca gaa gct gaa ggg tct cag agg agg agg ctg ctg gtt cca gca 1171Pro Ala Glu Ala Glu Gly Ser Gln Arg Arg Arg Leu Leu Val Pro Ala 340 345 350 355 aat ggt gct gac ccc act gag act ctg atg ctg ttc ttt gac aag ttt 1219Asn Gly Ala Asp Pro Thr Glu Thr Leu Met Leu Phe Phe Asp Lys Phe 360 365 370 gca aac atc gtg ccc ttt gac tcc tgg gac cag ctc atg agg cag ctg 1267Ala Asn Ile Val Pro Phe Asp Ser Trp Asp Gln Leu Met Arg Gln Leu 375 380 385 gac ctc acg aaa aat gag atc gat gtg gtc aga gct ggt aca gca ggc 1315Asp Leu Thr Lys Asn Glu Ile Asp Val Val Arg Ala Gly Thr Ala Gly 390 395 400 cca ggg gat gcc ttg tat gca atg ctg atg aaa tgg gtc aac aaa act 1363Pro Gly Asp Ala Leu Tyr Ala Met Leu Met Lys Trp Val Asn Lys Thr 405 410 415 gga cgg aac gcc tcg atc cac acc ctg ctg gat gcc ttg gag agg atg 1411Gly Arg Asn Ala Ser Ile His Thr Leu Leu Asp Ala Leu Glu Arg Met 420 425 430 435 gaa gag aga cat gca aga gag aag att cag gac ctc ttg gtg gac tct 1459Glu Glu Arg His Ala Arg Glu Lys Ile Gln Asp Leu Leu Val Asp Ser 440 445 450 gga aag ttc atc tac tta gaa gat ggc aca ggc tct gcc gtg tcc ttg 1507Gly Lys Phe Ile Tyr Leu Glu Asp Gly Thr Gly Ser Ala Val Ser Leu 455 460 465 gag tga aagactcttt ttaccagagg tttcctctta ggtgttagga gttaatacat 1563Glu attaggtttt tttttttttt aacatgtata caaagtaaat tcttagccag gtgtagtggc 1623tcatgcctgt aatcccagca ctttgggagg ctgaggcggg tggatcactt gaggtcagaa 1683gttcaagacc agcctgacca acatcgtgaa atgccgtctt tacaaaaaaa tacaaaaatt 1743aactggaaaa aaaaaaaaaa a 176410468PRTHomo sapiens 10Met Ala Pro Pro Pro Ala Arg Val His Leu Gly Ala Phe Leu Ala Val 1 5 10 15 Thr Pro Asn Pro Gly Ser Ala Ala Ser Gly Thr Glu Ala Ala Ala Ala 20 25 30 Thr Pro Ser Lys Val Trp Gly Ser Ser Ala Gly Arg Ile Glu Pro Arg 35 40 45 Gly Gly Gly Arg Gly Ala Leu Pro Thr Ser Met Gly Gln His Gly Pro 50 55 60 Ser Ala Arg Ala Arg Ala Gly Arg Ala Pro Gly Pro Arg Pro Ala Arg 65 70 75 80 Glu Ala Ser Pro Arg Leu Arg Val His Lys Thr Phe Lys Phe Val Val 85 90 95 Val Gly Val Leu Leu Gln Val Val Pro Ser Ser Ala Ala Thr Ile Lys 100 105 110 Leu His Asp Gln Ser Ile Gly Thr Gln Gln Trp Glu His Ser Pro Leu 115 120 125 Gly Glu Leu Cys Pro Pro Gly Ser His Arg Ser Glu His Pro Gly Ala 130 135 140 Cys Asn Arg Cys Thr Glu Gly Val Gly Tyr Thr Asn Ala Ser Asn Asn 145 150 155 160 Leu Phe Ala Cys Leu Pro Cys Thr Ala Cys Lys Ser Asp Glu Glu Glu 165 170 175 Arg Ser Pro Cys Thr Thr Thr Arg Asn Thr Ala Cys Gln Cys Lys Pro 180 185 190 Gly Thr Phe Arg Asn Asp Asn Ser Ala Glu Met Cys Arg Lys Cys Ser 195 200 205 Arg Gly Cys Pro Arg Gly Met Val Lys Val Lys Asp Cys Thr Pro Trp 210 215 220 Ser Asp Ile Glu Cys Val His Lys Glu Ser Gly Asn Gly His Asn Ile 225 230 235 240 Trp Val Ile Leu Val Val Thr Leu Val Val Pro Leu Leu Leu Val Ala 245 250 255 Val Leu Ile Val Cys Cys Cys Ile Gly Ser Gly Cys Gly Gly Asp Pro 260 265 270 Lys Cys Met Asp Arg Val Cys Phe Trp Arg Leu Gly Leu Leu Arg Gly 275 280 285 Pro Gly Ala Glu Asp Asn Ala His Asn Glu Ile Leu Ser Asn Ala Asp 290 295 300 Ser Leu Ser Thr Phe Val Ser Glu Gln Gln Met Glu Ser Gln Glu Pro 305 310 315 320 Ala Asp Leu Thr Gly Val Thr Val Gln Ser Pro Gly Glu Ala Gln Cys 325 330 335 Leu Leu Gly Pro Ala Glu Ala Glu Gly Ser Gln Arg Arg Arg Leu Leu 340 345 350 Val Pro Ala Asn Gly Ala Asp Pro Thr Glu Thr Leu Met Leu Phe Phe 355 360 365 Asp Lys Phe Ala Asn Ile Val Pro Phe Asp Ser Trp Asp Gln Leu Met 370 375 380 Arg Gln Leu Asp Leu Thr Lys Asn Glu Ile Asp Val Val Arg Ala Gly 385 390 395 400 Thr Ala Gly Pro Gly Asp Ala Leu Tyr Ala Met Leu Met Lys Trp Val 405 410 415 Asn Lys Thr Gly Arg Asn Ala Ser Ile His Thr Leu Leu Asp Ala Leu 420 425 430 Glu Arg Met Glu Glu Arg His Ala Arg Glu Lys Ile Gln Asp Leu Leu 435 440 445 Val Asp Ser Gly Lys Phe Ile Tyr Leu Glu Asp Gly Thr Gly Ser Ala 450 455 460 Val Ser Leu Glu 465 114154DNAHomo sapiensCDS(294)..(1616) 11acttggacgc gcttgcggag gattgcgttg acgagactct tatttattgt caccaacctg 60tggtggaatt tgcagttgca cattggatct gattcgcccc gccccgaatg acgcctgccc 120ggaggcagtg aaagtacagc cgcgccgccc caagtcagcc tggacacata aatcagcacg 180cggccggaga accccgcaat ctctgcgccc acaaaataca ccgacgatgc ccgatctact 240ttaagggctg aaacccacgg gcctgagaga ctataagagc gttccctacc gcc atg 296 Met 1 gaa caa cgg gga cag aac gcc ccg gcc gct tcg ggg gcc cgg aaa agg 344Glu Gln Arg Gly Gln Asn Ala Pro Ala Ala Ser Gly Ala Arg Lys Arg 5 10 15 cac ggc cca gga ccc agg gag gcg cgg gga gcc agg cct ggg ccc cgg 392His Gly Pro Gly Pro Arg Glu Ala Arg Gly Ala Arg Pro Gly Pro Arg 20 25 30 gtc ccc aag acc ctt gtg ctc gtt gtc gcc gcg gtc ctg ctg ttg gtc 440Val Pro Lys Thr Leu Val Leu Val Val Ala Ala

Val Leu Leu Leu Val 35 40 45 tca gct gag tct gct ctg atc acc caa caa gac cta gct ccc cag cag 488Ser Ala Glu Ser Ala Leu Ile Thr Gln Gln Asp Leu Ala Pro Gln Gln 50 55 60 65 aga gcg gcc cca caa caa aag agg tcc agc ccc tca gag gga ttg tgt 536Arg Ala Ala Pro Gln Gln Lys Arg Ser Ser Pro Ser Glu Gly Leu Cys 70 75 80 cca cct gga cac cat atc tca gaa gac ggt aga gat tgc atc tcc tgc 584Pro Pro Gly His His Ile Ser Glu Asp Gly Arg Asp Cys Ile Ser Cys 85 90 95 aaa tat gga cag gac tat agc act cac tgg aat gac ctc ctt ttc tgc 632Lys Tyr Gly Gln Asp Tyr Ser Thr His Trp Asn Asp Leu Leu Phe Cys 100 105 110 ttg cgc tgc acc agg tgt gat tca ggt gaa gtg gag cta agt ccc tgc 680Leu Arg Cys Thr Arg Cys Asp Ser Gly Glu Val Glu Leu Ser Pro Cys 115 120 125 acc acg acc aga aac aca gtg tgt cag tgc gaa gaa ggc acc ttc cgg 728Thr Thr Thr Arg Asn Thr Val Cys Gln Cys Glu Glu Gly Thr Phe Arg 130 135 140 145 gaa gaa gat tct cct gag atg tgc cgg aag tgc cgc aca ggg tgt ccc 776Glu Glu Asp Ser Pro Glu Met Cys Arg Lys Cys Arg Thr Gly Cys Pro 150 155 160 aga ggg atg gtc aag gtc ggt gat tgt aca ccc tgg agt gac atc gaa 824Arg Gly Met Val Lys Val Gly Asp Cys Thr Pro Trp Ser Asp Ile Glu 165 170 175 tgt gtc cac aaa gaa tca ggt aca aag cac agt ggg gaa gtc cca gct 872Cys Val His Lys Glu Ser Gly Thr Lys His Ser Gly Glu Val Pro Ala 180 185 190 gtg gag gag acg gtg acc tcc agc cca ggg act cct gcc tct ccc tgt 920Val Glu Glu Thr Val Thr Ser Ser Pro Gly Thr Pro Ala Ser Pro Cys 195 200 205 tct ctc tca ggc atc atc ata gga gtc aca gtt gca gcc gta gtc ttg 968Ser Leu Ser Gly Ile Ile Ile Gly Val Thr Val Ala Ala Val Val Leu 210 215 220 225 att gtg gct gtg ttt gtt tgc aag tct tta ctg tgg aag aaa gtc ctt 1016Ile Val Ala Val Phe Val Cys Lys Ser Leu Leu Trp Lys Lys Val Leu 230 235 240 cct tac ctg aaa ggc atc tgc tca ggt ggt ggt ggg gac cct gag cgt 1064Pro Tyr Leu Lys Gly Ile Cys Ser Gly Gly Gly Gly Asp Pro Glu Arg 245 250 255 gtg gac aga agc tca caa cga cct ggg gct gag gac aat gtc ctc aat 1112Val Asp Arg Ser Ser Gln Arg Pro Gly Ala Glu Asp Asn Val Leu Asn 260 265 270 gag atc gtg agt atc ttg cag ccc acc cag gtc cct gag cag gaa atg 1160Glu Ile Val Ser Ile Leu Gln Pro Thr Gln Val Pro Glu Gln Glu Met 275 280 285 gaa gtc cag gag cca gca gag cca aca ggt gtc aac atg ttg tcc ccc 1208Glu Val Gln Glu Pro Ala Glu Pro Thr Gly Val Asn Met Leu Ser Pro 290 295 300 305 ggg gag tca gag cat ctg ctg gaa ccg gca gaa gct gaa agg tct cag 1256Gly Glu Ser Glu His Leu Leu Glu Pro Ala Glu Ala Glu Arg Ser Gln 310 315 320 agg agg agg ctg ctg gtt cca gca aat gaa ggt gat ccc act gag act 1304Arg Arg Arg Leu Leu Val Pro Ala Asn Glu Gly Asp Pro Thr Glu Thr 325 330 335 ctg aga cag tgc ttc gat gac ttt gca gac ttg gtg ccc ttt gac tcc 1352Leu Arg Gln Cys Phe Asp Asp Phe Ala Asp Leu Val Pro Phe Asp Ser 340 345 350 tgg gag ccg ctc atg agg aag ttg ggc ctc atg gac aat gag ata aag 1400Trp Glu Pro Leu Met Arg Lys Leu Gly Leu Met Asp Asn Glu Ile Lys 355 360 365 gtg gct aaa gct gag gca gcg ggc cac agg gac acc ttg tac acg atg 1448Val Ala Lys Ala Glu Ala Ala Gly His Arg Asp Thr Leu Tyr Thr Met 370 375 380 385 ctg ata aag tgg gtc aac aaa acc ggg cga gat gcc tct gtc cac acc 1496Leu Ile Lys Trp Val Asn Lys Thr Gly Arg Asp Ala Ser Val His Thr 390 395 400 ctg ctg gat gcc ttg gag acg ctg gga gag aga ctt gcc aag cag aag 1544Leu Leu Asp Ala Leu Glu Thr Leu Gly Glu Arg Leu Ala Lys Gln Lys 405 410 415 att gag gac cac ttg ttg agc tct gga aag ttc atg tat cta gaa ggt 1592Ile Glu Asp His Leu Leu Ser Ser Gly Lys Phe Met Tyr Leu Glu Gly 420 425 430 aat gca gac tct gcc atg tcc taa gtgtgattct cttcaggaag tcagaccttc 1646Asn Ala Asp Ser Ala Met Ser 435 440 cctggtttac cttttttctg gaaaaagccc aactggactc cagtcagtag gaaagtgcca 1706caattgtcac atgaccggta ctggaagaaa ctctcccatc caacatcacc cagtggatgg 1766aacatcctgt aacttttcac tgcacttggc attattttta taagctgaat gtgataataa 1826ggacactatg gaaatgtctg gatcattccg tttgtgcgta ctttgagatt tggtttggga 1886tgtcattgtt ttcacagcac ttttttatcc taatgtaaat gctttattta tttatttggg 1946ctacattgta agatccatct acacagtcgt tgtccgactt cacttgatac tatatgatat 2006gaaccttttt tgggtggggg gtgcggggca gttcactctg tctcccaggc tggagtgcaa 2066tggtgcaatc ttggctcact atagccttga cctctcaggc tcaagcgatt ctcccacctc 2126agccatccaa atagctggga ccacaggtgt gcaccaccac gcccggctaa ttttttgtat 2186tttgtctaga tataggggct ctctatgttg ctcagggtgg tctcgaattc ctggactcaa 2246gcagtctgcc cacctcagac tcccaaagcg gtggaattag aggcgtgagc ccccatgctt 2306ggccttacct ttctactttt ataattctgt atgttattat tttatgaaca tgaagaaact 2366ttagtaaatg tacttgttta catagttatg tgaatagatt agataaacat aaaaggagga 2426gacatacaat gggggaagaa gaagaagtcc cctgtaagat gtcactgtct gggttccagc 2486cctccctcag atgtactttg gcttcaatga ttggcaactt ctacaggggc cagtcttttg 2546aactggacaa ccttacaagt atatgagtat tatttatagg tagttgttta catatgagtc 2606gggaccaaag agaactggat ccacgtgaag tcctgtgtgt ggctggtccc tacctgggca 2666gtctcatttg cacccatagc ccccatctat ggacaggctg ggacagaggc agatgggtta 2726gatcacacat aacaataggg tctatgtcat atcccaagtg aacttgagcc ctgtttgggc 2786tcaggagata gaagacaaaa tctgtctccc acgtctgcca tggcatcaag ggggaagagt 2846agatggtgct tgagaatggt gtgaaatggt tgccatctca ggagtagatg gcccggctca 2906cttctggtta tctgtcaccc tgagcccatg agctgccttt tagggtacag attgcctact 2966tgaggacctt ggccgctctg taagcatctg actcatctca gaaatgtcaa ttcttaaaca 3026ctgtggcaac aggacctaga atggctgacg cattaaggtt ttcttcttgt gtcctgttct 3086attattgttt taagacctca gtaaccattt cagcctcttt ccagcaaacc cttctccata 3146gtatttcagt catggaagga tcatttatgc aggtagtcat tccaggagtt tttggtcttt 3206tctgtctcaa ggcattgtgt gttttgttcc gggactggtt tgggtgggac aaagttagaa 3266ttgcctgaag atcacacatt cagactgttg tgtctgtgga gttttaggag tggggggtga 3326cctttctggt ctttgcactt ccatcctctc ccacttccat ctggcatccc acgcgttgtc 3386ccctgcactt ctggaaggca cagggtgctg ctgcctcctg gtctttgcct ttgctgggcc 3446ttctgtgcag gacgctcagc ctcagggctc agaaggtgcc agtccggtcc caggtccctt 3506gtcccttcca cagaggcctt cctagaagat gcatctagag tgtcagcctt atcagtgttt 3566aagatttttc ttttattttt aatttttttg agacagaatc tcactctctc gcccaggctg 3626gagtgcaacg gtacgatctt ggctcagtgc aacctccgcc tcctgggttc aagcgattct 3686cgtgcctcag cctccggagt agctgggatt gcaggcaccc gccaccacgc ctggctaatt 3746tttgtatttt tagtagagac ggggtttcac catgttggtc aggctggtct cgaactcctg 3806acctcaggtg atccaccttg gcctccgaaa gtgctgggat tacaggcgtg agccaccagc 3866caggccaagc tattctttta aagtaagctt cctgacgaca tgaaataatt gggggttttg 3926ttgtttagtt acattaggct ttgctatatc cccaggccaa atagcatgtg acacaggaca 3986gccatagtat agtgtgtcac tcgtggttgg tgtcctttca tgcttctgcc ctgtcaaagg 4046tccctatttg aaatgtgtta taatacaaac aaggaagcac attgtgtaca aaatacttat 4106gtatttatga atccatgacc aaattaaata tgaaacctta tataaaaa 415412440PRTHomo sapiens 12Met Glu Gln Arg Gly Gln Asn Ala Pro Ala Ala Ser Gly Ala Arg Lys 1 5 10 15 Arg His Gly Pro Gly Pro Arg Glu Ala Arg Gly Ala Arg Pro Gly Pro 20 25 30 Arg Val Pro Lys Thr Leu Val Leu Val Val Ala Ala Val Leu Leu Leu 35 40 45 Val Ser Ala Glu Ser Ala Leu Ile Thr Gln Gln Asp Leu Ala Pro Gln 50 55 60 Gln Arg Ala Ala Pro Gln Gln Lys Arg Ser Ser Pro Ser Glu Gly Leu 65 70 75 80 Cys Pro Pro Gly His His Ile Ser Glu Asp Gly Arg Asp Cys Ile Ser 85 90 95 Cys Lys Tyr Gly Gln Asp Tyr Ser Thr His Trp Asn Asp Leu Leu Phe 100 105 110 Cys Leu Arg Cys Thr Arg Cys Asp Ser Gly Glu Val Glu Leu Ser Pro 115 120 125 Cys Thr Thr Thr Arg Asn Thr Val Cys Gln Cys Glu Glu Gly Thr Phe 130 135 140 Arg Glu Glu Asp Ser Pro Glu Met Cys Arg Lys Cys Arg Thr Gly Cys 145 150 155 160 Pro Arg Gly Met Val Lys Val Gly Asp Cys Thr Pro Trp Ser Asp Ile 165 170 175 Glu Cys Val His Lys Glu Ser Gly Thr Lys His Ser Gly Glu Val Pro 180 185 190 Ala Val Glu Glu Thr Val Thr Ser Ser Pro Gly Thr Pro Ala Ser Pro 195 200 205 Cys Ser Leu Ser Gly Ile Ile Ile Gly Val Thr Val Ala Ala Val Val 210 215 220 Leu Ile Val Ala Val Phe Val Cys Lys Ser Leu Leu Trp Lys Lys Val 225 230 235 240 Leu Pro Tyr Leu Lys Gly Ile Cys Ser Gly Gly Gly Gly Asp Pro Glu 245 250 255 Arg Val Asp Arg Ser Ser Gln Arg Pro Gly Ala Glu Asp Asn Val Leu 260 265 270 Asn Glu Ile Val Ser Ile Leu Gln Pro Thr Gln Val Pro Glu Gln Glu 275 280 285 Met Glu Val Gln Glu Pro Ala Glu Pro Thr Gly Val Asn Met Leu Ser 290 295 300 Pro Gly Glu Ser Glu His Leu Leu Glu Pro Ala Glu Ala Glu Arg Ser 305 310 315 320 Gln Arg Arg Arg Leu Leu Val Pro Ala Asn Glu Gly Asp Pro Thr Glu 325 330 335 Thr Leu Arg Gln Cys Phe Asp Asp Phe Ala Asp Leu Val Pro Phe Asp 340 345 350 Ser Trp Glu Pro Leu Met Arg Lys Leu Gly Leu Met Asp Asn Glu Ile 355 360 365 Lys Val Ala Lys Ala Glu Ala Ala Gly His Arg Asp Thr Leu Tyr Thr 370 375 380 Met Leu Ile Lys Trp Val Asn Lys Thr Gly Arg Asp Ala Ser Val His 385 390 395 400 Thr Leu Leu Asp Ala Leu Glu Thr Leu Gly Glu Arg Leu Ala Lys Gln 405 410 415 Lys Ile Glu Asp His Leu Leu Ser Ser Gly Lys Phe Met Tyr Leu Glu 420 425 430 Gly Asn Ala Asp Ser Ala Met Ser 435 440 138588DNAHomo sapiensCDS(481)..(7953) 13gagtagctcc agcggccacg ctgaggcgag ggtgacacac catgctcacg gcccctggag 60accgtcgtgc tggcgagccg tgctccgtag ctccccggtc cgcctcggca gcggtcagag 120tcgcctacag gagttgagcc gcccgcgcca gaaggttttg gcgaagctct tggagaggcg 180tcgagcacag tagggcggcg ggggtgcgtt gagcgctcgg gggtcaggca gtcggccggg 240atcgccgctg gggagcgttt ccgaggcgag gaggaggagg aggagatgct gctcctcttc 300tccccctccc caggctcctt ctacagctcc ttcagcccac gcccgcagcc gcttgtggga 360gaagtggtgg tggctctcgg cgcccgcggc ggctgccggc ggcccgcccc gacgccgcgt 420ccctgcagcc ctcgcccggc gctccagtag caggacccgg tctcgggacc agccggtaat 480atg cac gtg tca cta gct gag gcc ctg gag gtt cgg ggt gga cca ctt 528Met His Val Ser Leu Ala Glu Ala Leu Glu Val Arg Gly Gly Pro Leu 1 5 10 15 cag gag gaa gaa ata tgg gct gta tta aat caa agt gct gaa agt ctc 576Gln Glu Glu Glu Ile Trp Ala Val Leu Asn Gln Ser Ala Glu Ser Leu 20 25 30 caa gaa tta ttc aga aaa gta agc cta gct gat cct gct gcc ctt ggc 624Gln Glu Leu Phe Arg Lys Val Ser Leu Ala Asp Pro Ala Ala Leu Gly 35 40 45 ttc atc att tct cca tgg tct ctg ctg ttg ctg cca tct ggt agt gtg 672Phe Ile Ile Ser Pro Trp Ser Leu Leu Leu Leu Pro Ser Gly Ser Val 50 55 60 tca ttt aca gat gaa aat att tcc aat cag gat ctt cga gca ttc act 720Ser Phe Thr Asp Glu Asn Ile Ser Asn Gln Asp Leu Arg Ala Phe Thr 65 70 75 80 gca cca gag gtt ctt caa aat cag tca cta act tct ctc tca gat gtt 768Ala Pro Glu Val Leu Gln Asn Gln Ser Leu Thr Ser Leu Ser Asp Val 85 90 95 gaa aag atc cac att tat tct ctt gga atg aca ctg tat tgg ggg gct 816Glu Lys Ile His Ile Tyr Ser Leu Gly Met Thr Leu Tyr Trp Gly Ala 100 105 110 gat tat gaa gtg cct cag agc caa cct att aag ctt gga gat cat ctc 864Asp Tyr Glu Val Pro Gln Ser Gln Pro Ile Lys Leu Gly Asp His Leu 115 120 125 aac agc ata ctg ctt gga atg tgt gag gat gtt att tac gct cga gtt 912Asn Ser Ile Leu Leu Gly Met Cys Glu Asp Val Ile Tyr Ala Arg Val 130 135 140 tct gtt cgg act gtg ctg gat gct tgc agt gcc cac att agg aat agc 960Ser Val Arg Thr Val Leu Asp Ala Cys Ser Ala His Ile Arg Asn Ser 145 150 155 160 aat tgt gca ccc tca ttt tcc tac gtg aaa cac ttg gta aaa ctg gtt 1008Asn Cys Ala Pro Ser Phe Ser Tyr Val Lys His Leu Val Lys Leu Val 165 170 175 ctg gga aat ctt tct ggg aca gat cag ctt tcc tgt aac agt gaa caa 1056Leu Gly Asn Leu Ser Gly Thr Asp Gln Leu Ser Cys Asn Ser Glu Gln 180 185 190 aag cct gat cga agc cag gct att cga gat cga ttg cga gga aaa gga 1104Lys Pro Asp Arg Ser Gln Ala Ile Arg Asp Arg Leu Arg Gly Lys Gly 195 200 205 tta cca aca gga aga agc tct act tct gat gta cta gac ata caa aag 1152Leu Pro Thr Gly Arg Ser Ser Thr Ser Asp Val Leu Asp Ile Gln Lys 210 215 220 cct cca ctc tct cat cag acc ttt ctt aac aaa ggg ctt agt aaa tct 1200Pro Pro Leu Ser His Gln Thr Phe Leu Asn Lys Gly Leu Ser Lys Ser 225 230 235 240 atg gga ttt ctg tcc atc aaa gat aca caa gat gag aat tat ttc aag 1248Met Gly Phe Leu Ser Ile Lys Asp Thr Gln Asp Glu Asn Tyr Phe Lys 245 250 255 gac att tta tca gat aat tct gga cgt gaa gat tct gaa aat aca ttc 1296Asp Ile Leu Ser Asp Asn Ser Gly Arg Glu Asp Ser Glu Asn Thr Phe 260 265 270 tcc cct tac cag ttc aaa act agt ggc cca gaa aaa aaa ccc atc cct 1344Ser Pro Tyr Gln Phe Lys Thr Ser Gly Pro Glu Lys Lys Pro Ile Pro 275 280 285 ggc att gat gtg ctt tct aag aag aag atc tgg gct tca tcc atg gac 1392Gly Ile Asp Val Leu Ser Lys Lys Lys Ile Trp Ala Ser Ser Met Asp 290 295 300 ttg ctt tgt aca gct gac aga gac ttc tct tca gga gag act gcc aca 1440Leu Leu Cys Thr Ala Asp Arg Asp Phe Ser Ser Gly Glu Thr Ala Thr 305 310 315 320 tat cgt cgt tgt cac cct gag gca gta aca gtg cgg act tca act act 1488Tyr Arg Arg Cys His Pro Glu Ala Val Thr Val Arg Thr Ser Thr Thr 325 330 335 cct aga aaa aag gag gca aga tac tca gat gga agt ata gcc ttg gat 1536Pro Arg Lys Lys Glu Ala Arg Tyr Ser Asp Gly Ser Ile Ala Leu Asp 340 345 350 atc ttt ggc cct cag aaa atg gat cca ata tat cac act cga gaa ttg 1584Ile Phe Gly Pro Gln Lys Met Asp Pro Ile Tyr His Thr Arg Glu Leu 355 360 365 ccc acc tcc tca gca ata tca agt gct ttg gac cga atc cga gag aga 1632Pro Thr Ser Ser Ala Ile Ser Ser Ala Leu Asp Arg Ile Arg Glu Arg 370 375 380 caa aag aaa ctt cag gtt ctg agg gaa gcc atg aat gta gaa gaa cca 1680Gln Lys Lys Leu Gln Val Leu Arg Glu Ala Met Asn Val Glu Glu Pro 385 390 395 400 gtt cga aga tac aaa act tat cat ggt gat gtc ttt agt acc tcc agt

1728Val Arg Arg Tyr Lys Thr Tyr His Gly Asp Val Phe Ser Thr Ser Ser 405 410 415 gaa agt cca tct att att tcc tct gaa tca gat ttc aga caa gtg aga 1776Glu Ser Pro Ser Ile Ile Ser Ser Glu Ser Asp Phe Arg Gln Val Arg 420 425 430 aga agt gaa gcc tca aag agg ttt gaa tcc agc agt ggt ctc cca ggg 1824Arg Ser Glu Ala Ser Lys Arg Phe Glu Ser Ser Ser Gly Leu Pro Gly 435 440 445 gta gat gaa acc tta agt caa ggc cag tca cag aga ccg agc aga caa 1872Val Asp Glu Thr Leu Ser Gln Gly Gln Ser Gln Arg Pro Ser Arg Gln 450 455 460 tat gaa aca ccc ttt gaa ggc aac tta att aat caa gag atc atg cta 1920Tyr Glu Thr Pro Phe Glu Gly Asn Leu Ile Asn Gln Glu Ile Met Leu 465 470 475 480 aaa cgg caa gag gaa gaa ctg atg cag cta caa gcc aaa atg gcc ctt 1968Lys Arg Gln Glu Glu Glu Leu Met Gln Leu Gln Ala Lys Met Ala Leu 485 490 495 aga cag tct cgg ttg agc cta tat cca gga gac aca atc aaa gcg tcc 2016Arg Gln Ser Arg Leu Ser Leu Tyr Pro Gly Asp Thr Ile Lys Ala Ser 500 505 510 atg ctt gac atc acc agg gat ccg tta aga gaa att gcc cta gaa aca 2064Met Leu Asp Ile Thr Arg Asp Pro Leu Arg Glu Ile Ala Leu Glu Thr 515 520 525 gcc atg act caa aga aaa ctg agg aat ttc ttt ggc cct gag ttt gtg 2112Ala Met Thr Gln Arg Lys Leu Arg Asn Phe Phe Gly Pro Glu Phe Val 530 535 540 aaa atg aca att gaa cca ttt ata tct ttg gat ttg cca cgg tct att 2160Lys Met Thr Ile Glu Pro Phe Ile Ser Leu Asp Leu Pro Arg Ser Ile 545 550 555 560 ctt act aag aaa ggg aag aat gag gat aac cga agg aaa gta aac ata 2208Leu Thr Lys Lys Gly Lys Asn Glu Asp Asn Arg Arg Lys Val Asn Ile 565 570 575 atg ctt ctg aac ggg caa aga ctg gaa ctg acc tgt gat acc aaa act 2256Met Leu Leu Asn Gly Gln Arg Leu Glu Leu Thr Cys Asp Thr Lys Thr 580 585 590 ata tgt aaa gat gtg ttt gat atg gtt gtg gca cat att ggc tta gta 2304Ile Cys Lys Asp Val Phe Asp Met Val Val Ala His Ile Gly Leu Val 595 600 605 gag cat cat ttg ttt gct tta gct acc ctc aaa gat aat gaa tat ttc 2352Glu His His Leu Phe Ala Leu Ala Thr Leu Lys Asp Asn Glu Tyr Phe 610 615 620 ttt gtt gat cct gac tta aaa tta acc aaa gtg gcc cca gag gga tgg 2400Phe Val Asp Pro Asp Leu Lys Leu Thr Lys Val Ala Pro Glu Gly Trp 625 630 635 640 aaa gaa gaa cca aag aaa aag acc aaa gcc act gtt aat ttt act ttg 2448Lys Glu Glu Pro Lys Lys Lys Thr Lys Ala Thr Val Asn Phe Thr Leu 645 650 655 ttt ttc aga att aaa ttt ttt atg gat gat gtt agt cta ata caa cat 2496Phe Phe Arg Ile Lys Phe Phe Met Asp Asp Val Ser Leu Ile Gln His 660 665 670 act ctg acg tgt cat cag tat tac ctt cag ctt cga aaa gat att ttg 2544Thr Leu Thr Cys His Gln Tyr Tyr Leu Gln Leu Arg Lys Asp Ile Leu 675 680 685 gag gaa agg atg cac tgt gat gat gag act tcc tta ttg ctg gca tcc 2592Glu Glu Arg Met His Cys Asp Asp Glu Thr Ser Leu Leu Leu Ala Ser 690 695 700 ttg gct ctc cag gct gag tat gga gat tat caa cca gag gtt cat ggt 2640Leu Ala Leu Gln Ala Glu Tyr Gly Asp Tyr Gln Pro Glu Val His Gly 705 710 715 720 gtg tct tac ttt aga atg gag cac tat ttg ccc gcc aga gtg atg gag 2688Val Ser Tyr Phe Arg Met Glu His Tyr Leu Pro Ala Arg Val Met Glu 725 730 735 aaa ctt gat tta tcc tat atc aaa gaa gag tta ccc aaa ttg cat aat 2736Lys Leu Asp Leu Ser Tyr Ile Lys Glu Glu Leu Pro Lys Leu His Asn 740 745 750 acc tat gtg gga gct tct gaa aaa gag aca gag tta gaa ttt tta aag 2784Thr Tyr Val Gly Ala Ser Glu Lys Glu Thr Glu Leu Glu Phe Leu Lys 755 760 765 gtc tgc caa aga ctg aca gaa tat gga gtt cat ttt cac cga gtg cac 2832Val Cys Gln Arg Leu Thr Glu Tyr Gly Val His Phe His Arg Val His 770 775 780 cct gag aag aag tca caa aca gga ata ttg ctt gga gtc tgt tct aaa 2880Pro Glu Lys Lys Ser Gln Thr Gly Ile Leu Leu Gly Val Cys Ser Lys 785 790 795 800 ggt gtc ctt gtg ttt gaa gtt cac aat gga gtg cgc aca ttg gtc ctt 2928Gly Val Leu Val Phe Glu Val His Asn Gly Val Arg Thr Leu Val Leu 805 810 815 cgc ttt cca tgg agg gaa acc aag aaa ata tct ttt tct aaa aag aaa 2976Arg Phe Pro Trp Arg Glu Thr Lys Lys Ile Ser Phe Ser Lys Lys Lys 820 825 830 atc aca ttg caa aat aca tca gat gga ata aaa cat ggc ttc cag aca 3024Ile Thr Leu Gln Asn Thr Ser Asp Gly Ile Lys His Gly Phe Gln Thr 835 840 845 gac aac agt aag ata tgc cag tac ctg ctg cac ctc tgc tct tac cag 3072Asp Asn Ser Lys Ile Cys Gln Tyr Leu Leu His Leu Cys Ser Tyr Gln 850 855 860 cat aag ttc cag cta cag atg aga gca aga cag agc aac caa gat gcc 3120His Lys Phe Gln Leu Gln Met Arg Ala Arg Gln Ser Asn Gln Asp Ala 865 870 875 880 caa gat att gag aga gct tcg ttt agg agc ctg aat ctc caa gca gag 3168Gln Asp Ile Glu Arg Ala Ser Phe Arg Ser Leu Asn Leu Gln Ala Glu 885 890 895 tct gtt aga gga ttt aat atg gga cga gca atc agc act ggc agt ctg 3216Ser Val Arg Gly Phe Asn Met Gly Arg Ala Ile Ser Thr Gly Ser Leu 900 905 910 gcc agc agc acc ctc aac aaa ctt gct gtt cga cct tta tca gtt caa 3264Ala Ser Ser Thr Leu Asn Lys Leu Ala Val Arg Pro Leu Ser Val Gln 915 920 925 gct gag att ctg aag agg cta tcc tgc tca gag ctg tcg ctt tac cag 3312Ala Glu Ile Leu Lys Arg Leu Ser Cys Ser Glu Leu Ser Leu Tyr Gln 930 935 940 cca ttg caa aac agt tca aaa gag aag aat gac aaa gct tca tgg gag 3360Pro Leu Gln Asn Ser Ser Lys Glu Lys Asn Asp Lys Ala Ser Trp Glu 945 950 955 960 gaa aag cct aga gag atg agt aaa tca tac cat gat ctc agt cag gcc 3408Glu Lys Pro Arg Glu Met Ser Lys Ser Tyr His Asp Leu Ser Gln Ala 965 970 975 tct ctc tat cca cat cgg aaa aat gtc att gtt aac atg gaa ccc cca 3456Ser Leu Tyr Pro His Arg Lys Asn Val Ile Val Asn Met Glu Pro Pro 980 985 990 cca caa acc gtt gca gag ttg gtg gga aaa cct tct cac cag atg tca 3504Pro Gln Thr Val Ala Glu Leu Val Gly Lys Pro Ser His Gln Met Ser 995 1000 1005 aga tct gat gca gaa tct ttg gca gga gtg aca aaa ctt aat aat 3549Arg Ser Asp Ala Glu Ser Leu Ala Gly Val Thr Lys Leu Asn Asn 1010 1015 1020 tca aag tct gtt gcg agt tta aat aga agt cct gaa agg agg aaa 3594Ser Lys Ser Val Ala Ser Leu Asn Arg Ser Pro Glu Arg Arg Lys 1025 1030 1035 cat gaa tca gac tcc tca tcc att gaa gac cct ggg caa gca tat 3639His Glu Ser Asp Ser Ser Ser Ile Glu Asp Pro Gly Gln Ala Tyr 1040 1045 1050 gtt cta gga atg act atg cat agt tct gga aac tct tca tcc caa 3684Val Leu Gly Met Thr Met His Ser Ser Gly Asn Ser Ser Ser Gln 1055 1060 1065 gta ccc tta aaa gaa aat gat gtg cta cac aaa aga tgg agc ata 3729Val Pro Leu Lys Glu Asn Asp Val Leu His Lys Arg Trp Ser Ile 1070 1075 1080 gta tct tca cca gaa agg gag atc acc tta gtg aac ctg aaa aaa 3774Val Ser Ser Pro Glu Arg Glu Ile Thr Leu Val Asn Leu Lys Lys 1085 1090 1095 gat gca aag tat ggc ttg gga ttt caa att att ggt ggg gag aag 3819Asp Ala Lys Tyr Gly Leu Gly Phe Gln Ile Ile Gly Gly Glu Lys 1100 1105 1110 atg gga aga ctg gac cta ggc ata ttt atc agt tca gtt gcc cct 3864Met Gly Arg Leu Asp Leu Gly Ile Phe Ile Ser Ser Val Ala Pro 1115 1120 1125 gga gga cca gct gac ttg gat gga tgc ttg aag cca gga gac cgt 3909Gly Gly Pro Ala Asp Leu Asp Gly Cys Leu Lys Pro Gly Asp Arg 1130 1135 1140 ttg ata tct gtg aat agt gtg agt ctg gag gga gtc agc cac cat 3954Leu Ile Ser Val Asn Ser Val Ser Leu Glu Gly Val Ser His His 1145 1150 1155 gct gca att gaa att ttg caa aat gca cct gaa gat gtg aca ctt 3999Ala Ala Ile Glu Ile Leu Gln Asn Ala Pro Glu Asp Val Thr Leu 1160 1165 1170 gtt atc tct cag cca aaa gaa aag ata tcc aaa gtg cct tct act 4044Val Ile Ser Gln Pro Lys Glu Lys Ile Ser Lys Val Pro Ser Thr 1175 1180 1185 cct gtg cat ctc acc aat gag atg aaa aac tac atg aag aaa tct 4089Pro Val His Leu Thr Asn Glu Met Lys Asn Tyr Met Lys Lys Ser 1190 1195 1200 tcc tac atg caa gac agt gct ata gat tct tct tcc aag gat cac 4134Ser Tyr Met Gln Asp Ser Ala Ile Asp Ser Ser Ser Lys Asp His 1205 1210 1215 cac tgg tca cgt ggt acc ctg agg cac atc tcg gag aac tcc ttt 4179His Trp Ser Arg Gly Thr Leu Arg His Ile Ser Glu Asn Ser Phe 1220 1225 1230 ggg cca tct ggg ggc ctg cgg gaa gga agc ctg agt tct caa gat 4224Gly Pro Ser Gly Gly Leu Arg Glu Gly Ser Leu Ser Ser Gln Asp 1235 1240 1245 tcc agg act gag agt gcc agc ttg tct caa agc cag gtc aat ggt 4269Ser Arg Thr Glu Ser Ala Ser Leu Ser Gln Ser Gln Val Asn Gly 1250 1255 1260 ttc ttt gcc agc cat tta ggt gac caa acc tgg cag gaa tca cag 4314Phe Phe Ala Ser His Leu Gly Asp Gln Thr Trp Gln Glu Ser Gln 1265 1270 1275 cat ggc agc cct tcc cca tct gta ata tcc aaa gcc acc gag aaa 4359His Gly Ser Pro Ser Pro Ser Val Ile Ser Lys Ala Thr Glu Lys 1280 1285 1290 gag act ttc act gat agt aac caa agc aaa act aaa aag cca ggc 4404Glu Thr Phe Thr Asp Ser Asn Gln Ser Lys Thr Lys Lys Pro Gly 1295 1300 1305 att tct gat gta act gat tac tca gac cgt gga gat tca gac atg 4449Ile Ser Asp Val Thr Asp Tyr Ser Asp Arg Gly Asp Ser Asp Met 1310 1315 1320 gat gaa gcc act tac tcc agc agt cag gat cat caa aca cca aaa 4494Asp Glu Ala Thr Tyr Ser Ser Ser Gln Asp His Gln Thr Pro Lys 1325 1330 1335 cag gaa tct tcc tct tca gtg aat aca tcc aac aag atg aat ttt 4539Gln Glu Ser Ser Ser Ser Val Asn Thr Ser Asn Lys Met Asn Phe 1340 1345 1350 aaa act ttt tct tca tca cct cct aag cct gga gat atc ttt gag 4584Lys Thr Phe Ser Ser Ser Pro Pro Lys Pro Gly Asp Ile Phe Glu 1355 1360 1365 gtt gaa ctg gct aaa aat gat aac agc ttg ggg ata agt gtc acg 4629Val Glu Leu Ala Lys Asn Asp Asn Ser Leu Gly Ile Ser Val Thr 1370 1375 1380 gta ctg ttt gac aag gga ggt gtg aat acg agt gtc aga cat ggt 4674Val Leu Phe Asp Lys Gly Gly Val Asn Thr Ser Val Arg His Gly 1385 1390 1395 ggc att tat gtg aaa gct gtt att ccc cag gga gca gca gag tct 4719Gly Ile Tyr Val Lys Ala Val Ile Pro Gln Gly Ala Ala Glu Ser 1400 1405 1410 gat ggt aga att cac aaa ggt gat cgc gtc cta gct gtc aat gga 4764Asp Gly Arg Ile His Lys Gly Asp Arg Val Leu Ala Val Asn Gly 1415 1420 1425 gtt agt cta gaa gga gcc acc cat aag caa gct gtg gaa aca ctg 4809Val Ser Leu Glu Gly Ala Thr His Lys Gln Ala Val Glu Thr Leu 1430 1435 1440 aga aat aca gga cag gtg gtt cat ctg tta tta gaa aag gga caa 4854Arg Asn Thr Gly Gln Val Val His Leu Leu Leu Glu Lys Gly Gln 1445 1450 1455 tct cca aca tct aaa gaa cat gtc ccg gta acc cca cag tgt acc 4899Ser Pro Thr Ser Lys Glu His Val Pro Val Thr Pro Gln Cys Thr 1460 1465 1470 ctt tca gat cag aat gcc caa ggt caa ggc cca gaa aaa gtg aag 4944Leu Ser Asp Gln Asn Ala Gln Gly Gln Gly Pro Glu Lys Val Lys 1475 1480 1485 aaa aca act cag gtc aaa gac tac agc ttt gtc act gaa gaa aat 4989Lys Thr Thr Gln Val Lys Asp Tyr Ser Phe Val Thr Glu Glu Asn 1490 1495 1500 aca ttt gag gta aaa tta ttt aaa aat agc tca ggt cta gga ttc 5034Thr Phe Glu Val Lys Leu Phe Lys Asn Ser Ser Gly Leu Gly Phe 1505 1510 1515 agt ttt tct cga gaa gat aat ctt ata ccg gag caa att aat gcc 5079Ser Phe Ser Arg Glu Asp Asn Leu Ile Pro Glu Gln Ile Asn Ala 1520 1525 1530 agc ata gta agg gtt aaa aag ctc ttt cct gga cag cca gca gca 5124Ser Ile Val Arg Val Lys Lys Leu Phe Pro Gly Gln Pro Ala Ala 1535 1540 1545 gaa agt gga aaa att gat gta gga gat gtt atc ttg aaa gtg aat 5169Glu Ser Gly Lys Ile Asp Val Gly Asp Val Ile Leu Lys Val Asn 1550 1555 1560 gga gcc tct ttg aaa gga cta tct cag cag gaa gtc ata tct gct 5214Gly Ala Ser Leu Lys Gly Leu Ser Gln Gln Glu Val Ile Ser Ala 1565 1570 1575 ctc agg gga act gct cca gaa gta ttc ttg ctt ctc tgc aga cct 5259Leu Arg Gly Thr Ala Pro Glu Val Phe Leu Leu Leu Cys Arg Pro 1580 1585 1590 cca cct ggt gtg cta ccg gaa att gat act gcg ctt ttg acc cca 5304Pro Pro Gly Val Leu Pro Glu Ile Asp Thr Ala Leu Leu Thr Pro 1595 1600 1605 ctt cag tct cca gca caa gta ctt cca aac agc agt aaa gac tct 5349Leu Gln Ser Pro Ala Gln Val Leu Pro Asn Ser Ser Lys Asp Ser 1610 1615 1620 tct cag cca tca tgt gtg gag caa agc acc agc tca gat gaa aat 5394Ser Gln Pro Ser Cys Val Glu Gln Ser Thr Ser Ser Asp Glu Asn 1625 1630 1635 gaa atg tca gac aaa agc aaa aaa cag tgc aag tcc cca tcc aga 5439Glu Met Ser Asp Lys Ser Lys Lys Gln Cys Lys Ser Pro Ser Arg 1640 1645 1650 aga gac agt tac agt gac agc agt ggg agt gga gaa gat gac tta 5484Arg Asp Ser Tyr Ser Asp Ser Ser Gly Ser Gly Glu Asp Asp Leu 1655 1660 1665 gtg aca gct cca gca aac ata tca aat tcg acc tgg agt tca gct 5529Val Thr Ala Pro Ala Asn Ile Ser Asn Ser Thr Trp Ser Ser Ala 1670 1675 1680 ttg cat cag act cta agc aac atg gta tca cag gca cag agt cat 5574Leu His Gln Thr Leu Ser Asn Met Val Ser Gln Ala Gln Ser His 1685 1690 1695

cat gaa gca ccc aag agt caa gaa gat acc att tgt acc atg ttt 5619His Glu Ala Pro Lys Ser Gln Glu Asp Thr Ile Cys Thr Met Phe 1700 1705 1710 tac tat cct cag aaa att ccc aat aaa cca gag ttt gag gac agt 5664Tyr Tyr Pro Gln Lys Ile Pro Asn Lys Pro Glu Phe Glu Asp Ser 1715 1720 1725 aat cct tcc cct cta cca ccg gat atg gct cct ggg cag agt tat 5709Asn Pro Ser Pro Leu Pro Pro Asp Met Ala Pro Gly Gln Ser Tyr 1730 1735 1740 caa ccc caa tca gaa tct gct tcc tct agt tcg atg gat aag tat 5754Gln Pro Gln Ser Glu Ser Ala Ser Ser Ser Ser Met Asp Lys Tyr 1745 1750 1755 cat ata cat cac att tct gaa cca act aga caa gaa aac tgg aca 5799His Ile His His Ile Ser Glu Pro Thr Arg Gln Glu Asn Trp Thr 1760 1765 1770 cct ttg aaa aat gac ttg gaa aat cac ctt gaa gac ttt gaa ctg 5844Pro Leu Lys Asn Asp Leu Glu Asn His Leu Glu Asp Phe Glu Leu 1775 1780 1785 gaa gta gaa ctc ctc att acc cta att aaa tca gaa aaa gga agc 5889Glu Val Glu Leu Leu Ile Thr Leu Ile Lys Ser Glu Lys Gly Ser 1790 1795 1800 ctg ggt ttt aca gta acc aaa ggc aat cag aga att ggt tgt tat 5934Leu Gly Phe Thr Val Thr Lys Gly Asn Gln Arg Ile Gly Cys Tyr 1805 1810 1815 gtt cat gat gtc ata cag gat cca gcc aaa agt gat gga agg cta 5979Val His Asp Val Ile Gln Asp Pro Ala Lys Ser Asp Gly Arg Leu 1820 1825 1830 aaa cct ggg gac cgg ctc ata aag gtt aat gat aca gat gtt act 6024Lys Pro Gly Asp Arg Leu Ile Lys Val Asn Asp Thr Asp Val Thr 1835 1840 1845 aat atg act cat aca gat gca gtt aat ctg ctc cgg gct gca tcc 6069Asn Met Thr His Thr Asp Ala Val Asn Leu Leu Arg Ala Ala Ser 1850 1855 1860 aaa aca gtc aga tta gtt att gga cga gtt cta gaa tta ccc aga 6114Lys Thr Val Arg Leu Val Ile Gly Arg Val Leu Glu Leu Pro Arg 1865 1870 1875 ata cca atg ttg cct cat ttg cta ccg gac ata aca cta acg tgc 6159Ile Pro Met Leu Pro His Leu Leu Pro Asp Ile Thr Leu Thr Cys 1880 1885 1890 aac aaa gag gag ttg ggt ttt tcc tta tgt gga ggt cat gac agc 6204Asn Lys Glu Glu Leu Gly Phe Ser Leu Cys Gly Gly His Asp Ser 1895 1900 1905 ctt tat caa gtg gta tat att agt gat att aat cca agg tcc gtc 6249Leu Tyr Gln Val Val Tyr Ile Ser Asp Ile Asn Pro Arg Ser Val 1910 1915 1920 gca gcc att gag ggt aat ctc cag cta tta gat gtc atc cat tat 6294Ala Ala Ile Glu Gly Asn Leu Gln Leu Leu Asp Val Ile His Tyr 1925 1930 1935 gtg aac gga gtc agc aca caa gga atg acc ttg gag gaa gtt aac 6339Val Asn Gly Val Ser Thr Gln Gly Met Thr Leu Glu Glu Val Asn 1940 1945 1950 aga gca tta gac atg tca ctt cct tca ttg gta ttg aaa gca aca 6384Arg Ala Leu Asp Met Ser Leu Pro Ser Leu Val Leu Lys Ala Thr 1955 1960 1965 aga aat gat ctt cca gtg gtc ccc agc tca aag agg tct gct gtt 6429Arg Asn Asp Leu Pro Val Val Pro Ser Ser Lys Arg Ser Ala Val 1970 1975 1980 tca gct cca aag tca acc aaa ggc aat ggt tcc tac agt gtg ggg 6474Ser Ala Pro Lys Ser Thr Lys Gly Asn Gly Ser Tyr Ser Val Gly 1985 1990 1995 tct tgc agc cag cct gcc ctc act cct aat gat tca ttc tcc acg 6519Ser Cys Ser Gln Pro Ala Leu Thr Pro Asn Asp Ser Phe Ser Thr 2000 2005 2010 gtt gct ggg gaa gaa ata aat gaa ata tcg tac ccc aaa gga aaa 6564Val Ala Gly Glu Glu Ile Asn Glu Ile Ser Tyr Pro Lys Gly Lys 2015 2020 2025 tgt tct act tat cag ata aag gga tca cca aac ttg act ctg ccc 6609Cys Ser Thr Tyr Gln Ile Lys Gly Ser Pro Asn Leu Thr Leu Pro 2030 2035 2040 aaa gaa tct tat ata caa gaa gat gac att tat gat gat tcc caa 6654Lys Glu Ser Tyr Ile Gln Glu Asp Asp Ile Tyr Asp Asp Ser Gln 2045 2050 2055 gaa gct gaa gtt atc cag tct ctg ctg gat gtt gtg gat gag gaa 6699Glu Ala Glu Val Ile Gln Ser Leu Leu Asp Val Val Asp Glu Glu 2060 2065 2070 gcc cag aat ctt tta aac gaa aat aat gca gca gga tac tcc tgt 6744Ala Gln Asn Leu Leu Asn Glu Asn Asn Ala Ala Gly Tyr Ser Cys 2075 2080 2085 ggt cca ggt aca tta aag atg aat ggg aag tta tca gaa gag aga 6789Gly Pro Gly Thr Leu Lys Met Asn Gly Lys Leu Ser Glu Glu Arg 2090 2095 2100 aca gaa gat aca gac tgc gat ggt tca cct tta cct gag tat ttt 6834Thr Glu Asp Thr Asp Cys Asp Gly Ser Pro Leu Pro Glu Tyr Phe 2105 2110 2115 act gag gcc acc aaa atg aat ggc tgt gaa gaa tat tgt gaa gaa 6879Thr Glu Ala Thr Lys Met Asn Gly Cys Glu Glu Tyr Cys Glu Glu 2120 2125 2130 aaa gta aaa agt gaa agc tta att cag aag cca caa gaa aag aag 6924Lys Val Lys Ser Glu Ser Leu Ile Gln Lys Pro Gln Glu Lys Lys 2135 2140 2145 act gat gat gat gaa ata aca tgg gga aat gat gag ttg cca ata 6969Thr Asp Asp Asp Glu Ile Thr Trp Gly Asn Asp Glu Leu Pro Ile 2150 2155 2160 gag aga aca aac cat gaa gat tct gat aaa gat cat tcc ttt ctg 7014Glu Arg Thr Asn His Glu Asp Ser Asp Lys Asp His Ser Phe Leu 2165 2170 2175 aca aac gat gag ctc gct gta ctc cct gtc gtc aaa gtg ctt ccc 7059Thr Asn Asp Glu Leu Ala Val Leu Pro Val Val Lys Val Leu Pro 2180 2185 2190 tct ggt aaa tac acg ggt gcc aac tta aaa tca gtc att cga gtc 7104Ser Gly Lys Tyr Thr Gly Ala Asn Leu Lys Ser Val Ile Arg Val 2195 2200 2205 ctg cgg ggt ttg cta gat caa gga att cct tct aag gag ctg gag 7149Leu Arg Gly Leu Leu Asp Gln Gly Ile Pro Ser Lys Glu Leu Glu 2210 2215 2220 aat ctt caa gaa tta aaa cct ttg gat cag tgt cta att ggg caa 7194Asn Leu Gln Glu Leu Lys Pro Leu Asp Gln Cys Leu Ile Gly Gln 2225 2230 2235 act aag gaa aac aga agg aag aac aga tat aaa aat ata ctt ccc 7239Thr Lys Glu Asn Arg Arg Lys Asn Arg Tyr Lys Asn Ile Leu Pro 2240 2245 2250 tat gat gct aca aga gtg cct ctt gga gat gaa ggt ggc tat atc 7284Tyr Asp Ala Thr Arg Val Pro Leu Gly Asp Glu Gly Gly Tyr Ile 2255 2260 2265 aat gcc agc ttc att aag ata cca gtt ggg aaa gaa gag ttc gtt 7329Asn Ala Ser Phe Ile Lys Ile Pro Val Gly Lys Glu Glu Phe Val 2270 2275 2280 tac att gcc tgc caa gga cca ctg cct aca act gtt gga gac ttc 7374Tyr Ile Ala Cys Gln Gly Pro Leu Pro Thr Thr Val Gly Asp Phe 2285 2290 2295 tgg cag atg att tgg gag caa aaa tcc aca gtg ata gcc atg atg 7419Trp Gln Met Ile Trp Glu Gln Lys Ser Thr Val Ile Ala Met Met 2300 2305 2310 act caa gaa gta gaa gga gaa aaa atc aaa tgc cag cgc tat tgg 7464Thr Gln Glu Val Glu Gly Glu Lys Ile Lys Cys Gln Arg Tyr Trp 2315 2320 2325 ccc aac atc cta ggc aaa aca aca atg gtc agc aac aga ctt cga 7509Pro Asn Ile Leu Gly Lys Thr Thr Met Val Ser Asn Arg Leu Arg 2330 2335 2340 ctg gct ctt gtg aga atg cag cag ctg aag ggc ttt gtg gtg agg 7554Leu Ala Leu Val Arg Met Gln Gln Leu Lys Gly Phe Val Val Arg 2345 2350 2355 gca atg acc ctt gaa gat att cag acc aga gag gtg cgc cat att 7599Ala Met Thr Leu Glu Asp Ile Gln Thr Arg Glu Val Arg His Ile 2360 2365 2370 tct cat ctg aat ttc act gcc tgg cca gac cat gat aca cct tct 7644Ser His Leu Asn Phe Thr Ala Trp Pro Asp His Asp Thr Pro Ser 2375 2380 2385 caa cca gat gat ctg ctt act ttt atc tcc tac atg aga cac atc 7689Gln Pro Asp Asp Leu Leu Thr Phe Ile Ser Tyr Met Arg His Ile 2390 2395 2400 cac aga tca ggc cca atc att acg cac tgc agt gct ggc att gga 7734His Arg Ser Gly Pro Ile Ile Thr His Cys Ser Ala Gly Ile Gly 2405 2410 2415 cgt tca ggg acc ctg att tgc ata gat gtg gtt ctg gga tta atc 7779Arg Ser Gly Thr Leu Ile Cys Ile Asp Val Val Leu Gly Leu Ile 2420 2425 2430 agt cag gat ctt gat ttt gac atc tct gat ttg gtg cgc tgc atg 7824Ser Gln Asp Leu Asp Phe Asp Ile Ser Asp Leu Val Arg Cys Met 2435 2440 2445 aga cta caa aga cac gga atg gtt cag aca gag gat caa tat att 7869Arg Leu Gln Arg His Gly Met Val Gln Thr Glu Asp Gln Tyr Ile 2450 2455 2460 ttc tgc tat caa gtc atc ctt tat gtc ctg aca cgt ctt caa gca 7914Phe Cys Tyr Gln Val Ile Leu Tyr Val Leu Thr Arg Leu Gln Ala 2465 2470 2475 gaa gaa gag caa aaa cag cag cct cag ctt ctg aag tga catgaaaaga 7963Glu Glu Glu Gln Lys Gln Gln Pro Gln Leu Leu Lys 2480 2485 2490 gcctctggat gcatttccat ttctctcctt aacctccagc agactcctgc tctctatcca 8023aaataaagat cacagagcag caagttcata caacatgcat gttctcctct atcttagagg 8083ggtattcttc ttgaaaataa aaaatattga aatgctgtat ttttacagct actttaacct 8143atgataatta tttacaaaat tttaacacta accaaacaat gcagatctta gggatgatta 8203aaggcagcat ttgatgatag cagacattgt tacaaggaca tggtgagtct atttttaatg 8263caccaatctt gtttatagca aaaatgtttt ccaatatttt aataaagtag ttattttata 8323ggggatactt gaaaccagta tttaagcttt aaatgacagt aatattggca tagaaaaaag 8383tagcaaatgt ttactgtatc aatttctaat gtttactata tagaatttcc tgtaatatat 8443ttatatactt tttcatgaaa atggagttat cagttatctg tttgttactg catcatctgt 8503ttgtaatcat tatctcactt tgtaaataaa aacacacctt aaaacatgaa caagccaaaa 8563ctgtgtgcag acaaaaaaaa aaaaa 8588142490PRTHomo sapiens 14Met His Val Ser Leu Ala Glu Ala Leu Glu Val Arg Gly Gly Pro Leu 1 5 10 15 Gln Glu Glu Glu Ile Trp Ala Val Leu Asn Gln Ser Ala Glu Ser Leu 20 25 30 Gln Glu Leu Phe Arg Lys Val Ser Leu Ala Asp Pro Ala Ala Leu Gly 35 40 45 Phe Ile Ile Ser Pro Trp Ser Leu Leu Leu Leu Pro Ser Gly Ser Val 50 55 60 Ser Phe Thr Asp Glu Asn Ile Ser Asn Gln Asp Leu Arg Ala Phe Thr 65 70 75 80 Ala Pro Glu Val Leu Gln Asn Gln Ser Leu Thr Ser Leu Ser Asp Val 85 90 95 Glu Lys Ile His Ile Tyr Ser Leu Gly Met Thr Leu Tyr Trp Gly Ala 100 105 110 Asp Tyr Glu Val Pro Gln Ser Gln Pro Ile Lys Leu Gly Asp His Leu 115 120 125 Asn Ser Ile Leu Leu Gly Met Cys Glu Asp Val Ile Tyr Ala Arg Val 130 135 140 Ser Val Arg Thr Val Leu Asp Ala Cys Ser Ala His Ile Arg Asn Ser 145 150 155 160 Asn Cys Ala Pro Ser Phe Ser Tyr Val Lys His Leu Val Lys Leu Val 165 170 175 Leu Gly Asn Leu Ser Gly Thr Asp Gln Leu Ser Cys Asn Ser Glu Gln 180 185 190 Lys Pro Asp Arg Ser Gln Ala Ile Arg Asp Arg Leu Arg Gly Lys Gly 195 200 205 Leu Pro Thr Gly Arg Ser Ser Thr Ser Asp Val Leu Asp Ile Gln Lys 210 215 220 Pro Pro Leu Ser His Gln Thr Phe Leu Asn Lys Gly Leu Ser Lys Ser 225 230 235 240 Met Gly Phe Leu Ser Ile Lys Asp Thr Gln Asp Glu Asn Tyr Phe Lys 245 250 255 Asp Ile Leu Ser Asp Asn Ser Gly Arg Glu Asp Ser Glu Asn Thr Phe 260 265 270 Ser Pro Tyr Gln Phe Lys Thr Ser Gly Pro Glu Lys Lys Pro Ile Pro 275 280 285 Gly Ile Asp Val Leu Ser Lys Lys Lys Ile Trp Ala Ser Ser Met Asp 290 295 300 Leu Leu Cys Thr Ala Asp Arg Asp Phe Ser Ser Gly Glu Thr Ala Thr 305 310 315 320 Tyr Arg Arg Cys His Pro Glu Ala Val Thr Val Arg Thr Ser Thr Thr 325 330 335 Pro Arg Lys Lys Glu Ala Arg Tyr Ser Asp Gly Ser Ile Ala Leu Asp 340 345 350 Ile Phe Gly Pro Gln Lys Met Asp Pro Ile Tyr His Thr Arg Glu Leu 355 360 365 Pro Thr Ser Ser Ala Ile Ser Ser Ala Leu Asp Arg Ile Arg Glu Arg 370 375 380 Gln Lys Lys Leu Gln Val Leu Arg Glu Ala Met Asn Val Glu Glu Pro 385 390 395 400 Val Arg Arg Tyr Lys Thr Tyr His Gly Asp Val Phe Ser Thr Ser Ser 405 410 415 Glu Ser Pro Ser Ile Ile Ser Ser Glu Ser Asp Phe Arg Gln Val Arg 420 425 430 Arg Ser Glu Ala Ser Lys Arg Phe Glu Ser Ser Ser Gly Leu Pro Gly 435 440 445 Val Asp Glu Thr Leu Ser Gln Gly Gln Ser Gln Arg Pro Ser Arg Gln 450 455 460 Tyr Glu Thr Pro Phe Glu Gly Asn Leu Ile Asn Gln Glu Ile Met Leu 465 470 475 480 Lys Arg Gln Glu Glu Glu Leu Met Gln Leu Gln Ala Lys Met Ala Leu 485 490 495 Arg Gln Ser Arg Leu Ser Leu Tyr Pro Gly Asp Thr Ile Lys Ala Ser 500 505 510 Met Leu Asp Ile Thr Arg Asp Pro Leu Arg Glu Ile Ala Leu Glu Thr 515 520 525 Ala Met Thr Gln Arg Lys Leu Arg Asn Phe Phe Gly Pro Glu Phe Val 530 535 540 Lys Met Thr Ile Glu Pro Phe Ile Ser Leu Asp Leu Pro Arg Ser Ile 545 550 555 560 Leu Thr Lys Lys Gly Lys Asn Glu Asp Asn Arg Arg Lys Val Asn Ile 565 570 575 Met Leu Leu Asn Gly Gln Arg Leu Glu Leu Thr Cys Asp Thr Lys Thr 580 585 590 Ile Cys Lys Asp Val Phe Asp Met Val Val Ala His Ile Gly Leu Val 595 600 605 Glu His His Leu Phe Ala Leu Ala Thr Leu Lys Asp Asn Glu Tyr Phe 610 615 620 Phe Val Asp Pro Asp Leu Lys Leu Thr Lys Val Ala Pro Glu Gly Trp 625 630 635 640 Lys Glu Glu Pro Lys Lys Lys Thr Lys Ala Thr Val Asn Phe Thr Leu 645 650 655 Phe Phe Arg Ile Lys Phe Phe Met Asp Asp Val Ser Leu Ile Gln His 660 665 670 Thr Leu Thr Cys His Gln Tyr Tyr Leu Gln Leu Arg Lys Asp Ile Leu 675 680 685 Glu Glu Arg Met His Cys Asp Asp Glu Thr Ser Leu Leu Leu Ala Ser 690 695 700 Leu Ala Leu Gln Ala Glu Tyr Gly Asp Tyr Gln Pro Glu Val His Gly 705 710 715 720 Val Ser Tyr Phe Arg Met Glu His Tyr Leu Pro Ala Arg Val Met Glu 725 730 735 Lys Leu Asp Leu Ser Tyr Ile Lys Glu Glu

Leu Pro Lys Leu His Asn 740 745 750 Thr Tyr Val Gly Ala Ser Glu Lys Glu Thr Glu Leu Glu Phe Leu Lys 755 760 765 Val Cys Gln Arg Leu Thr Glu Tyr Gly Val His Phe His Arg Val His 770 775 780 Pro Glu Lys Lys Ser Gln Thr Gly Ile Leu Leu Gly Val Cys Ser Lys 785 790 795 800 Gly Val Leu Val Phe Glu Val His Asn Gly Val Arg Thr Leu Val Leu 805 810 815 Arg Phe Pro Trp Arg Glu Thr Lys Lys Ile Ser Phe Ser Lys Lys Lys 820 825 830 Ile Thr Leu Gln Asn Thr Ser Asp Gly Ile Lys His Gly Phe Gln Thr 835 840 845 Asp Asn Ser Lys Ile Cys Gln Tyr Leu Leu His Leu Cys Ser Tyr Gln 850 855 860 His Lys Phe Gln Leu Gln Met Arg Ala Arg Gln Ser Asn Gln Asp Ala 865 870 875 880 Gln Asp Ile Glu Arg Ala Ser Phe Arg Ser Leu Asn Leu Gln Ala Glu 885 890 895 Ser Val Arg Gly Phe Asn Met Gly Arg Ala Ile Ser Thr Gly Ser Leu 900 905 910 Ala Ser Ser Thr Leu Asn Lys Leu Ala Val Arg Pro Leu Ser Val Gln 915 920 925 Ala Glu Ile Leu Lys Arg Leu Ser Cys Ser Glu Leu Ser Leu Tyr Gln 930 935 940 Pro Leu Gln Asn Ser Ser Lys Glu Lys Asn Asp Lys Ala Ser Trp Glu 945 950 955 960 Glu Lys Pro Arg Glu Met Ser Lys Ser Tyr His Asp Leu Ser Gln Ala 965 970 975 Ser Leu Tyr Pro His Arg Lys Asn Val Ile Val Asn Met Glu Pro Pro 980 985 990 Pro Gln Thr Val Ala Glu Leu Val Gly Lys Pro Ser His Gln Met Ser 995 1000 1005 Arg Ser Asp Ala Glu Ser Leu Ala Gly Val Thr Lys Leu Asn Asn 1010 1015 1020 Ser Lys Ser Val Ala Ser Leu Asn Arg Ser Pro Glu Arg Arg Lys 1025 1030 1035 His Glu Ser Asp Ser Ser Ser Ile Glu Asp Pro Gly Gln Ala Tyr 1040 1045 1050 Val Leu Gly Met Thr Met His Ser Ser Gly Asn Ser Ser Ser Gln 1055 1060 1065 Val Pro Leu Lys Glu Asn Asp Val Leu His Lys Arg Trp Ser Ile 1070 1075 1080 Val Ser Ser Pro Glu Arg Glu Ile Thr Leu Val Asn Leu Lys Lys 1085 1090 1095 Asp Ala Lys Tyr Gly Leu Gly Phe Gln Ile Ile Gly Gly Glu Lys 1100 1105 1110 Met Gly Arg Leu Asp Leu Gly Ile Phe Ile Ser Ser Val Ala Pro 1115 1120 1125 Gly Gly Pro Ala Asp Leu Asp Gly Cys Leu Lys Pro Gly Asp Arg 1130 1135 1140 Leu Ile Ser Val Asn Ser Val Ser Leu Glu Gly Val Ser His His 1145 1150 1155 Ala Ala Ile Glu Ile Leu Gln Asn Ala Pro Glu Asp Val Thr Leu 1160 1165 1170 Val Ile Ser Gln Pro Lys Glu Lys Ile Ser Lys Val Pro Ser Thr 1175 1180 1185 Pro Val His Leu Thr Asn Glu Met Lys Asn Tyr Met Lys Lys Ser 1190 1195 1200 Ser Tyr Met Gln Asp Ser Ala Ile Asp Ser Ser Ser Lys Asp His 1205 1210 1215 His Trp Ser Arg Gly Thr Leu Arg His Ile Ser Glu Asn Ser Phe 1220 1225 1230 Gly Pro Ser Gly Gly Leu Arg Glu Gly Ser Leu Ser Ser Gln Asp 1235 1240 1245 Ser Arg Thr Glu Ser Ala Ser Leu Ser Gln Ser Gln Val Asn Gly 1250 1255 1260 Phe Phe Ala Ser His Leu Gly Asp Gln Thr Trp Gln Glu Ser Gln 1265 1270 1275 His Gly Ser Pro Ser Pro Ser Val Ile Ser Lys Ala Thr Glu Lys 1280 1285 1290 Glu Thr Phe Thr Asp Ser Asn Gln Ser Lys Thr Lys Lys Pro Gly 1295 1300 1305 Ile Ser Asp Val Thr Asp Tyr Ser Asp Arg Gly Asp Ser Asp Met 1310 1315 1320 Asp Glu Ala Thr Tyr Ser Ser Ser Gln Asp His Gln Thr Pro Lys 1325 1330 1335 Gln Glu Ser Ser Ser Ser Val Asn Thr Ser Asn Lys Met Asn Phe 1340 1345 1350 Lys Thr Phe Ser Ser Ser Pro Pro Lys Pro Gly Asp Ile Phe Glu 1355 1360 1365 Val Glu Leu Ala Lys Asn Asp Asn Ser Leu Gly Ile Ser Val Thr 1370 1375 1380 Val Leu Phe Asp Lys Gly Gly Val Asn Thr Ser Val Arg His Gly 1385 1390 1395 Gly Ile Tyr Val Lys Ala Val Ile Pro Gln Gly Ala Ala Glu Ser 1400 1405 1410 Asp Gly Arg Ile His Lys Gly Asp Arg Val Leu Ala Val Asn Gly 1415 1420 1425 Val Ser Leu Glu Gly Ala Thr His Lys Gln Ala Val Glu Thr Leu 1430 1435 1440 Arg Asn Thr Gly Gln Val Val His Leu Leu Leu Glu Lys Gly Gln 1445 1450 1455 Ser Pro Thr Ser Lys Glu His Val Pro Val Thr Pro Gln Cys Thr 1460 1465 1470 Leu Ser Asp Gln Asn Ala Gln Gly Gln Gly Pro Glu Lys Val Lys 1475 1480 1485 Lys Thr Thr Gln Val Lys Asp Tyr Ser Phe Val Thr Glu Glu Asn 1490 1495 1500 Thr Phe Glu Val Lys Leu Phe Lys Asn Ser Ser Gly Leu Gly Phe 1505 1510 1515 Ser Phe Ser Arg Glu Asp Asn Leu Ile Pro Glu Gln Ile Asn Ala 1520 1525 1530 Ser Ile Val Arg Val Lys Lys Leu Phe Pro Gly Gln Pro Ala Ala 1535 1540 1545 Glu Ser Gly Lys Ile Asp Val Gly Asp Val Ile Leu Lys Val Asn 1550 1555 1560 Gly Ala Ser Leu Lys Gly Leu Ser Gln Gln Glu Val Ile Ser Ala 1565 1570 1575 Leu Arg Gly Thr Ala Pro Glu Val Phe Leu Leu Leu Cys Arg Pro 1580 1585 1590 Pro Pro Gly Val Leu Pro Glu Ile Asp Thr Ala Leu Leu Thr Pro 1595 1600 1605 Leu Gln Ser Pro Ala Gln Val Leu Pro Asn Ser Ser Lys Asp Ser 1610 1615 1620 Ser Gln Pro Ser Cys Val Glu Gln Ser Thr Ser Ser Asp Glu Asn 1625 1630 1635 Glu Met Ser Asp Lys Ser Lys Lys Gln Cys Lys Ser Pro Ser Arg 1640 1645 1650 Arg Asp Ser Tyr Ser Asp Ser Ser Gly Ser Gly Glu Asp Asp Leu 1655 1660 1665 Val Thr Ala Pro Ala Asn Ile Ser Asn Ser Thr Trp Ser Ser Ala 1670 1675 1680 Leu His Gln Thr Leu Ser Asn Met Val Ser Gln Ala Gln Ser His 1685 1690 1695 His Glu Ala Pro Lys Ser Gln Glu Asp Thr Ile Cys Thr Met Phe 1700 1705 1710 Tyr Tyr Pro Gln Lys Ile Pro Asn Lys Pro Glu Phe Glu Asp Ser 1715 1720 1725 Asn Pro Ser Pro Leu Pro Pro Asp Met Ala Pro Gly Gln Ser Tyr 1730 1735 1740 Gln Pro Gln Ser Glu Ser Ala Ser Ser Ser Ser Met Asp Lys Tyr 1745 1750 1755 His Ile His His Ile Ser Glu Pro Thr Arg Gln Glu Asn Trp Thr 1760 1765 1770 Pro Leu Lys Asn Asp Leu Glu Asn His Leu Glu Asp Phe Glu Leu 1775 1780 1785 Glu Val Glu Leu Leu Ile Thr Leu Ile Lys Ser Glu Lys Gly Ser 1790 1795 1800 Leu Gly Phe Thr Val Thr Lys Gly Asn Gln Arg Ile Gly Cys Tyr 1805 1810 1815 Val His Asp Val Ile Gln Asp Pro Ala Lys Ser Asp Gly Arg Leu 1820 1825 1830 Lys Pro Gly Asp Arg Leu Ile Lys Val Asn Asp Thr Asp Val Thr 1835 1840 1845 Asn Met Thr His Thr Asp Ala Val Asn Leu Leu Arg Ala Ala Ser 1850 1855 1860 Lys Thr Val Arg Leu Val Ile Gly Arg Val Leu Glu Leu Pro Arg 1865 1870 1875 Ile Pro Met Leu Pro His Leu Leu Pro Asp Ile Thr Leu Thr Cys 1880 1885 1890 Asn Lys Glu Glu Leu Gly Phe Ser Leu Cys Gly Gly His Asp Ser 1895 1900 1905 Leu Tyr Gln Val Val Tyr Ile Ser Asp Ile Asn Pro Arg Ser Val 1910 1915 1920 Ala Ala Ile Glu Gly Asn Leu Gln Leu Leu Asp Val Ile His Tyr 1925 1930 1935 Val Asn Gly Val Ser Thr Gln Gly Met Thr Leu Glu Glu Val Asn 1940 1945 1950 Arg Ala Leu Asp Met Ser Leu Pro Ser Leu Val Leu Lys Ala Thr 1955 1960 1965 Arg Asn Asp Leu Pro Val Val Pro Ser Ser Lys Arg Ser Ala Val 1970 1975 1980 Ser Ala Pro Lys Ser Thr Lys Gly Asn Gly Ser Tyr Ser Val Gly 1985 1990 1995 Ser Cys Ser Gln Pro Ala Leu Thr Pro Asn Asp Ser Phe Ser Thr 2000 2005 2010 Val Ala Gly Glu Glu Ile Asn Glu Ile Ser Tyr Pro Lys Gly Lys 2015 2020 2025 Cys Ser Thr Tyr Gln Ile Lys Gly Ser Pro Asn Leu Thr Leu Pro 2030 2035 2040 Lys Glu Ser Tyr Ile Gln Glu Asp Asp Ile Tyr Asp Asp Ser Gln 2045 2050 2055 Glu Ala Glu Val Ile Gln Ser Leu Leu Asp Val Val Asp Glu Glu 2060 2065 2070 Ala Gln Asn Leu Leu Asn Glu Asn Asn Ala Ala Gly Tyr Ser Cys 2075 2080 2085 Gly Pro Gly Thr Leu Lys Met Asn Gly Lys Leu Ser Glu Glu Arg 2090 2095 2100 Thr Glu Asp Thr Asp Cys Asp Gly Ser Pro Leu Pro Glu Tyr Phe 2105 2110 2115 Thr Glu Ala Thr Lys Met Asn Gly Cys Glu Glu Tyr Cys Glu Glu 2120 2125 2130 Lys Val Lys Ser Glu Ser Leu Ile Gln Lys Pro Gln Glu Lys Lys 2135 2140 2145 Thr Asp Asp Asp Glu Ile Thr Trp Gly Asn Asp Glu Leu Pro Ile 2150 2155 2160 Glu Arg Thr Asn His Glu Asp Ser Asp Lys Asp His Ser Phe Leu 2165 2170 2175 Thr Asn Asp Glu Leu Ala Val Leu Pro Val Val Lys Val Leu Pro 2180 2185 2190 Ser Gly Lys Tyr Thr Gly Ala Asn Leu Lys Ser Val Ile Arg Val 2195 2200 2205 Leu Arg Gly Leu Leu Asp Gln Gly Ile Pro Ser Lys Glu Leu Glu 2210 2215 2220 Asn Leu Gln Glu Leu Lys Pro Leu Asp Gln Cys Leu Ile Gly Gln 2225 2230 2235 Thr Lys Glu Asn Arg Arg Lys Asn Arg Tyr Lys Asn Ile Leu Pro 2240 2245 2250 Tyr Asp Ala Thr Arg Val Pro Leu Gly Asp Glu Gly Gly Tyr Ile 2255 2260 2265 Asn Ala Ser Phe Ile Lys Ile Pro Val Gly Lys Glu Glu Phe Val 2270 2275 2280 Tyr Ile Ala Cys Gln Gly Pro Leu Pro Thr Thr Val Gly Asp Phe 2285 2290 2295 Trp Gln Met Ile Trp Glu Gln Lys Ser Thr Val Ile Ala Met Met 2300 2305 2310 Thr Gln Glu Val Glu Gly Glu Lys Ile Lys Cys Gln Arg Tyr Trp 2315 2320 2325 Pro Asn Ile Leu Gly Lys Thr Thr Met Val Ser Asn Arg Leu Arg 2330 2335 2340 Leu Ala Leu Val Arg Met Gln Gln Leu Lys Gly Phe Val Val Arg 2345 2350 2355 Ala Met Thr Leu Glu Asp Ile Gln Thr Arg Glu Val Arg His Ile 2360 2365 2370 Ser His Leu Asn Phe Thr Ala Trp Pro Asp His Asp Thr Pro Ser 2375 2380 2385 Gln Pro Asp Asp Leu Leu Thr Phe Ile Ser Tyr Met Arg His Ile 2390 2395 2400 His Arg Ser Gly Pro Ile Ile Thr His Cys Ser Ala Gly Ile Gly 2405 2410 2415 Arg Ser Gly Thr Leu Ile Cys Ile Asp Val Val Leu Gly Leu Ile 2420 2425 2430 Ser Gln Asp Leu Asp Phe Asp Ile Ser Asp Leu Val Arg Cys Met 2435 2440 2445 Arg Leu Gln Arg His Gly Met Val Gln Thr Glu Asp Gln Tyr Ile 2450 2455 2460 Phe Cys Tyr Gln Val Ile Leu Tyr Val Leu Thr Arg Leu Gln Ala 2465 2470 2475 Glu Glu Glu Gln Lys Gln Gln Pro Gln Leu Leu Lys 2480 2485 2490 152236DNAHomo sapiensCDS(282)..(1649) 15gctgttgcaa cactgcctca ctcttcccct cccaccttct ctcccctcct ctctgcttta 60attttctcag aattctctgg actgaggctc cagttctggc ctttggggtt caagatcact 120gggaccaggc cgtgatctct atgcccgagt ctcaaccctc aactgtcacc ccaaggcact 180tgggacgtcc tggacagacc gagtcccggg aagccccagc actgccgctg ccacactgcc 240ctgagcccaa atgggggagt gagaggccat agctgtctgg c atg ggc ctc tcc acc 296 Met Gly Leu Ser Thr 1 5 gtg cct gac ctg ctg ctg cca ctg gtg ctc ctg gag ctg ttg gtg gga 344Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu Glu Leu Leu Val Gly 10 15 20 ata tac ccc tca ggg gtt att gga ctg gtc cct cac cta ggg gac agg 392Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro His Leu Gly Asp Arg 25 30 35 gag aag aga gat agt gtg tgt ccc caa gga aaa tat atc cac cct caa 440Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys Tyr Ile His Pro Gln 40 45 50 aat aat tcg att tgc tgt acc aag tgc cac aaa gga acc tac ttg tac 488Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys Gly Thr Tyr Leu Tyr 55 60 65 aat gac tgt cca ggc ccg ggg cag gat acg gac tgc agg gag tgt gag 536Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp Cys Arg Glu Cys Glu 70 75 80 85 agc ggc tcc ttc acc gct tca gaa aac cac ctc aga cac tgc ctc agc 584Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu Arg His Cys Leu Ser 90 95 100 tgc tcc aaa tgc cga aag gaa atg ggt cag gtg gag atc tct tct tgc 632Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val Glu Ile Ser Ser Cys 105 110 115 aca gtg gac cgg gac acc gtg tgt ggc tgc agg aag aac cag tac cgg 680Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg Lys Asn Gln Tyr Arg 120 125 130 cat tat tgg agt gaa aac ctt ttc cag tgc ttc aat tgc agc ctc tgc 728His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe Asn Cys Ser Leu Cys 135 140 145 ctc aat ggg acc gtg cac ctc tcc tgc cag gag aaa cag aac acc gtg 776Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu Lys Gln Asn Thr Val 150 155 160 165 tgc acc tgc cat gca ggt ttc ttt cta aga gaa aac gag tgt gtc tcc 824Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu Asn Glu Cys Val Ser 170 175 180 tgt agt aac tgt aag aaa agc ctg gag tgc acg aag ttg tgc cta ccc 872Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr Lys Leu Cys Leu Pro 185 190 195 cag att gag aat gtt aag ggc act gag gac tca ggc acc aca gtg ctg 920Gln Ile Glu Asn Val Lys Gly Thr Glu Asp Ser Gly Thr Thr Val Leu 200 205 210 ttg ccc ctg gtc att ttc ttt ggt ctt tgc ctt tta tcc ctc ctc ttc 968Leu Pro Leu Val Ile Phe Phe Gly Leu Cys Leu Leu Ser Leu Leu Phe 215 220 225 att ggt tta atg tat cgc tac caa cgg tgg aag tcc aag ctc tac tcc 1016Ile Gly Leu Met Tyr Arg Tyr Gln Arg Trp Lys Ser Lys Leu Tyr Ser 230 235 240

245 att gtt tgt ggg aaa tcg aca cct gaa aaa gag ggg gag ctt gaa gga 1064Ile Val Cys Gly Lys Ser Thr Pro Glu Lys Glu Gly Glu Leu Glu Gly 250 255 260 act act act aag ccc ctg gcc cca aac cca agc ttc agt ccc act cca 1112Thr Thr Thr Lys Pro Leu Ala Pro Asn Pro Ser Phe Ser Pro Thr Pro 265 270 275 ggc ttc acc ccc acc ctg ggc ttc agt ccc gtg ccc agt tcc acc ttc 1160Gly Phe Thr Pro Thr Leu Gly Phe Ser Pro Val Pro Ser Ser Thr Phe 280 285 290 acc tcc agc tcc acc tat acc ccc ggt gac tgt ccc aac ttt gcg gct 1208Thr Ser Ser Ser Thr Tyr Thr Pro Gly Asp Cys Pro Asn Phe Ala Ala 295 300 305 ccc cgc aga gag gtg gca cca ccc tat cag ggg gct gac ccc atc ctt 1256Pro Arg Arg Glu Val Ala Pro Pro Tyr Gln Gly Ala Asp Pro Ile Leu 310 315 320 325 gcg aca gcc ctc gcc tcc gac ccc atc ccc aac ccc ctt cag aag tgg 1304Ala Thr Ala Leu Ala Ser Asp Pro Ile Pro Asn Pro Leu Gln Lys Trp 330 335 340 gag gac agc gcc cac aag cca cag agc cta gac act gat gac ccc gcg 1352Glu Asp Ser Ala His Lys Pro Gln Ser Leu Asp Thr Asp Asp Pro Ala 345 350 355 acg ctg tac gcc gtg gtg gag aac gtg ccc ccg ttg cgc tgg aag gaa 1400Thr Leu Tyr Ala Val Val Glu Asn Val Pro Pro Leu Arg Trp Lys Glu 360 365 370 ttc gtg cgg cgc cta ggg ctg agc gac cac gag atc gat cgg ctg gag 1448Phe Val Arg Arg Leu Gly Leu Ser Asp His Glu Ile Asp Arg Leu Glu 375 380 385 ctg cag aac ggg cgc tgc ctg cgc gag gcg caa tac agc atg ctg gcg 1496Leu Gln Asn Gly Arg Cys Leu Arg Glu Ala Gln Tyr Ser Met Leu Ala 390 395 400 405 acc tgg agg cgg cgc acg ccg cgg cgc gag gcc acg ctg gag ctg ctg 1544Thr Trp Arg Arg Arg Thr Pro Arg Arg Glu Ala Thr Leu Glu Leu Leu 410 415 420 gga cgc gtg ctc cgc gac atg gac ctg ctg ggc tgc ctg gag gac atc 1592Gly Arg Val Leu Arg Asp Met Asp Leu Leu Gly Cys Leu Glu Asp Ile 425 430 435 gag gag gcg ctt tgc ggc ccc gcc gcc ctc ccg ccc gcg ccc agt ctt 1640Glu Glu Ala Leu Cys Gly Pro Ala Ala Leu Pro Pro Ala Pro Ser Leu 440 445 450 ctc aga tga ggctgcgccc ctgcgggcag ctctaaggac cgtcctgcga 1689Leu Arg 455 gatcgccttc caaccccact tttttctgga aaggaggggt cctgcagggg caagcaggag 1749ctagcagccg cctacttggt gctaacccct cgatgtacat agcttttctc agctgcctgc 1809gcgccgccga cagtcagcgc tgtgcgcgcg gagagaggtg cgccgtgggc tcaagagcct 1869gagtgggtgg tttgcgagga tgagggacgc tatgcctcat gcccgttttg ggtgtcctca 1929ccagcaaggc tgctcggggg cccctggttc gtccctgagc ctttttcaca gtgcataagc 1989agtttttttt gtttttgttt tgttttgttt tgtttttaaa tcaatcatgt tacactaata 2049gaaacttggc actcctgtgc cctctgcctg gacaagcaca tagcaagctg aactgtccta 2109aggcaggggc gagcacggaa caatggggcc ttcagctgga gctgtggact tttgtacata 2169cactaaaatt ctgaagttaa agctctgctc ttggaaaaaa aaaaaaaaaa aaaaaaaaaa 2229aaaaaaa 223616455PRTHomo sapiens 16Met Gly Leu Ser Thr Val Pro Asp Leu Leu Leu Pro Leu Val Leu Leu 1 5 10 15 Glu Leu Leu Val Gly Ile Tyr Pro Ser Gly Val Ile Gly Leu Val Pro 20 25 30 His Leu Gly Asp Arg Glu Lys Arg Asp Ser Val Cys Pro Gln Gly Lys 35 40 45 Tyr Ile His Pro Gln Asn Asn Ser Ile Cys Cys Thr Lys Cys His Lys 50 55 60 Gly Thr Tyr Leu Tyr Asn Asp Cys Pro Gly Pro Gly Gln Asp Thr Asp 65 70 75 80 Cys Arg Glu Cys Glu Ser Gly Ser Phe Thr Ala Ser Glu Asn His Leu 85 90 95 Arg His Cys Leu Ser Cys Ser Lys Cys Arg Lys Glu Met Gly Gln Val 100 105 110 Glu Ile Ser Ser Cys Thr Val Asp Arg Asp Thr Val Cys Gly Cys Arg 115 120 125 Lys Asn Gln Tyr Arg His Tyr Trp Ser Glu Asn Leu Phe Gln Cys Phe 130 135 140 Asn Cys Ser Leu Cys Leu Asn Gly Thr Val His Leu Ser Cys Gln Glu 145 150 155 160 Lys Gln Asn Thr Val Cys Thr Cys His Ala Gly Phe Phe Leu Arg Glu 165 170 175 Asn Glu Cys Val Ser Cys Ser Asn Cys Lys Lys Ser Leu Glu Cys Thr 180 185 190 Lys Leu Cys Leu Pro Gln Ile Glu Asn Val Lys Gly Thr Glu Asp Ser 195 200 205 Gly Thr Thr Val Leu Leu Pro Leu Val Ile Phe Phe Gly Leu Cys Leu 210 215 220 Leu Ser Leu Leu Phe Ile Gly Leu Met Tyr Arg Tyr Gln Arg Trp Lys 225 230 235 240 Ser Lys Leu Tyr Ser Ile Val Cys Gly Lys Ser Thr Pro Glu Lys Glu 245 250 255 Gly Glu Leu Glu Gly Thr Thr Thr Lys Pro Leu Ala Pro Asn Pro Ser 260 265 270 Phe Ser Pro Thr Pro Gly Phe Thr Pro Thr Leu Gly Phe Ser Pro Val 275 280 285 Pro Ser Ser Thr Phe Thr Ser Ser Ser Thr Tyr Thr Pro Gly Asp Cys 290 295 300 Pro Asn Phe Ala Ala Pro Arg Arg Glu Val Ala Pro Pro Tyr Gln Gly 305 310 315 320 Ala Asp Pro Ile Leu Ala Thr Ala Leu Ala Ser Asp Pro Ile Pro Asn 325 330 335 Pro Leu Gln Lys Trp Glu Asp Ser Ala His Lys Pro Gln Ser Leu Asp 340 345 350 Thr Asp Asp Pro Ala Thr Leu Tyr Ala Val Val Glu Asn Val Pro Pro 355 360 365 Leu Arg Trp Lys Glu Phe Val Arg Arg Leu Gly Leu Ser Asp His Glu 370 375 380 Ile Asp Arg Leu Glu Leu Gln Asn Gly Arg Cys Leu Arg Glu Ala Gln 385 390 395 400 Tyr Ser Met Leu Ala Thr Trp Arg Arg Arg Thr Pro Arg Arg Glu Ala 405 410 415 Thr Leu Glu Leu Leu Gly Arg Val Leu Arg Asp Met Asp Leu Leu Gly 420 425 430 Cys Leu Glu Asp Ile Glu Glu Ala Leu Cys Gly Pro Ala Ala Leu Pro 435 440 445 Pro Ala Pro Ser Leu Leu Arg 450 455 173682DNAHomo sapiensCDS(90)..(1475) 17gcgagcgcag cggagcctgg agagaaggcg ctgggctgcg agggcgcgag ggcgcgaggg 60cagggggcaa ccggaccccg cccgcaccc atg gcg ccc gtc gcc gtc tgg gcc 113 Met Ala Pro Val Ala Val Trp Ala 1 5 gcg ctg gcc gtc gga ctg gag ctc tgg gct gcg gcg cac gcc ttg ccc 161Ala Leu Ala Val Gly Leu Glu Leu Trp Ala Ala Ala His Ala Leu Pro 10 15 20 gcc cag gtg gca ttt aca ccc tac gcc ccg gag ccc ggg agc aca tgc 209Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser Thr Cys 25 30 35 40 cgg ctc aga gaa tac tat gac cag aca gct cag atg tgc tgc agc aaa 257Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Cys Cys Ser Lys 45 50 55 tgc tcg ccg ggc caa cat gca aaa gtc ttc tgt acc aag acc tcg gac 305Cys Ser Pro Gly Gln His Ala Lys Val Phe Cys Thr Lys Thr Ser Asp 60 65 70 acc gtg tgt gac tcc tgt gag gac agc aca tac acc cag ctc tgg aac 353Thr Val Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu Trp Asn 75 80 85 tgg gtt ccc gag tgc ttg agc tgt ggc tcc cgc tgt agc tct gac cag 401Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser Asp Gln 90 95 100 gtg gaa act caa gcc tgc act cgg gaa cag aac cgc atc tgc acc tgc 449Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys Thr Cys 105 110 115 120 agg ccc ggc tgg tac tgc gcg ctg agc aag cag gag ggg tgc cgg ctg 497Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys Arg Leu 125 130 135 tgc gcg ccg ctg cgc aag tgc cgc ccg ggc ttc ggc gtg gcc aga cca 545Cys Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala Arg Pro 140 145 150 gga act gaa aca tca gac gtg gtg tgc aag ccc tgt gcc ccg ggg acg 593Gly Thr Glu Thr Ser Asp Val Val Cys Lys Pro Cys Ala Pro Gly Thr 155 160 165 ttc tcc aac acg act tca tcc acg gat att tgc agg ccc cac cag atc 641Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His Gln Ile 170 175 180 tgt aac gtg gtg gcc atc cct ggg aat gca agc atg gat gca gtc tgc 689Cys Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala Val Cys 185 190 195 200 acg tcc acg tcc ccc acc cgg agt atg gcc cca ggg gca gta cac tta 737Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val His Leu 205 210 215 ccc cag cca gtg tcc aca cga tcc caa cac acg cag cca act cca gaa 785Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr Gln Pro Thr Pro Glu 220 225 230 ccc agc act gct cca agc acc tcc ttc ctg ctc cca atg ggc ccc agc 833Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly Pro Ser 235 240 245 ccc cca gct gaa ggg agc act ggc gac ttc gct ctt cca gtt gga ctg 881Pro Pro Ala Glu Gly Ser Thr Gly Asp Phe Ala Leu Pro Val Gly Leu 250 255 260 att gtg ggt gtg aca gcc ttg ggt cta cta ata ata gga gtg gtg aac 929Ile Val Gly Val Thr Ala Leu Gly Leu Leu Ile Ile Gly Val Val Asn 265 270 275 280 tgt gtc atc atg acc cag gtg aaa aag aag ccc ttg tgc ctg cag aga 977Cys Val Ile Met Thr Gln Val Lys Lys Lys Pro Leu Cys Leu Gln Arg 285 290 295 gaa gcc aag gtg cct cac ttg cct gcc gat aag gcc cgg ggt aca cag 1025Glu Ala Lys Val Pro His Leu Pro Ala Asp Lys Ala Arg Gly Thr Gln 300 305 310 ggc ccc gag cag cag cac ctg ctg atc aca gcg ccg agc tcc agc agc 1073Gly Pro Glu Gln Gln His Leu Leu Ile Thr Ala Pro Ser Ser Ser Ser 315 320 325 agc tcc ctg gag agc tcg gcc agt gcg ttg gac aga agg gcg ccc act 1121Ser Ser Leu Glu Ser Ser Ala Ser Ala Leu Asp Arg Arg Ala Pro Thr 330 335 340 cgg aac cag cca cag gca cca ggc gtg gag gcc agt ggg gcc ggg gag 1169Arg Asn Gln Pro Gln Ala Pro Gly Val Glu Ala Ser Gly Ala Gly Glu 345 350 355 360 gcc cgg gcc agc acc ggg agc tca gat tct tcc cct ggt ggc cat ggg 1217Ala Arg Ala Ser Thr Gly Ser Ser Asp Ser Ser Pro Gly Gly His Gly 365 370 375 acc cag gtc aat gtc acc tgc atc gtg aac gtc tgt agc agc tct gac 1265Thr Gln Val Asn Val Thr Cys Ile Val Asn Val Cys Ser Ser Ser Asp 380 385 390 cac agc tca cag tgc tcc tcc caa gcc agc tcc aca atg gga gac aca 1313His Ser Ser Gln Cys Ser Ser Gln Ala Ser Ser Thr Met Gly Asp Thr 395 400 405 gat tcc agc ccc tcg gag tcc ccg aag gac gag cag gtc ccc ttc tcc 1361Asp Ser Ser Pro Ser Glu Ser Pro Lys Asp Glu Gln Val Pro Phe Ser 410 415 420 aag gag gaa tgt gcc ttt cgg tca cag ctg gag acg cca gag acc ctg 1409Lys Glu Glu Cys Ala Phe Arg Ser Gln Leu Glu Thr Pro Glu Thr Leu 425 430 435 440 ctg ggg agc acc gaa gag aag ccc ctg ccc ctt gga gtg cct gat gct 1457Leu Gly Ser Thr Glu Glu Lys Pro Leu Pro Leu Gly Val Pro Asp Ala 445 450 455 ggg atg aag ccc agt taa ccaggccggt gtgggctgtg tcgtagccaa 1505Gly Met Lys Pro Ser 460 ggtgggctga gccctggcag gatgaccctg cgaaggggcc ctggtccttc caggccccca 1565ccactaggac tctgaggctc tttctgggcc aagttcctct agtgccctcc acagccgcag 1625cctccctctg acctgcaggc caagagcaga ggcagcgagt tgtggaaagc ctctgctgcc 1685atggcgtgtc cctctcggaa ggctggctgg gcatggacgt tcggggcatg ctggggcaag 1745tccctgactc tctgtgacct gccccgccca gctgcacctg ccagcctggc ttctggagcc 1805cttgggtttt ttgtttgttt gtttgtttgt ttgtttgttt ctccccctgg gctctgcccc 1865agctctggct tccagaaaac cccagcatcc ttttctgcag aggggctttc tggagaggag 1925ggatgctgcc tgagtcaccc atgaagacag gacagtgctt cagcctgagg ctgagactgc 1985gggatggtcc tggggctctg tgcagggagg aggtggcagc cctgtaggga acggggtcct 2045tcaagttagc tcaggaggct tggaaagcat cacctcaggc caggtgcagt ggctcacgcc 2105tatgatccca gcactttggg aggctgaggc gggtggatca cctgaggtta ggagttcgag 2165accagcctgg ccaacatggt aaaaccccat ctctactaaa aatacagaaa ttagccgggc 2225gtggtggcgg gcacctatag tcccagctac tcagaagcct gaggctggga aatcgtttga 2285acccgggaag cggaggttgc agggagccga gatcacgcca ctgcactcca gcctgggcga 2345cagagcgaga gtctgtctca aaagaaaaaa aaaagcaccg cctccaaatg ccaacttgtc 2405cttttgtacc atggtgtgaa agtcagatgc ccagagggcc caggcaggcc accatattca 2465gtgctgtggc ctgggcaaga taacgcactt ctaactagaa atctgccaat tttttaaaaa 2525agtaagtacc actcaggcca acaagccaac gacaaagcca aactctgcca gccacatcca 2585accccccacc tgccatttgc accctccgcc ttcactccgg tgtgcctgca gccccgcgcc 2645tccttccttg ctgtcctagg ccacaccatc tcctttcagg gaatttcagg aactagagat 2705gactgagtcc tcgtagccat ctctctactc ctacctcagc ctagaccctc ctcctccccc 2765agaggggtgg gttcctcttc cccactcccc accttcaatt cctgggcccc aaacgggctg 2825ccctgccact ttggtacatg gccagtgtga tcccaagtgc cagtcttgtg tctgcgtctg 2885tgttgcgtgt cgtgggtgtg tgtagccaag gtcggtaagt tgaatggcct gccttgaagc 2945cactgaagct gggattcctc cccattagag tcagccttcc ccctcccagg gccagggccc 3005tgcagagggg aaaccagtgt agccttgccc ggattctggg aggaagcagg ttgaggggct 3065cctggaaagg ctcagtctca ggagcatggg gataaaggag aaggcatgaa attgtctagc 3125agagcagggg cagggtgata aattgttgat aaattccact ggacttgagc ttggcagctg 3185aactattgga gggtgggaga gcccagccat taccatggag acaagaaggg ttttccaccc 3245tggaatcaag atgtcagact ggctggctgc agtgacgtgc acctgtactc aggaggctga 3305ggggaggatc actggagccc aggagtttga ggctgcagcg agctatgatc gcgccactac 3365actccagcct gagcaacaga gtgagaccct gtctcttaaa gaaaaaaaaa gtcagactgc 3425tgggactggc caggtttctg cccacattgg acccacatga ggacatgatg gagcgcacct 3485gccccctggt ggacagtcct gggagaacct caggcttcct tggcatcaca gggcagagcc 3545gggaagcgat gaatttggag actctgtggg gccttggttc ccttgtgtgt gtgtgttgat 3605cccaagacaa tgaaagtttg cactgtatgc tggacggcat tcctgcttat caataaacct 3665gtttgtttta aaaaaaa 368218461PRTHomo sapiens 18Met Ala Pro Val Ala Val Trp Ala Ala Leu Ala Val Gly Leu Glu Leu 1 5 10 15 Trp Ala Ala Ala His Ala Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr 20 25 30 Ala Pro Glu Pro Gly Ser Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln 35 40 45 Thr Ala Gln Met Cys Cys Ser Lys Cys Ser Pro Gly Gln His Ala Lys 50 55 60 Val Phe Cys Thr Lys Thr Ser Asp Thr Val Cys Asp Ser Cys Glu Asp 65 70 75 80 Ser Thr Tyr Thr Gln Leu Trp Asn Trp Val Pro Glu Cys Leu Ser Cys 85 90 95 Gly Ser Arg Cys Ser Ser Asp Gln Val Glu Thr Gln Ala Cys Thr Arg 100 105 110 Glu Gln Asn Arg Ile Cys Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu 115 120 125 Ser Lys Gln Glu Gly Cys Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg 130 135 140 Pro Gly Phe Gly Val Ala Arg Pro Gly Thr Glu Thr Ser Asp Val Val 145 150 155 160 Cys Lys Pro Cys Ala Pro Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr 165 170 175 Asp Ile Cys Arg Pro His Gln Ile Cys

Asn Val Val Ala Ile Pro Gly 180 185 190 Asn Ala Ser Met Asp Ala Val Cys Thr Ser Thr Ser Pro Thr Arg Ser 195 200 205 Met Ala Pro Gly Ala Val His Leu Pro Gln Pro Val Ser Thr Arg Ser 210 215 220 Gln His Thr Gln Pro Thr Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser 225 230 235 240 Phe Leu Leu Pro Met Gly Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly 245 250 255 Asp Phe Ala Leu Pro Val Gly Leu Ile Val Gly Val Thr Ala Leu Gly 260 265 270 Leu Leu Ile Ile Gly Val Val Asn Cys Val Ile Met Thr Gln Val Lys 275 280 285 Lys Lys Pro Leu Cys Leu Gln Arg Glu Ala Lys Val Pro His Leu Pro 290 295 300 Ala Asp Lys Ala Arg Gly Thr Gln Gly Pro Glu Gln Gln His Leu Leu 305 310 315 320 Ile Thr Ala Pro Ser Ser Ser Ser Ser Ser Leu Glu Ser Ser Ala Ser 325 330 335 Ala Leu Asp Arg Arg Ala Pro Thr Arg Asn Gln Pro Gln Ala Pro Gly 340 345 350 Val Glu Ala Ser Gly Ala Gly Glu Ala Arg Ala Ser Thr Gly Ser Ser 355 360 365 Asp Ser Ser Pro Gly Gly His Gly Thr Gln Val Asn Val Thr Cys Ile 370 375 380 Val Asn Val Cys Ser Ser Ser Asp His Ser Ser Gln Cys Ser Ser Gln 385 390 395 400 Ala Ser Ser Thr Met Gly Asp Thr Asp Ser Ser Pro Ser Glu Ser Pro 405 410 415 Lys Asp Glu Gln Val Pro Phe Ser Lys Glu Glu Cys Ala Phe Arg Ser 420 425 430 Gln Leu Glu Thr Pro Glu Thr Leu Leu Gly Ser Thr Glu Glu Lys Pro 435 440 445 Leu Pro Leu Gly Val Pro Asp Ala Gly Met Lys Pro Ser 450 455 460 192136DNAHomo sapiensCDS(169)..(1476) 19gccctggagg cccggcctgg ccgctcccgg ccctggggtg cacatcggcc ctgagtcccg 60tcccaggctc tgggctcggg cagccgccgc caccgctgcc caggacgtcg ggcctcctgc 120cttcctccca ggcccccacg ttgctggccg cctggccgag tggccgcc atg ctc ctg 177 Met Leu Leu 1 cct tgg gcc acc tct gcc ccc ggc ctg gcc tgg ggg cct ctg gtg ctg 225Pro Trp Ala Thr Ser Ala Pro Gly Leu Ala Trp Gly Pro Leu Val Leu 5 10 15 ggc ctc ttc ggg ctc ctg gca gca tcg cag ccc cag gcg gtg cct cca 273Gly Leu Phe Gly Leu Leu Ala Ala Ser Gln Pro Gln Ala Val Pro Pro 20 25 30 35 tat gcg tcg gag aac cag acc tgc agg gac cag gaa aag gaa tac tat 321Tyr Ala Ser Glu Asn Gln Thr Cys Arg Asp Gln Glu Lys Glu Tyr Tyr 40 45 50 gag ccc cag cac cgc atc tgc tgc tcc cgc tgc ccg cca ggc acc tat 369Glu Pro Gln His Arg Ile Cys Cys Ser Arg Cys Pro Pro Gly Thr Tyr 55 60 65 gtc tca gct aaa tgt agc cgc atc cgg gac aca gtt tgt gcc aca tgt 417Val Ser Ala Lys Cys Ser Arg Ile Arg Asp Thr Val Cys Ala Thr Cys 70 75 80 gcc gag aat tcc tac aac gag cac tgg aac tac ctg acc atc tgc cag 465Ala Glu Asn Ser Tyr Asn Glu His Trp Asn Tyr Leu Thr Ile Cys Gln 85 90 95 ctg tgc cgc ccc tgt gac cca gtg atg ggc ctc gag gag att gcc ccc 513Leu Cys Arg Pro Cys Asp Pro Val Met Gly Leu Glu Glu Ile Ala Pro 100 105 110 115 tgc aca agc aaa cgg aag acc cag tgc cgc tgc cag ccg gga atg ttc 561Cys Thr Ser Lys Arg Lys Thr Gln Cys Arg Cys Gln Pro Gly Met Phe 120 125 130 tgt gct gcc tgg gcc ctc gag tgt aca cac tgc gag cta ctt tct gac 609Cys Ala Ala Trp Ala Leu Glu Cys Thr His Cys Glu Leu Leu Ser Asp 135 140 145 tgc ccg cct ggc act gaa gcc gag ctc aaa gat gaa gtt ggg aag ggt 657Cys Pro Pro Gly Thr Glu Ala Glu Leu Lys Asp Glu Val Gly Lys Gly 150 155 160 aac aac cac tgc gtc ccc tgc aag gca ggg cac ttc cag aat acc tcc 705Asn Asn His Cys Val Pro Cys Lys Ala Gly His Phe Gln Asn Thr Ser 165 170 175 tcc ccc agc gcc cgc tgc cag ccc cac acc agg tgt gag aac caa ggt 753Ser Pro Ser Ala Arg Cys Gln Pro His Thr Arg Cys Glu Asn Gln Gly 180 185 190 195 ctg gtg gag gca gct cca ggc act gcc cag tcc gac aca acc tgc aaa 801Leu Val Glu Ala Ala Pro Gly Thr Ala Gln Ser Asp Thr Thr Cys Lys 200 205 210 aat cca tta gag cca ctg ccc cca gag atg tca gga acc atg ctg atg 849Asn Pro Leu Glu Pro Leu Pro Pro Glu Met Ser Gly Thr Met Leu Met 215 220 225 ctg gcc gtt ctg ctg cca ctg gcc ttc ttt ctg ctc ctt gcc acc gtc 897Leu Ala Val Leu Leu Pro Leu Ala Phe Phe Leu Leu Leu Ala Thr Val 230 235 240 ttc tcc tgc atc tgg aag agc cac cct tct ctc tgc agg aaa ctg gga 945Phe Ser Cys Ile Trp Lys Ser His Pro Ser Leu Cys Arg Lys Leu Gly 245 250 255 tcg ctg ctc aag agg cgt ccg cag gga gag gga ccc aat cct gta gct 993Ser Leu Leu Lys Arg Arg Pro Gln Gly Glu Gly Pro Asn Pro Val Ala 260 265 270 275 gga agc tgg gag cct ccg aag gcc cat cca tac ttc cct gac ttg gta 1041Gly Ser Trp Glu Pro Pro Lys Ala His Pro Tyr Phe Pro Asp Leu Val 280 285 290 cag cca ctg cta ccc att tct gga gat gtt tcc cca gta tcc act ggg 1089Gln Pro Leu Leu Pro Ile Ser Gly Asp Val Ser Pro Val Ser Thr Gly 295 300 305 ctc ccc gca gcc cca gtt ttg gag gca ggg gtg ccg caa cag cag agt 1137Leu Pro Ala Ala Pro Val Leu Glu Ala Gly Val Pro Gln Gln Gln Ser 310 315 320 cct ctg gac ctg acc agg gag ccg cag ttg gaa ccc ggg gag cag agc 1185Pro Leu Asp Leu Thr Arg Glu Pro Gln Leu Glu Pro Gly Glu Gln Ser 325 330 335 cag gtg gcc cac ggt acc aat ggc att cat gtc acc ggc ggg tct atg 1233Gln Val Ala His Gly Thr Asn Gly Ile His Val Thr Gly Gly Ser Met 340 345 350 355 act atc act ggc aac atc tac atc tac aat gga cca gta ctg ggg gga 1281Thr Ile Thr Gly Asn Ile Tyr Ile Tyr Asn Gly Pro Val Leu Gly Gly 360 365 370 cca ccg ggt cct gga gac ctc cca gct acc ccc gaa cct cca tac ccc 1329Pro Pro Gly Pro Gly Asp Leu Pro Ala Thr Pro Glu Pro Pro Tyr Pro 375 380 385 att ccc gaa gag ggg gac cct ggc cct ccc ggg ctc tct aca ccc cac 1377Ile Pro Glu Glu Gly Asp Pro Gly Pro Pro Gly Leu Ser Thr Pro His 390 395 400 cag gaa gat ggc aag gct tgg cac cta gcg gag aca gag cac tgt ggt 1425Gln Glu Asp Gly Lys Ala Trp His Leu Ala Glu Thr Glu His Cys Gly 405 410 415 gcc aca ccc tct aac agg ggc cca agg aac caa ttt atc acc cat gac 1473Ala Thr Pro Ser Asn Arg Gly Pro Arg Asn Gln Phe Ile Thr His Asp 420 425 430 435 tga cggagtctga gaaaaggcag aagaaggggg gcacaagggc actttctccc 1526ttgaggctgc cctgcccacg tgggattcac aggggcctga gtagggcccg gggaagcaga 1586gccctaaggg attaaggctc agacacctct gagagcaggt gggcactggc tgggtacggt 1646gccctccaca ggactctccc tactgcctga gcaaacctga ggcctcccgg cagacccacc 1706caccccctgg ggctgctcag cctcaggcac ggacagggca catgatacca actgctgccc 1766actacggcac gccgcaccgg agcacggcac cgagggagcc gccacacggt cacctgcaag 1826gacgtcacgg gcccctctaa aggattcgtg gtgctcatcc ccaagcttca gagacccttt 1886ggggttccac acttcacgtg gactgaggta gaccctgcat gaagatgaaa ttatagggag 1946gacgctcctt ccctcccctc ctagaggaga ggaaagggag tcattaacaa ctagggggtt 2006gggtaggatt cctaggtatg gggaagagtt ttggaagggg aggaaaatgg caagtgtatt 2066tatattgtaa ccacatgcaa ataaaaagaa tgggacctaa actcgtgccg ctcgtgccga 2126attcctgcag 213620435PRTHomo sapiens 20Met Leu Leu Pro Trp Ala Thr Ser Ala Pro Gly Leu Ala Trp Gly Pro 1 5 10 15 Leu Val Leu Gly Leu Phe Gly Leu Leu Ala Ala Ser Gln Pro Gln Ala 20 25 30 Val Pro Pro Tyr Ala Ser Glu Asn Gln Thr Cys Arg Asp Gln Glu Lys 35 40 45 Glu Tyr Tyr Glu Pro Gln His Arg Ile Cys Cys Ser Arg Cys Pro Pro 50 55 60 Gly Thr Tyr Val Ser Ala Lys Cys Ser Arg Ile Arg Asp Thr Val Cys 65 70 75 80 Ala Thr Cys Ala Glu Asn Ser Tyr Asn Glu His Trp Asn Tyr Leu Thr 85 90 95 Ile Cys Gln Leu Cys Arg Pro Cys Asp Pro Val Met Gly Leu Glu Glu 100 105 110 Ile Ala Pro Cys Thr Ser Lys Arg Lys Thr Gln Cys Arg Cys Gln Pro 115 120 125 Gly Met Phe Cys Ala Ala Trp Ala Leu Glu Cys Thr His Cys Glu Leu 130 135 140 Leu Ser Asp Cys Pro Pro Gly Thr Glu Ala Glu Leu Lys Asp Glu Val 145 150 155 160 Gly Lys Gly Asn Asn His Cys Val Pro Cys Lys Ala Gly His Phe Gln 165 170 175 Asn Thr Ser Ser Pro Ser Ala Arg Cys Gln Pro His Thr Arg Cys Glu 180 185 190 Asn Gln Gly Leu Val Glu Ala Ala Pro Gly Thr Ala Gln Ser Asp Thr 195 200 205 Thr Cys Lys Asn Pro Leu Glu Pro Leu Pro Pro Glu Met Ser Gly Thr 210 215 220 Met Leu Met Leu Ala Val Leu Leu Pro Leu Ala Phe Phe Leu Leu Leu 225 230 235 240 Ala Thr Val Phe Ser Cys Ile Trp Lys Ser His Pro Ser Leu Cys Arg 245 250 255 Lys Leu Gly Ser Leu Leu Lys Arg Arg Pro Gln Gly Glu Gly Pro Asn 260 265 270 Pro Val Ala Gly Ser Trp Glu Pro Pro Lys Ala His Pro Tyr Phe Pro 275 280 285 Asp Leu Val Gln Pro Leu Leu Pro Ile Ser Gly Asp Val Ser Pro Val 290 295 300 Ser Thr Gly Leu Pro Ala Ala Pro Val Leu Glu Ala Gly Val Pro Gln 305 310 315 320 Gln Gln Ser Pro Leu Asp Leu Thr Arg Glu Pro Gln Leu Glu Pro Gly 325 330 335 Glu Gln Ser Gln Val Ala His Gly Thr Asn Gly Ile His Val Thr Gly 340 345 350 Gly Ser Met Thr Ile Thr Gly Asn Ile Tyr Ile Tyr Asn Gly Pro Val 355 360 365 Leu Gly Gly Pro Pro Gly Pro Gly Asp Leu Pro Ala Thr Pro Glu Pro 370 375 380 Pro Tyr Pro Ile Pro Glu Glu Gly Asp Pro Gly Pro Pro Gly Leu Ser 385 390 395 400 Thr Pro His Gln Glu Asp Gly Lys Ala Trp His Leu Ala Glu Thr Glu 405 410 415 His Cys Gly Ala Thr Pro Ser Asn Arg Gly Pro Arg Asn Gln Phe Ile 420 425 430 Thr His Asp 435 214093DNAHomo sapiensCDS(468)..(3377) 21gtgagagagt gagcgagaca gaaagagaga gaagtgcacc agcgagccgg ggcaggaaga 60ggaggtttcg ccaccggagc ggcccggcga cgcgctgaca gcttcccctg cccttcccgt 120cggtcgggcc gccagccgcc gcagccctcg gcctgcacgc agccaccggc cccgctcccg 180gagcccagcg ccgccgaggc cgcagccgcc cggccagtaa ggcggcgccg ccgcccggcc 240accgcgcgcc ctgcgcttcc ctccgcccgc gctgcggcca tggcgcggcg ctgactggcc 300tggcccggcc ccgccgcgct cccgctcgcc ccgacccgca ctcgggcccg cccgggctcc 360ggcctgccgc cgcctcttcc ttctccagcc ggcaggcccg cgccgcttag gagggagagc 420ccacccgcgc caggaggccg aacgcggact cgccacccgg cttcaga atg gca gaa 476 Met Ala Glu 1 gat gat cca tat ttg gga agg cct gaa caa atg ttt cat ttg gat cct 524Asp Asp Pro Tyr Leu Gly Arg Pro Glu Gln Met Phe His Leu Asp Pro 5 10 15 tct ttg act cat aca ata ttt aat cca gaa gta ttt caa cca cag atg 572Ser Leu Thr His Thr Ile Phe Asn Pro Glu Val Phe Gln Pro Gln Met 20 25 30 35 gca ctg cca aca gca gat ggc cca tac ctt caa ata tta gag caa cct 620Ala Leu Pro Thr Ala Asp Gly Pro Tyr Leu Gln Ile Leu Glu Gln Pro 40 45 50 aaa cag aga gga ttt cgt ttc cgt tat gta tgt gaa ggc cca tcc cat 668Lys Gln Arg Gly Phe Arg Phe Arg Tyr Val Cys Glu Gly Pro Ser His 55 60 65 ggt gga cta cct ggt gcc tct agt gaa aag aac aag aag tct tac cct 716Gly Gly Leu Pro Gly Ala Ser Ser Glu Lys Asn Lys Lys Ser Tyr Pro 70 75 80 cag gtc aaa atc tgc aac tat gtg gga cca gca aag gtt att gtt cag 764Gln Val Lys Ile Cys Asn Tyr Val Gly Pro Ala Lys Val Ile Val Gln 85 90 95 ttg gtc aca aat gga aaa aat atc cac ctg cat gcc cac agc ctg gtg 812Leu Val Thr Asn Gly Lys Asn Ile His Leu His Ala His Ser Leu Val 100 105 110 115 gga aaa cac tgt gag gat ggg atc tgc act gta act gct gga ccc aag 860Gly Lys His Cys Glu Asp Gly Ile Cys Thr Val Thr Ala Gly Pro Lys 120 125 130 gac atg gtg gtc ggc ttc gca aac ctg ggt ata ctt cat gtg aca aag 908Asp Met Val Val Gly Phe Ala Asn Leu Gly Ile Leu His Val Thr Lys 135 140 145 aaa aaa gta ttt gaa aca ctg gaa gca cga atg aca gag gcg tgt ata 956Lys Lys Val Phe Glu Thr Leu Glu Ala Arg Met Thr Glu Ala Cys Ile 150 155 160 agg ggc tat aat cct gga ctc ttg gtg cac cct gac ctt gcc tat ttg 1004Arg Gly Tyr Asn Pro Gly Leu Leu Val His Pro Asp Leu Ala Tyr Leu 165 170 175 caa gca gaa ggt gga ggg gac cgg cag ctg gga gat cgg gaa aaa gag 1052Gln Ala Glu Gly Gly Gly Asp Arg Gln Leu Gly Asp Arg Glu Lys Glu 180 185 190 195 cta atc cgc caa gca gct ctg cag cag acc aag gag atg gac ctc agc 1100Leu Ile Arg Gln Ala Ala Leu Gln Gln Thr Lys Glu Met Asp Leu Ser 200 205 210 gtg gtg cgg ctc atg ttt aca gct ttt ctt ccg gat agc act ggc agc 1148Val Val Arg Leu Met Phe Thr Ala Phe Leu Pro Asp Ser Thr Gly Ser 215 220 225 ttc aca agg cgc ctg gaa ccc gtg gta tca gac gcc atc tat gac agt 1196Phe Thr Arg Arg Leu Glu Pro Val Val Ser Asp Ala Ile Tyr Asp Ser 230 235 240 aaa gcc ccc aat gca tcc aac ttg aaa att gta aga atg gac agg aca 1244Lys Ala Pro Asn Ala Ser Asn Leu Lys Ile Val Arg Met Asp Arg Thr 245 250 255 gct gga tgt gtg act gga ggg gag gaa att tat ctt ctt tgt gac aaa 1292Ala Gly Cys Val Thr Gly Gly Glu Glu Ile Tyr Leu Leu Cys Asp Lys 260 265 270 275 gtt cag aaa gat gac atc cag att cga ttt tat gaa gag gaa gaa aat 1340Val Gln Lys Asp Asp Ile Gln Ile Arg Phe Tyr Glu Glu Glu Glu Asn 280 285 290 ggt gga gtc tgg gaa gga ttt gga gat ttt tcc ccc aca gat gtt cat 1388Gly Gly Val Trp Glu Gly Phe Gly Asp Phe Ser Pro Thr Asp Val His 295 300 305 aga caa ttt gcc att gtc ttc aaa act cca aag tat aaa gat att aat 1436Arg Gln Phe Ala Ile Val Phe Lys Thr Pro Lys Tyr Lys Asp Ile Asn 310 315 320 att aca aaa cca gcc tct gtg ttt gtc cag ctt cgg agg aaa tct gac 1484Ile Thr Lys Pro Ala Ser Val Phe Val Gln Leu Arg Arg Lys Ser Asp 325 330 335 ttg gaa act agt gaa cca aaa cct ttc ctc tac

tat cct gaa atc aaa 1532Leu Glu Thr Ser Glu Pro Lys Pro Phe Leu Tyr Tyr Pro Glu Ile Lys 340 345 350 355 gat aaa gaa gaa gtg cag agg aaa cgt cag aag ctc atg ccc aat ttt 1580Asp Lys Glu Glu Val Gln Arg Lys Arg Gln Lys Leu Met Pro Asn Phe 360 365 370 tcg gat agt ttc ggc ggt ggt agt ggt gct gga gct gga ggc gga ggc 1628Ser Asp Ser Phe Gly Gly Gly Ser Gly Ala Gly Ala Gly Gly Gly Gly 375 380 385 atg ttt ggt agt ggc ggt gga gga ggg ggc act gga agt aca ggt cca 1676Met Phe Gly Ser Gly Gly Gly Gly Gly Gly Thr Gly Ser Thr Gly Pro 390 395 400 ggg tat agc ttc cca cac tat gga ttt cct act tat ggt ggg att act 1724Gly Tyr Ser Phe Pro His Tyr Gly Phe Pro Thr Tyr Gly Gly Ile Thr 405 410 415 ttc cat cct gga act act aaa tct aat gct ggg atg aag cat gga acc 1772Phe His Pro Gly Thr Thr Lys Ser Asn Ala Gly Met Lys His Gly Thr 420 425 430 435 atg gac act gaa tct aaa aag gac cct gaa ggt tgt gac aaa agt gat 1820Met Asp Thr Glu Ser Lys Lys Asp Pro Glu Gly Cys Asp Lys Ser Asp 440 445 450 gac aaa aac act gta aac ctc ttt ggg aaa gtt att gaa acc aca gag 1868Asp Lys Asn Thr Val Asn Leu Phe Gly Lys Val Ile Glu Thr Thr Glu 455 460 465 caa gat cag gag ccc agc gag gcc acc gtt ggg aat ggt gag gtc act 1916Gln Asp Gln Glu Pro Ser Glu Ala Thr Val Gly Asn Gly Glu Val Thr 470 475 480 cta acg tat gca aca gga aca aaa gaa gag agt gct gga gtt cag gat 1964Leu Thr Tyr Ala Thr Gly Thr Lys Glu Glu Ser Ala Gly Val Gln Asp 485 490 495 aac ctc ttt cta gag aag gct atg cag ctt gca aag agg cat gcc aat 2012Asn Leu Phe Leu Glu Lys Ala Met Gln Leu Ala Lys Arg His Ala Asn 500 505 510 515 gcc ctt ttc gac tac gcg gtg aca gga gac gtg aag atg ctg ctg gcc 2060Ala Leu Phe Asp Tyr Ala Val Thr Gly Asp Val Lys Met Leu Leu Ala 520 525 530 gtc cag cgc cat ctc act gct gtg cag gat gag aat ggg gac agt gtc 2108Val Gln Arg His Leu Thr Ala Val Gln Asp Glu Asn Gly Asp Ser Val 535 540 545 tta cac tta gca atc atc cac ctt cat tct caa ctt gtg agg gat cta 2156Leu His Leu Ala Ile Ile His Leu His Ser Gln Leu Val Arg Asp Leu 550 555 560 cta gaa gtc aca tct ggt ttg att tct gat gac att atc aac atg aga 2204Leu Glu Val Thr Ser Gly Leu Ile Ser Asp Asp Ile Ile Asn Met Arg 565 570 575 aat gat ctg tac cag acg ccc ttg cac ttg gca gtg atc act aag cag 2252Asn Asp Leu Tyr Gln Thr Pro Leu His Leu Ala Val Ile Thr Lys Gln 580 585 590 595 gaa gat gtg gtg gag gat ttg ctg agg gct ggg gcc gac ctg agc ctt 2300Glu Asp Val Val Glu Asp Leu Leu Arg Ala Gly Ala Asp Leu Ser Leu 600 605 610 ctg gac cgc ttg ggt aac tct gtt ttg cac cta gct gcc aaa gaa gga 2348Leu Asp Arg Leu Gly Asn Ser Val Leu His Leu Ala Ala Lys Glu Gly 615 620 625 cat gat aaa gtt ctc agt atc tta ctc aag cac aaa aag gca gca cta 2396His Asp Lys Val Leu Ser Ile Leu Leu Lys His Lys Lys Ala Ala Leu 630 635 640 ctt ctt gac cac ccc aac ggg gac ggt ctg aat gcc att cat cta gcc 2444Leu Leu Asp His Pro Asn Gly Asp Gly Leu Asn Ala Ile His Leu Ala 645 650 655 atg atg agc aat agc ctg cca tgt ttg ctg ctg ctg gtg gcc gct ggg 2492Met Met Ser Asn Ser Leu Pro Cys Leu Leu Leu Leu Val Ala Ala Gly 660 665 670 675 gct gac gtc aat gct cag gag cag aag tcc ggg cgc aca gca ctg cac 2540Ala Asp Val Asn Ala Gln Glu Gln Lys Ser Gly Arg Thr Ala Leu His 680 685 690 ctg gct gtg gag cac gac aac atc tca ttg gca ggc tgc ctg ctc ctg 2588Leu Ala Val Glu His Asp Asn Ile Ser Leu Ala Gly Cys Leu Leu Leu 695 700 705 gag ggt gat gcc cat gtg gac agt act acc tac gat gga acc aca ccc 2636Glu Gly Asp Ala His Val Asp Ser Thr Thr Tyr Asp Gly Thr Thr Pro 710 715 720 ctg cat ata gca gct ggg aga ggg tcc acc agg ctg gca gct ctt ctc 2684Leu His Ile Ala Ala Gly Arg Gly Ser Thr Arg Leu Ala Ala Leu Leu 725 730 735 aaa gca gca gga gca gat ccc ctg gtg gag aac ttt gag cct ctc tat 2732Lys Ala Ala Gly Ala Asp Pro Leu Val Glu Asn Phe Glu Pro Leu Tyr 740 745 750 755 gac ctg gat gac tct tgg gaa aat gca gga gag gat gaa gga gtt gtg 2780Asp Leu Asp Asp Ser Trp Glu Asn Ala Gly Glu Asp Glu Gly Val Val 760 765 770 cct gga acc acg cct cta gat atg gcc acc agc tgg cag gta ttt gac 2828Pro Gly Thr Thr Pro Leu Asp Met Ala Thr Ser Trp Gln Val Phe Asp 775 780 785 ata tta aat ggg aaa cca tat gag cca gag ttt aca tct gat gat tta 2876Ile Leu Asn Gly Lys Pro Tyr Glu Pro Glu Phe Thr Ser Asp Asp Leu 790 795 800 cta gca caa gga gac atg aaa cag ctg gct gaa gat gtg aag ctg cag 2924Leu Ala Gln Gly Asp Met Lys Gln Leu Ala Glu Asp Val Lys Leu Gln 805 810 815 ctg tat aag tta cta gaa att cct gat cca gac aaa aac tgg gct act 2972Leu Tyr Lys Leu Leu Glu Ile Pro Asp Pro Asp Lys Asn Trp Ala Thr 820 825 830 835 ctg gcg cag aaa tta ggt ctg ggg ata ctt aat aat gcc ttc cgg ctg 3020Leu Ala Gln Lys Leu Gly Leu Gly Ile Leu Asn Asn Ala Phe Arg Leu 840 845 850 agt cct gct cct tcc aaa aca ctt atg gac aac tat gag gtc tct ggg 3068Ser Pro Ala Pro Ser Lys Thr Leu Met Asp Asn Tyr Glu Val Ser Gly 855 860 865 ggt aca gtc aga gag ctg gtg gag gcc ctg aga caa atg ggc tac acc 3116Gly Thr Val Arg Glu Leu Val Glu Ala Leu Arg Gln Met Gly Tyr Thr 870 875 880 gaa gca att gaa gtg atc cag gca gcc tcc agc cca gtg aag acc acc 3164Glu Ala Ile Glu Val Ile Gln Ala Ala Ser Ser Pro Val Lys Thr Thr 885 890 895 tct cag gcc cac tcg ctg cct ctc tcg cct gcc tcc aca agg cag caa 3212Ser Gln Ala His Ser Leu Pro Leu Ser Pro Ala Ser Thr Arg Gln Gln 900 905 910 915 ata gac gag ctc cga gac agt gac agt gtc tgc gac agc ggc gtg gag 3260Ile Asp Glu Leu Arg Asp Ser Asp Ser Val Cys Asp Ser Gly Val Glu 920 925 930 aca tcc ttc cgc aaa ctc agc ttt acc gag tct ctg acc agt ggt gcc 3308Thr Ser Phe Arg Lys Leu Ser Phe Thr Glu Ser Leu Thr Ser Gly Ala 935 940 945 tca ctg cta act ctc aac aaa atg ccc cat gat tat ggg cag gaa gga 3356Ser Leu Leu Thr Leu Asn Lys Met Pro His Asp Tyr Gly Gln Glu Gly 950 955 960 cct cta gaa ggc aaa att tag cctgctgaca atttcccaca ccgtgtaaac 3407Pro Leu Glu Gly Lys Ile 965 caaagcccta aaattccact gcgttgtcca caagacagaa gctgaagtgc atccaaaggt 3467gctcagagag ccggcccgcc tgaatcattc tcgatttaac tcgagacctt ttcaacttgg 3527cttcctttct tggttcataa atgaatttta gtttggttca cttacagata gtatctagca 3587atcacaacac tggctgagcg gatgcatctg gggatgaggt tgcttactaa gctttgccag 3647ctgctgctgg atcacagctg ctttctgttg tcattgctgt tgtccctctg ctacgttcct 3707attgtcatta aaggtatcac ggtcgccacc tggcattcct tctgaccaca gcatcatttt 3767gcattcaaat taagggttaa gaaaagagat attttaaaat gagagtcact tgatgtgcca 3827ttttaaaaaa aaaggcatat tgctttttct aatgtggtta tttctctgat ttgcaaaaaa 3887aaaaaaaaaa aaaatacttg tcaatattta aacatggtta caatcattgc tgaaaatggt 3947attttccccc ttttctgcat tttgctattg taaatatgtt ttttagatca aatactttaa 4007aggaaaaaat gttggattta taaatgctat tttttatttt acttttataa taaaaggaaa 4067agcaaattga tgacctcaaa aaaaaa 409322969PRTHomo sapiens 22Met Ala Glu Asp Asp Pro Tyr Leu Gly Arg Pro Glu Gln Met Phe His 1 5 10 15 Leu Asp Pro Ser Leu Thr His Thr Ile Phe Asn Pro Glu Val Phe Gln 20 25 30 Pro Gln Met Ala Leu Pro Thr Ala Asp Gly Pro Tyr Leu Gln Ile Leu 35 40 45 Glu Gln Pro Lys Gln Arg Gly Phe Arg Phe Arg Tyr Val Cys Glu Gly 50 55 60 Pro Ser His Gly Gly Leu Pro Gly Ala Ser Ser Glu Lys Asn Lys Lys 65 70 75 80 Ser Tyr Pro Gln Val Lys Ile Cys Asn Tyr Val Gly Pro Ala Lys Val 85 90 95 Ile Val Gln Leu Val Thr Asn Gly Lys Asn Ile His Leu His Ala His 100 105 110 Ser Leu Val Gly Lys His Cys Glu Asp Gly Ile Cys Thr Val Thr Ala 115 120 125 Gly Pro Lys Asp Met Val Val Gly Phe Ala Asn Leu Gly Ile Leu His 130 135 140 Val Thr Lys Lys Lys Val Phe Glu Thr Leu Glu Ala Arg Met Thr Glu 145 150 155 160 Ala Cys Ile Arg Gly Tyr Asn Pro Gly Leu Leu Val His Pro Asp Leu 165 170 175 Ala Tyr Leu Gln Ala Glu Gly Gly Gly Asp Arg Gln Leu Gly Asp Arg 180 185 190 Glu Lys Glu Leu Ile Arg Gln Ala Ala Leu Gln Gln Thr Lys Glu Met 195 200 205 Asp Leu Ser Val Val Arg Leu Met Phe Thr Ala Phe Leu Pro Asp Ser 210 215 220 Thr Gly Ser Phe Thr Arg Arg Leu Glu Pro Val Val Ser Asp Ala Ile 225 230 235 240 Tyr Asp Ser Lys Ala Pro Asn Ala Ser Asn Leu Lys Ile Val Arg Met 245 250 255 Asp Arg Thr Ala Gly Cys Val Thr Gly Gly Glu Glu Ile Tyr Leu Leu 260 265 270 Cys Asp Lys Val Gln Lys Asp Asp Ile Gln Ile Arg Phe Tyr Glu Glu 275 280 285 Glu Glu Asn Gly Gly Val Trp Glu Gly Phe Gly Asp Phe Ser Pro Thr 290 295 300 Asp Val His Arg Gln Phe Ala Ile Val Phe Lys Thr Pro Lys Tyr Lys 305 310 315 320 Asp Ile Asn Ile Thr Lys Pro Ala Ser Val Phe Val Gln Leu Arg Arg 325 330 335 Lys Ser Asp Leu Glu Thr Ser Glu Pro Lys Pro Phe Leu Tyr Tyr Pro 340 345 350 Glu Ile Lys Asp Lys Glu Glu Val Gln Arg Lys Arg Gln Lys Leu Met 355 360 365 Pro Asn Phe Ser Asp Ser Phe Gly Gly Gly Ser Gly Ala Gly Ala Gly 370 375 380 Gly Gly Gly Met Phe Gly Ser Gly Gly Gly Gly Gly Gly Thr Gly Ser 385 390 395 400 Thr Gly Pro Gly Tyr Ser Phe Pro His Tyr Gly Phe Pro Thr Tyr Gly 405 410 415 Gly Ile Thr Phe His Pro Gly Thr Thr Lys Ser Asn Ala Gly Met Lys 420 425 430 His Gly Thr Met Asp Thr Glu Ser Lys Lys Asp Pro Glu Gly Cys Asp 435 440 445 Lys Ser Asp Asp Lys Asn Thr Val Asn Leu Phe Gly Lys Val Ile Glu 450 455 460 Thr Thr Glu Gln Asp Gln Glu Pro Ser Glu Ala Thr Val Gly Asn Gly 465 470 475 480 Glu Val Thr Leu Thr Tyr Ala Thr Gly Thr Lys Glu Glu Ser Ala Gly 485 490 495 Val Gln Asp Asn Leu Phe Leu Glu Lys Ala Met Gln Leu Ala Lys Arg 500 505 510 His Ala Asn Ala Leu Phe Asp Tyr Ala Val Thr Gly Asp Val Lys Met 515 520 525 Leu Leu Ala Val Gln Arg His Leu Thr Ala Val Gln Asp Glu Asn Gly 530 535 540 Asp Ser Val Leu His Leu Ala Ile Ile His Leu His Ser Gln Leu Val 545 550 555 560 Arg Asp Leu Leu Glu Val Thr Ser Gly Leu Ile Ser Asp Asp Ile Ile 565 570 575 Asn Met Arg Asn Asp Leu Tyr Gln Thr Pro Leu His Leu Ala Val Ile 580 585 590 Thr Lys Gln Glu Asp Val Val Glu Asp Leu Leu Arg Ala Gly Ala Asp 595 600 605 Leu Ser Leu Leu Asp Arg Leu Gly Asn Ser Val Leu His Leu Ala Ala 610 615 620 Lys Glu Gly His Asp Lys Val Leu Ser Ile Leu Leu Lys His Lys Lys 625 630 635 640 Ala Ala Leu Leu Leu Asp His Pro Asn Gly Asp Gly Leu Asn Ala Ile 645 650 655 His Leu Ala Met Met Ser Asn Ser Leu Pro Cys Leu Leu Leu Leu Val 660 665 670 Ala Ala Gly Ala Asp Val Asn Ala Gln Glu Gln Lys Ser Gly Arg Thr 675 680 685 Ala Leu His Leu Ala Val Glu His Asp Asn Ile Ser Leu Ala Gly Cys 690 695 700 Leu Leu Leu Glu Gly Asp Ala His Val Asp Ser Thr Thr Tyr Asp Gly 705 710 715 720 Thr Thr Pro Leu His Ile Ala Ala Gly Arg Gly Ser Thr Arg Leu Ala 725 730 735 Ala Leu Leu Lys Ala Ala Gly Ala Asp Pro Leu Val Glu Asn Phe Glu 740 745 750 Pro Leu Tyr Asp Leu Asp Asp Ser Trp Glu Asn Ala Gly Glu Asp Glu 755 760 765 Gly Val Val Pro Gly Thr Thr Pro Leu Asp Met Ala Thr Ser Trp Gln 770 775 780 Val Phe Asp Ile Leu Asn Gly Lys Pro Tyr Glu Pro Glu Phe Thr Ser 785 790 795 800 Asp Asp Leu Leu Ala Gln Gly Asp Met Lys Gln Leu Ala Glu Asp Val 805 810 815 Lys Leu Gln Leu Tyr Lys Leu Leu Glu Ile Pro Asp Pro Asp Lys Asn 820 825 830 Trp Ala Thr Leu Ala Gln Lys Leu Gly Leu Gly Ile Leu Asn Asn Ala 835 840 845 Phe Arg Leu Ser Pro Ala Pro Ser Lys Thr Leu Met Asp Asn Tyr Glu 850 855 860 Val Ser Gly Gly Thr Val Arg Glu Leu Val Glu Ala Leu Arg Gln Met 865 870 875 880 Gly Tyr Thr Glu Ala Ile Glu Val Ile Gln Ala Ala Ser Ser Pro Val 885 890 895 Lys Thr Thr Ser Gln Ala His Ser Leu Pro Leu Ser Pro Ala Ser Thr 900 905 910 Arg Gln Gln Ile Asp Glu Leu Arg Asp Ser Asp Ser Val Cys Asp Ser 915 920 925 Gly Val Glu Thr Ser Phe Arg Lys Leu Ser Phe Thr Glu Ser Leu Thr 930 935 940 Ser Gly Ala Ser Leu Leu Thr Leu Asn Lys Met Pro His Asp Tyr Gly 945 950 955 960 Gln Glu Gly Pro Leu Glu Gly Lys Ile 965 234978DNAHomo sapiensCDS(241)..(2553) 23ggtttccgga gctgcggcgg cgcagactgg gagggggagc cgggggttcc gacgtcgcag 60ccgagggaac aagccccaac cggatcctgg acaggcaccc cggcttggcg ctgtctctcc 120ccctcggctc ggagaggccc ttcggcctga gggagcctcg ccgcccgtcc ccggcacacg 180cgcagccccg gcctctcggc ctctgccgga gaaacagttg ggacccctga ttttagcagg 240atg gcc caa tgg aat cag cta cag cag ctt gac aca cgg tac ctg gag 288Met Ala Gln Trp Asn Gln Leu Gln Gln Leu Asp Thr Arg Tyr Leu Glu 1 5 10 15 cag ctc cat cag ctc tac agt gac agc ttc cca atg gag ctg cgg cag 336Gln Leu His Gln Leu Tyr Ser Asp Ser Phe Pro Met Glu Leu Arg Gln 20 25 30 ttt ctg gcc cct tgg att gag agt caa gat tgg gca tat gcg gcc agc 384Phe Leu Ala Pro Trp Ile Glu Ser Gln Asp Trp Ala Tyr Ala Ala Ser 35 40 45 aaa gaa tca

cat gcc act ttg gtg ttt cat aat ctc ctg gga gag att 432Lys Glu Ser His Ala Thr Leu Val Phe His Asn Leu Leu Gly Glu Ile 50 55 60 gac cag cag tat agc cgc ttc ctg caa gag tcg aat gtt ctc tat cag 480Asp Gln Gln Tyr Ser Arg Phe Leu Gln Glu Ser Asn Val Leu Tyr Gln 65 70 75 80 cac aat cta cga aga atc aag cag ttt ctt cag agc agg tat ctt gag 528His Asn Leu Arg Arg Ile Lys Gln Phe Leu Gln Ser Arg Tyr Leu Glu 85 90 95 aag cca atg gag att gcc cgg att gtg gcc cgg tgc ctg tgg gaa gaa 576Lys Pro Met Glu Ile Ala Arg Ile Val Ala Arg Cys Leu Trp Glu Glu 100 105 110 tca cgc ctt cta cag act gca gcc act gcg gcc cag caa ggg ggc cag 624Ser Arg Leu Leu Gln Thr Ala Ala Thr Ala Ala Gln Gln Gly Gly Gln 115 120 125 gcc aac cac ccc aca gca gcc gtg gtg acg gag aag cag cag atg ctg 672Ala Asn His Pro Thr Ala Ala Val Val Thr Glu Lys Gln Gln Met Leu 130 135 140 gag cag cac ctt cag gat gtc cgg aag aga gtg cag gat cta gaa cag 720Glu Gln His Leu Gln Asp Val Arg Lys Arg Val Gln Asp Leu Glu Gln 145 150 155 160 aaa atg aaa gtg gta gag aat ctc cag gat gac ttt gat ttc aac tat 768Lys Met Lys Val Val Glu Asn Leu Gln Asp Asp Phe Asp Phe Asn Tyr 165 170 175 aaa acc ctc aag agt caa gga gac atg caa gat ctg aat gga aac aac 816Lys Thr Leu Lys Ser Gln Gly Asp Met Gln Asp Leu Asn Gly Asn Asn 180 185 190 cag tca gtg acc agg cag aag atg cag cag ctg gaa cag atg ctc act 864Gln Ser Val Thr Arg Gln Lys Met Gln Gln Leu Glu Gln Met Leu Thr 195 200 205 gcg ctg gac cag atg cgg aga agc atc gtg agt gag ctg gcg ggg ctt 912Ala Leu Asp Gln Met Arg Arg Ser Ile Val Ser Glu Leu Ala Gly Leu 210 215 220 ttg tca gcg atg gag tac gtg cag aaa act ctc acg gac gag gag ctg 960Leu Ser Ala Met Glu Tyr Val Gln Lys Thr Leu Thr Asp Glu Glu Leu 225 230 235 240 gct gac tgg aag agg cgg caa cag att gcc tgc att gga ggc ccg ccc 1008Ala Asp Trp Lys Arg Arg Gln Gln Ile Ala Cys Ile Gly Gly Pro Pro 245 250 255 aac atc tgc cta gat cgg cta gaa aac tgg ata acg tca tta gca gaa 1056Asn Ile Cys Leu Asp Arg Leu Glu Asn Trp Ile Thr Ser Leu Ala Glu 260 265 270 tct caa ctt cag acc cgt caa caa att aag aaa ctg gag gag ttg cag 1104Ser Gln Leu Gln Thr Arg Gln Gln Ile Lys Lys Leu Glu Glu Leu Gln 275 280 285 caa aaa gtt tcc tac aaa ggg gac ccc att gta cag cac cgg ccg atg 1152Gln Lys Val Ser Tyr Lys Gly Asp Pro Ile Val Gln His Arg Pro Met 290 295 300 ctg gag gag aga atc gtg gag ctg ttt aga aac tta atg aaa agt gcc 1200Leu Glu Glu Arg Ile Val Glu Leu Phe Arg Asn Leu Met Lys Ser Ala 305 310 315 320 ttt gtg gtg gag cgg cag ccc tgc atg ccc atg cat cct gac cgg ccc 1248Phe Val Val Glu Arg Gln Pro Cys Met Pro Met His Pro Asp Arg Pro 325 330 335 ctc gtc atc aag acc ggc gtc cag ttc act act aaa gtc agg ttg ctg 1296Leu Val Ile Lys Thr Gly Val Gln Phe Thr Thr Lys Val Arg Leu Leu 340 345 350 gtc aaa ttc cct gag ttg aat tat cag ctt aaa att aaa gtg tgc att 1344Val Lys Phe Pro Glu Leu Asn Tyr Gln Leu Lys Ile Lys Val Cys Ile 355 360 365 gac aaa gac tct ggg gac gtt gca gct ctc aga gga tcc cgg aaa ttt 1392Asp Lys Asp Ser Gly Asp Val Ala Ala Leu Arg Gly Ser Arg Lys Phe 370 375 380 aac att ctg ggc aca aac aca aaa gtg atg aac atg gaa gaa tcc aac 1440Asn Ile Leu Gly Thr Asn Thr Lys Val Met Asn Met Glu Glu Ser Asn 385 390 395 400 aac ggc agc ctc tct gca gaa ttc aaa cac ttg acc ctg agg gag cag 1488Asn Gly Ser Leu Ser Ala Glu Phe Lys His Leu Thr Leu Arg Glu Gln 405 410 415 aga tgt ggg aat ggg ggc cga gcc aat tgt gat gct tcc ctg att gtg 1536Arg Cys Gly Asn Gly Gly Arg Ala Asn Cys Asp Ala Ser Leu Ile Val 420 425 430 act gag gag ctg cac ctg atc acc ttt gag acc gag gtg tat cac caa 1584Thr Glu Glu Leu His Leu Ile Thr Phe Glu Thr Glu Val Tyr His Gln 435 440 445 ggc ctc aag att gac cta gag acc cac tcc ttg cca gtt gtg gtg atc 1632Gly Leu Lys Ile Asp Leu Glu Thr His Ser Leu Pro Val Val Val Ile 450 455 460 tcc aac atc tgt cag atg cca aat gcc tgg gcg tcc atc ctg tgg tac 1680Ser Asn Ile Cys Gln Met Pro Asn Ala Trp Ala Ser Ile Leu Trp Tyr 465 470 475 480 aac atg ctg acc aac aat ccc aag aat gta aac ttt ttt acc aag ccc 1728Asn Met Leu Thr Asn Asn Pro Lys Asn Val Asn Phe Phe Thr Lys Pro 485 490 495 cca att gga acc tgg gat caa gtg gcc gag gtc ctg agc tgg cag ttc 1776Pro Ile Gly Thr Trp Asp Gln Val Ala Glu Val Leu Ser Trp Gln Phe 500 505 510 tcc tcc acc acc aag cga gga ctg agc atc gag cag ctg act aca ctg 1824Ser Ser Thr Thr Lys Arg Gly Leu Ser Ile Glu Gln Leu Thr Thr Leu 515 520 525 gca gag aaa ctc ttg gga cct ggt gtg aat tat tca ggg tgt cag atc 1872Ala Glu Lys Leu Leu Gly Pro Gly Val Asn Tyr Ser Gly Cys Gln Ile 530 535 540 aca tgg gct aaa ttt tgc aaa gaa aac atg gct ggc aag ggc ttc tcc 1920Thr Trp Ala Lys Phe Cys Lys Glu Asn Met Ala Gly Lys Gly Phe Ser 545 550 555 560 ttc tgg gtc tgg ctg gac aat atc att gac ctt gtg aaa aag tac atc 1968Phe Trp Val Trp Leu Asp Asn Ile Ile Asp Leu Val Lys Lys Tyr Ile 565 570 575 ctg gcc ctt tgg aac gaa ggg tac atc atg ggc ttt atc agt aag gag 2016Leu Ala Leu Trp Asn Glu Gly Tyr Ile Met Gly Phe Ile Ser Lys Glu 580 585 590 cgg gag cgg gcc atc ttg agc act aag cct cca ggc acc ttc ctg cta 2064Arg Glu Arg Ala Ile Leu Ser Thr Lys Pro Pro Gly Thr Phe Leu Leu 595 600 605 aga ttc agt gaa agc agc aaa gaa gga ggc gtc act ttc act tgg gtg 2112Arg Phe Ser Glu Ser Ser Lys Glu Gly Gly Val Thr Phe Thr Trp Val 610 615 620 gag aag gac atc agc ggt aag acc cag atc cag tcc gtg gaa cca tac 2160Glu Lys Asp Ile Ser Gly Lys Thr Gln Ile Gln Ser Val Glu Pro Tyr 625 630 635 640 aca aag cag cag ctg aac aac atg tca ttt gct gaa atc atc atg ggc 2208Thr Lys Gln Gln Leu Asn Asn Met Ser Phe Ala Glu Ile Ile Met Gly 645 650 655 tat aag atc atg gat gct acc aat atc ctg gtg tct cca ctg gtc tat 2256Tyr Lys Ile Met Asp Ala Thr Asn Ile Leu Val Ser Pro Leu Val Tyr 660 665 670 ctc tat cct gac att ccc aag gag gag gca ttc gga aag tat tgt cgg 2304Leu Tyr Pro Asp Ile Pro Lys Glu Glu Ala Phe Gly Lys Tyr Cys Arg 675 680 685 cca gag agc cag gag cat cct gaa gct gac cca ggt agc gct gcc cca 2352Pro Glu Ser Gln Glu His Pro Glu Ala Asp Pro Gly Ser Ala Ala Pro 690 695 700 tac ctg aag acc aag ttt atc tgt gtg aca cca acg acc tgc agc aat 2400Tyr Leu Lys Thr Lys Phe Ile Cys Val Thr Pro Thr Thr Cys Ser Asn 705 710 715 720 acc att gac ctg ccg atg tcc ccc cgc act tta gat tca ttg atg cag 2448Thr Ile Asp Leu Pro Met Ser Pro Arg Thr Leu Asp Ser Leu Met Gln 725 730 735 ttt gga aat aat ggt gaa ggt gct gaa ccc tca gca gga ggg cag ttt 2496Phe Gly Asn Asn Gly Glu Gly Ala Glu Pro Ser Ala Gly Gly Gln Phe 740 745 750 gag tcc ctc acc ttt gac atg gag ttg acc tcg gag tgc gct acc tcc 2544Glu Ser Leu Thr Phe Asp Met Glu Leu Thr Ser Glu Cys Ala Thr Ser 755 760 765 ccc atg tga ggagctgaga acggaagctg cagaaagata cgactgaggc 2593Pro Met 770 gcctacctgc attctgccac ccctcacaca gccaaacccc agatcatctg aaactactaa 2653ctttgtggtt ccagattttt tttaatctcc tacttctgct atctttgagc aatctgggca 2713cttttaaaaa tagagaaatg agtgaatgtg ggtgatctgc ttttatctaa atgcaaataa 2773ggatgtgttc tctgagaccc atgatcaggg gatgtggcgg ggggtggcta gagggagaaa 2833aaggaaatgt cttgtgttgt tttgttcccc tgccctcctt tctcagcagc tttttgttat 2893tgttgttgtt gttcttagac aagtgcctcc tggtgcctgc ggcatccttc tgcctgtttc 2953tgtaagcaaa tgccacaggc cacctatagc tacatactcc tggcattgca ctttttaacc 3013ttgctgacat ccaaatagaa gataggacta tctaagccct aggtttcttt ttaaattaag 3073aaataataac aattaaaggg caaaaaacac tgtatcagca tagcctttct gtatttaaga 3133aacttaagca gccgggcatg gtggctcacg cctgtaatcc cagcactttg ggaggccgag 3193gcggatcata aggtcaggag atcaagacca tcctggctaa cacggtgaaa ccccgtctct 3253actaaaagta caaaaaatta gctgggtgtg gtggtgggcg cctgtagtcc cagctactcg 3313ggaggctgag gcaggagaat cgcttgaacc tgagaggcgg aggttgcagt gagccaaaat 3373tgcaccactg cacactgcac tccatcctgg gcgacagtct gagactctgt ctcaaaaaaa 3433aaaaaaaaaa aaagaaactt cagttaacag cctccttggt gctttaagca ttcagcttcc 3493ttcaggctgg taatttatat aatccctgaa acgggcttca ggtcaaaccc ttaagacatc 3553tgaagctgca acctggcctt tggtgttgaa ataggaaggt ttaaggagaa tctaagcatt 3613ttagactttt ttttataaat agacttattt tcctttgtaa tgtattggcc ttttagtgag 3673taaggctggg cagagggtgc ttacaacctt gactcccttt ctccctggac ttgatctgct 3733gtttcagagg ctaggttgtt tctgtgggtg ccttatcagg gctgggatac ttctgattct 3793ggcttccttc ctgccccacc ctcccgaccc cagtccccct gatcctgcta gaggcatgtc 3853tccttgcgtg tctaaaggtc cctcatcctg tttgttttag gaatcctggt ctcaggacct 3913catggaagaa gagggggaga gagttacagg ttggacatga tgcacactat ggggccccag 3973cgacgtgtct ggttgagctc agggaatatg gttcttagcc agtttcttgg tgatatccag 4033tggcacttgt aatggcgtct tcattcagtt catgcagggc aaaggcttac tgataaactt 4093gagtctgccc tcgtatgagg gtgtatacct ggcctccctc tgaggctggt gactcctccc 4153tgctggggcc ccacaggtga ggcagaacag ctagagggcc tccccgcctg cccgccttgg 4213ctggctagct cgcctctcct gtgcgtatgg gaacacctag cacgtgctgg atgggctgcc 4273tctgactcag aggcatggcc ggatttggca actcaaaacc accttgcctc agctgatcag 4333agtttctgtg gaattctgtt tgttaaatca aattagctgg tctctgaatt aagggggaga 4393cgaccttctc taagatgaac agggttcgcc ccagtcctcc tgcctggaga cagttgatgt 4453gtcatgcaga gctcttactt ctccagcaac actcttcagt acataataag cttaactgat 4513aaacagaata tttagaaagg tgagacttgg gcttaccatt gggtttaaat catagggacc 4573tagggcgagg gttcagggct tctctggagc agatattgtc aagttcatgg ccttaggtag 4633catgtatctg gtcttaactc tgattgtagc aaaagttctg agaggagctg agccctgttg 4693tggcccatta aagaacaggg tcctcaggcc ctgcccgctt cctgtccact gccccctccc 4753catccccagc ccagccgagg gaatcccgtg ggttgcttac ctacctataa ggtggtttat 4813aagctgctgt cctggccact gcattcaaat tccaatgtgt acttcatagt gtaaaaattt 4873atattattgt gaggtttttt gtcttttttt tttttttttt tttttggtat attgctgtat 4933ctactttaac ttccagaaat aaacgttata taggaaccgt aaaaa 497824770PRTHomo sapiens 24Met Ala Gln Trp Asn Gln Leu Gln Gln Leu Asp Thr Arg Tyr Leu Glu 1 5 10 15 Gln Leu His Gln Leu Tyr Ser Asp Ser Phe Pro Met Glu Leu Arg Gln 20 25 30 Phe Leu Ala Pro Trp Ile Glu Ser Gln Asp Trp Ala Tyr Ala Ala Ser 35 40 45 Lys Glu Ser His Ala Thr Leu Val Phe His Asn Leu Leu Gly Glu Ile 50 55 60 Asp Gln Gln Tyr Ser Arg Phe Leu Gln Glu Ser Asn Val Leu Tyr Gln 65 70 75 80 His Asn Leu Arg Arg Ile Lys Gln Phe Leu Gln Ser Arg Tyr Leu Glu 85 90 95 Lys Pro Met Glu Ile Ala Arg Ile Val Ala Arg Cys Leu Trp Glu Glu 100 105 110 Ser Arg Leu Leu Gln Thr Ala Ala Thr Ala Ala Gln Gln Gly Gly Gln 115 120 125 Ala Asn His Pro Thr Ala Ala Val Val Thr Glu Lys Gln Gln Met Leu 130 135 140 Glu Gln His Leu Gln Asp Val Arg Lys Arg Val Gln Asp Leu Glu Gln 145 150 155 160 Lys Met Lys Val Val Glu Asn Leu Gln Asp Asp Phe Asp Phe Asn Tyr 165 170 175 Lys Thr Leu Lys Ser Gln Gly Asp Met Gln Asp Leu Asn Gly Asn Asn 180 185 190 Gln Ser Val Thr Arg Gln Lys Met Gln Gln Leu Glu Gln Met Leu Thr 195 200 205 Ala Leu Asp Gln Met Arg Arg Ser Ile Val Ser Glu Leu Ala Gly Leu 210 215 220 Leu Ser Ala Met Glu Tyr Val Gln Lys Thr Leu Thr Asp Glu Glu Leu 225 230 235 240 Ala Asp Trp Lys Arg Arg Gln Gln Ile Ala Cys Ile Gly Gly Pro Pro 245 250 255 Asn Ile Cys Leu Asp Arg Leu Glu Asn Trp Ile Thr Ser Leu Ala Glu 260 265 270 Ser Gln Leu Gln Thr Arg Gln Gln Ile Lys Lys Leu Glu Glu Leu Gln 275 280 285 Gln Lys Val Ser Tyr Lys Gly Asp Pro Ile Val Gln His Arg Pro Met 290 295 300 Leu Glu Glu Arg Ile Val Glu Leu Phe Arg Asn Leu Met Lys Ser Ala 305 310 315 320 Phe Val Val Glu Arg Gln Pro Cys Met Pro Met His Pro Asp Arg Pro 325 330 335 Leu Val Ile Lys Thr Gly Val Gln Phe Thr Thr Lys Val Arg Leu Leu 340 345 350 Val Lys Phe Pro Glu Leu Asn Tyr Gln Leu Lys Ile Lys Val Cys Ile 355 360 365 Asp Lys Asp Ser Gly Asp Val Ala Ala Leu Arg Gly Ser Arg Lys Phe 370 375 380 Asn Ile Leu Gly Thr Asn Thr Lys Val Met Asn Met Glu Glu Ser Asn 385 390 395 400 Asn Gly Ser Leu Ser Ala Glu Phe Lys His Leu Thr Leu Arg Glu Gln 405 410 415 Arg Cys Gly Asn Gly Gly Arg Ala Asn Cys Asp Ala Ser Leu Ile Val 420 425 430 Thr Glu Glu Leu His Leu Ile Thr Phe Glu Thr Glu Val Tyr His Gln 435 440 445 Gly Leu Lys Ile Asp Leu Glu Thr His Ser Leu Pro Val Val Val Ile 450 455 460 Ser Asn Ile Cys Gln Met Pro Asn Ala Trp Ala Ser Ile Leu Trp Tyr 465 470 475 480 Asn Met Leu Thr Asn Asn Pro Lys Asn Val Asn Phe Phe Thr Lys Pro 485 490 495 Pro Ile Gly Thr Trp Asp Gln Val Ala Glu Val Leu Ser Trp Gln Phe 500 505 510 Ser Ser Thr Thr Lys Arg Gly Leu Ser Ile Glu Gln Leu Thr Thr Leu 515 520 525 Ala Glu Lys Leu Leu Gly Pro Gly Val Asn Tyr Ser Gly Cys Gln Ile 530 535 540 Thr Trp Ala Lys Phe Cys Lys Glu Asn Met Ala Gly Lys Gly Phe Ser 545 550 555 560 Phe Trp Val Trp Leu Asp Asn Ile Ile Asp Leu Val Lys Lys Tyr Ile 565 570 575 Leu Ala Leu Trp Asn Glu Gly Tyr Ile Met Gly Phe Ile Ser Lys Glu 580 585 590 Arg Glu Arg Ala Ile Leu Ser Thr Lys Pro Pro Gly Thr Phe Leu Leu 595 600 605 Arg Phe Ser Glu Ser Ser Lys Glu Gly Gly Val Thr Phe Thr Trp Val 610 615 620 Glu Lys Asp Ile Ser Gly Lys Thr Gln Ile Gln Ser Val Glu Pro Tyr 625 630 635 640 Thr Lys Gln Gln Leu Asn Asn Met Ser Phe Ala Glu Ile Ile Met Gly 645 650 655 Tyr Lys Ile Met Asp Ala Thr Asn Ile Leu Val Ser Pro Leu Val Tyr 660 665

670 Leu Tyr Pro Asp Ile Pro Lys Glu Glu Ala Phe Gly Lys Tyr Cys Arg 675 680 685 Pro Glu Ser Gln Glu His Pro Glu Ala Asp Pro Gly Ser Ala Ala Pro 690 695 700 Tyr Leu Lys Thr Lys Phe Ile Cys Val Thr Pro Thr Thr Cys Ser Asn 705 710 715 720 Thr Ile Asp Leu Pro Met Ser Pro Arg Thr Leu Asp Ser Leu Met Gln 725 730 735 Phe Gly Asn Asn Gly Glu Gly Ala Glu Pro Ser Ala Gly Gly Gln Phe 740 745 750 Glu Ser Leu Thr Phe Asp Met Glu Leu Thr Ser Glu Cys Ala Thr Ser 755 760 765 Pro Met 770 252655DNAHomo sapiensCDS(122)..(550) 25cccagaaggc cgcggggggt ggaccgccta agagggcgtg cgctcccgac atgccccgcg 60gcgcgccatt aaccgccaga tttgaatcgc gggacccgtt ggcagaggtg gcggcggcgg 120c atg ggt gcc ccg acg ttg ccc cct gcc tgg cag ccc ttt ctc aag gac 169 Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 cac cgc atc tct aca ttc aag aac tgg ccc ttc ttg gag ggc tgc gcc 217His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 tgc acc ccg gag cgg atg gcc gag gct ggc ttc atc cac tgc ccc act 265Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 gag aac gag cca gac ttg gcc cag tgt ttc ttc tgc ttc aag gag ctg 313Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 gaa ggc tgg gag cca gat gac gac ccc ata gag gaa cat aaa aag cat 361Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Glu Glu His Lys Lys His 65 70 75 80 tcg tcc ggt tgc gct ttc ctt tct gtc aag aag cag ttt gaa gaa tta 409Ser Ser Gly Cys Ala Phe Leu Ser Val Lys Lys Gln Phe Glu Glu Leu 85 90 95 acc ctt ggt gaa ttt ttg aaa ctg gac aga gaa aga gcc aag aac aaa 457Thr Leu Gly Glu Phe Leu Lys Leu Asp Arg Glu Arg Ala Lys Asn Lys 100 105 110 att gca aag gaa acc aac aat aag aag aaa gaa ttt gag gaa act gcg 505Ile Ala Lys Glu Thr Asn Asn Lys Lys Lys Glu Phe Glu Glu Thr Ala 115 120 125 gag aaa gtg cgc cgt gcc atc gag cag ctg gct gcc atg gat tga 550Glu Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp 130 135 140 ggcctctggc cggagctgcc tggtcccaga gtggctgcac cacttccagg gtttattccc 610tggtgccacc agccttcctg tgggcccctt agcaatgtct taggaaagga gatcaacatt 670ttcaaattag atgtttcaac tgtgctcttg ttttgtcttg aaagtggcac cagaggtgct 730tctgcctgtg cagcgggtgc tgctggtaac agtggctgct tctctctctc tctctctttt 790ttgggggctc atttttgctg ttttgattcc cgggcttacc aggtgagaag tgagggagga 850agaaggcagt gtcccttttg ctagagctga cagctttgtt cgcgtgggca gagccttcca 910cagtgaatgt gtctggacct catgttgttg aggctgtcac agtcctgagt gtggacttgg 970caggtgcctg ttgaatctga gctgcaggtt ccttatctgt cacacctgtg cctcctcaga 1030ggacagtttt tttgttgttg tgtttttttg tttttttttt tttggtagat gcatgacttg 1090tgtgtgatga gagaatggag acagagtccc tggctcctct actgtttaac aacatggctt 1150tcttattttg tttgaattgt taattcacag aatagcacaa actacaatta aaactaagca 1210caaagccatt ctaagtcatt ggggaaacgg ggtgaacttc aggtggatga ggagacagaa 1270tagagtgata ggaagcgtct ggcagatact ccttttgcca ctgctgtgtg attagacagg 1330cccagtgagc cgcggggcac atgctggccg ctcctccctc agaaaaaggc agtggcctaa 1390atccttttta aatgacttgg ctcgatgctg tgggggactg gctgggctgc tgcaggccgt 1450gtgtctgtca gcccaacctt cacatctgtc acgttctcca cacgggggag agacgcagtc 1510cgcccaggtc cccgctttct ttggaggcag cagctcccgc agggctgaag tctggcgtaa 1570gatgatggat ttgattcgcc ctcctccctg tcatagagct gcagggtgga ttgttacagc 1630ttcgctggaa acctctggag gtcatctcgg ctgttcctga gaaataaaaa gcctgtcatt 1690tcaaacactg ctgtggaccc tactgggttt ttaaaatatt gtcagttttt catcgtcgtc 1750cctagcctgc caacagccat ctgcccagac agccgcagtg aggatgagcg tcctggcaga 1810gacgcagttg tctctgggcg cttgccagag ccacgaaccc cagacctgtt tgtatcatcc 1870gggctccttc cgggcagaaa caactgaaaa tgcacttcag acccacttat ttctgccaca 1930tctgagtcgg cctgagatag acttttccct ctaaactggg agaatatcac agtggttttt 1990gttagcagaa aatgcactcc agcctctgta ctcatctaag ctgcttattt ttgatatttg 2050tgtcagtctg taaatggata cttcacttta ataactgttg cttagtaatt ggctttgtag 2110agaagctgga aaaaaatggt tttgtcttca actcctttgc atgccaggcg gtgatgtgga 2170tctcggcttc tgtgagcctg tgctgtgggc agggctgagc tggagccgcc cctctcagcc 2230cgcctgccac ggcctttcct taaaggccat ccttaaaacc agaccctcat ggctaccagc 2290acctgaaagc ttcctcgaca tctgttaata aagccgtagg cccttgtcta agtgcaaccg 2350cctagacttt ctttcagata catgtccaca tgtccatttt tcaggttctc taagttggag 2410tggagtctgg gaagggttgt gaatgaggct tctgggctat gggtgaggtt ccaatggcag 2470gttagagccc ctcgggccaa ctgccatcct ggaaagtaga gacagcagtg cccgctgccc 2530agaagagacc agcaagccaa actggagccc ccattgcagg ctgtcgccat gtggaaagag 2590taactcacaa ttgccaataa agtctcatgt ggttttatct aaaaaaaaaa aaaaaaaaaa 2650aaaaa 265526142PRTHomo sapiens 26Met Gly Ala Pro Thr Leu Pro Pro Ala Trp Gln Pro Phe Leu Lys Asp 1 5 10 15 His Arg Ile Ser Thr Phe Lys Asn Trp Pro Phe Leu Glu Gly Cys Ala 20 25 30 Cys Thr Pro Glu Arg Met Ala Glu Ala Gly Phe Ile His Cys Pro Thr 35 40 45 Glu Asn Glu Pro Asp Leu Ala Gln Cys Phe Phe Cys Phe Lys Glu Leu 50 55 60 Glu Gly Trp Glu Pro Asp Asp Asp Pro Ile Glu Glu His Lys Lys His 65 70 75 80 Ser Ser Gly Cys Ala Phe Leu Ser Val Lys Lys Gln Phe Glu Glu Leu 85 90 95 Thr Leu Gly Glu Phe Leu Lys Leu Asp Arg Glu Arg Ala Lys Asn Lys 100 105 110 Ile Ala Lys Glu Thr Asn Asn Lys Lys Lys Glu Phe Glu Glu Thr Ala 115 120 125 Glu Lys Val Arg Arg Ala Ile Glu Gln Leu Ala Ala Met Asp 130 135 140 276492DNAHomo sapiensCDS(494)..(1213) 27tttctgtgaa gcagaagtct gggaatcgat ctggaaatcc tcctaatttt tactccctct 60ccccgcgact cctgattcat tgggaagttt caaatcagct ataactggag agtgctgaag 120attgatggga tcgttgcctt atgcatttgt tttggtttta caaaaaggaa acttgacaga 180ggatcatgct gtacttaaaa aatacaacat cacagaggaa gtagactgat attaacaata 240cttactaata ataacgtgcc tcatgaaata aagatccgaa aggaattgga ataaaaattt 300cctgcatctc atgccaaggg ggaaacacca gaatcaagtg ttccgcgtga ttgaagacac 360cccctcgtcc aagaatgcaa agcacatcca ataaaatagc tggattataa ctcctcttct 420ttctctgggg gccgtggggt gggagctggg gcgagaggtg ccgttggccc ccgttgcttt 480tcctctggga agg atg gcg cac gct ggg aga aca ggg tac gat aac cgg 529 Met Ala His Ala Gly Arg Thr Gly Tyr Asp Asn Arg 1 5 10 gag ata gtg atg aag tac atc cat tat aag ctg tcg cag agg ggc tac 577Glu Ile Val Met Lys Tyr Ile His Tyr Lys Leu Ser Gln Arg Gly Tyr 15 20 25 gag tgg gat gcg gga gat gtg ggc gcc gcg ccc ccg ggg gcc gcc ccc 625Glu Trp Asp Ala Gly Asp Val Gly Ala Ala Pro Pro Gly Ala Ala Pro 30 35 40 gca ccg ggc atc ttc tcc tcc cag ccc ggg cac acg ccc cat cca gcc 673Ala Pro Gly Ile Phe Ser Ser Gln Pro Gly His Thr Pro His Pro Ala 45 50 55 60 gca tcc cgg gac ccg gtc gcc agg acc tcg ccg ctg cag acc ccg gct 721Ala Ser Arg Asp Pro Val Ala Arg Thr Ser Pro Leu Gln Thr Pro Ala 65 70 75 gcc ccc ggc gcc gcc gcg ggg cct gcg ctc agc ccg gtg cca cct gtg 769Ala Pro Gly Ala Ala Ala Gly Pro Ala Leu Ser Pro Val Pro Pro Val 80 85 90 gtc cac ctg acc ctc cgc cag gcc ggc gac gac ttc tcc cgc cgc tac 817Val His Leu Thr Leu Arg Gln Ala Gly Asp Asp Phe Ser Arg Arg Tyr 95 100 105 cgc cgc gac ttc gcc gag atg tcc agc cag ctg cac ctg acg ccc ttc 865Arg Arg Asp Phe Ala Glu Met Ser Ser Gln Leu His Leu Thr Pro Phe 110 115 120 acc gcg cgg gga cgc ttt gcc acg gtg gtg gag gag ctc ttc agg gac 913Thr Ala Arg Gly Arg Phe Ala Thr Val Val Glu Glu Leu Phe Arg Asp 125 130 135 140 ggg gtg aac tgg ggg agg att gtg gcc ttc ttt gag ttc ggt ggg gtc 961Gly Val Asn Trp Gly Arg Ile Val Ala Phe Phe Glu Phe Gly Gly Val 145 150 155 atg tgt gtg gag agc gtc aac cgg gag atg tcg ccc ctg gtg gac aac 1009Met Cys Val Glu Ser Val Asn Arg Glu Met Ser Pro Leu Val Asp Asn 160 165 170 atc gcc ctg tgg atg act gag tac ctg aac cgg cac ctg cac acc tgg 1057Ile Ala Leu Trp Met Thr Glu Tyr Leu Asn Arg His Leu His Thr Trp 175 180 185 atc cag gat aac gga ggc tgg gat gcc ttt gtg gaa ctg tac ggc ccc 1105Ile Gln Asp Asn Gly Gly Trp Asp Ala Phe Val Glu Leu Tyr Gly Pro 190 195 200 agc atg cgg cct ctg ttt gat ttc tcc tgg ctg tct ctg aag act ctg 1153Ser Met Arg Pro Leu Phe Asp Phe Ser Trp Leu Ser Leu Lys Thr Leu 205 210 215 220 ctc agt ttg gcc ctg gtg gga gct tgc atc acc ctg ggt gcc tat ctg 1201Leu Ser Leu Ala Leu Val Gly Ala Cys Ile Thr Leu Gly Ala Tyr Leu 225 230 235 ggc cac aag tga agtcaacatg cctgccccaa acaaatatgc aaaaggttca 1253Gly His Lys ctaaagcagt agaaataata tgcattgtca gtgatgtacc atgaaacaaa gctgcaggct 1313gtttaagaaa aaataacaca catataaaca tcacacacac agacagacac acacacacac 1373aacaattaac agtcttcagg caaaacgtcg aatcagctat ttactgccaa agggaaatat 1433catttatttt ttacattatt aagaaaaaaa gatttattta tttaagacag tcccatcaaa 1493actcctgtct ttggaaatcc gaccactaat tgccaagcac cgcttcgtgt ggctccacct 1553ggatgttctg tgcctgtaaa catagattcg ctttccatgt tgttggccgg atcaccatct 1613gaagagcaga cggatggaaa aaggacctga tcattgggga agctggcttt ctggctgctg 1673gaggctgggg agaaggtgtt cattcacttg catttctttg ccctgggggc tgtgatatta 1733acagagggag ggttcctgtg gggggaagtc catgcctccc tggcctgaag aagagactct 1793ttgcatatga ctcacatgat gcatacctgg tgggaggaaa agagttggga acttcagatg 1853gacctagtac ccactgagat ttccacgccg aaggacagcg atgggaaaaa tgcccttaaa 1913tcataggaaa gtattttttt aagctaccaa ttgtgccgag aaaagcattt tagcaattta 1973tacaatatca tccagtacct taagccctga ttgtgtatat tcatatattt tggatacgca 2033ccccccaact cccaatactg gctctgtctg agtaagaaac agaatcctct ggaacttgag 2093gaagtgaaca tttcggtgac ttccgcatca ggaaggctag agttacccag agcatcaggc 2153cgccacaagt gcctgctttt aggagaccga agtccgcaga acctgcctgt gtcccagctt 2213ggaggcctgg tcctggaact gagccggggc cctcactggc ctcctccagg gatgatcaac 2273agggcagtgt ggtctccgaa tgtctggaag ctgatggagc tcagaattcc actgtcaaga 2333aagagcagta gaggggtgtg gctgggcctg tcaccctggg gccctccagg taggcccgtt 2393ttcacgtgga gcatgggagc cacgaccctt cttaagacat gtatcactgt agagggaagg 2453aacagaggcc ctgggccctt cctatcagaa ggacatggtg aaggctggga acgtgaggag 2513aggcaatggc cacggcccat tttggctgta gcacatggca cgttggctgt gtggccttgg 2573cccacctgtg agtttaaagc aaggctttaa atgactttgg agagggtcac aaatcctaaa 2633agaagcattg aagtgaggtg tcatggatta attgacccct gtctatggaa ttacatgtaa 2693aacattatct tgtcactgta gtttggtttt atttgaaaac ctgacaaaaa aaaagttcca 2753ggtgtggaat atgggggtta tctgtacatc ctggggcatt aaaaaaaaaa tcaatggtgg 2813ggaactataa agaagtaaca aaagaagtga catcttcagc aaataaacta ggaaattttt 2873ttttcttcca gtttagaatc agccttgaaa cattgatgga ataactctgt ggcattattg 2933cattatatac catttatctg tattaacttt ggaatgtact ctgttcaatg tttaatgctg 2993tggttgatat ttcgaaagct gctttaaaaa aatacatgca tctcagcgtt tttttgtttt 3053taattgtatt tagttatggc ctatacacta tttgtgagca aaggtgatcg ttttctgttt 3113gagattttta tctcttgatt cttcaaaagc attctgagaa ggtgagataa gccctgagtc 3173tcagctacct aagaaaaacc tggatgtcac tggccactga ggagctttgt ttcaaccaag 3233tcatgtgcat ttccacgtca acagaattgt ttattgtgac agttatatct gttgtccctt 3293tgaccttgtt tcttgaaggt ttcctcgtcc ctgggcaatt ccgcatttaa ttcatggtat 3353tcaggattac atgcatgttt ggttaaaccc atgagattca ttcagttaaa aatccagatg 3413gcaaatgacc agcagattca aatctatggt ggtttgacct ttagagagtt gctttacgtg 3473gcctgtttca acacagaccc acccagagcc ctcctgccct ccttccgcgg gggctttctc 3533atggctgtcc ttcagggtct tcctgaaatg cagtggtgct tacgctccac caagaaagca 3593ggaaacctgt ggtatgaagc cagacctccc cggcgggcct cagggaacag aatgatcaga 3653cctttgaatg attctaattt ttaagcaaaa tattatttta tgaaaggttt acattgtcaa 3713agtgatgaat atggaatatc caatcctgtg ctgctatcct gccaaaatca ttttaatgga 3773gtcagtttgc agtatgctcc acgtggtaag atcctccaag ctgctttaga agtaacaatg 3833aagaacgtgg acgtttttaa tataaagcct gttttgtctt ttgttgttgt tcaaacggga 3893ttcacagagt atttgaaaaa tgtatatata ttaagaggtc acgggggcta attgctggct 3953ggctgccttt tgctgtgggg ttttgttacc tggttttaat aacagtaaat gtgcccagcc 4013tcttggcccc agaactgtac agtattgtgg ctgcacttgc tctaagagta gttgatgttg 4073cattttcctt attgttaaaa acatgttaga agcaatgaat gtatataaaa gcctcaacta 4133gtcatttttt tctcctcttc ttttttttca ttatatctaa ttattttgca gttgggcaac 4193agagaaccat ccctattttg tattgaagag ggattcacat ctgcatctta actgctcttt 4253atgaatgaaa aaacagtcct ctgtatgtac tcctctttac actggccagg gtcagagtta 4313aatagagtat atgcactttc caaattgggg acaagggctc taaaaaaagc cccaaaagga 4373gaagaacatc tgagaacctc ctcggccctc ccagtccctc gctgcacaaa tactccgcaa 4433gagaggccag aatgacagct gacagggtct atggccatcg ggtcgtctcc gaagatttgg 4493caggggcaga aaactctggc aggcttaaga tttggaataa agtcacagaa ttaaggaagc 4553acctcaattt agttcaaaca agacgccaac attctctcca cagctcactt acctctctgt 4613gttcagatgt ggccttccat ttatatgtga tctttgtttt attagtaaat gcttatcatc 4673taaagatgta gctctggccc agtgggaaaa attaggaagt gattataaat cgagaggagt 4733tataataatc aagattaaat gtaaataatc agggcaatcc caacacatgt ctagctttca 4793cctccaggat ctattgagtg aacagaattg caaatagtct ctatttgtaa ttgaacttat 4853cctaaaacaa atagtttata aatgtgaact taaactctaa ttaattccaa ctgtactttt 4913aaggcagtgg ctgtttttag actttcttat cacttatagt tagtaatgta cacctactct 4973atcagagaaa aacaggaaag gctcgaaata caagccattc taaggaaatt agggagtcag 5033ttgaaattct attctgatct tattctgtgg tgtcttttgc agcccagaca aatgtggtta 5093cacacttttt aagaaataca attctacatt gtcaagctta tgaaggttcc aatcagatct 5153ttattgttat tcaatttgga tctttcaggg attttttttt taaattatta tgggacaaag 5213gacatttgtt ggaggggtgg gagggaggaa gaatttttaa atgtaaaaca ttcccaagtt 5273tggatcaggg agttggaagt tttcagaata accagaacta agggtatgaa ggacctgtat 5333tggggtcgat gtgatgcctc tgcgaagaac cttgtgtgac aaatgagaaa cattttgaag 5393tttgtggtac gacctttaga ttccagagac atcagcatgg ctcaaagtgc agctccgttt 5453ggcagtgcaa tggtataaat ttcaagctgg atatgtctaa tgggtattta aacaataaat 5513gtgcagtttt aactaacagg atatttaatg acaaccttct ggttggtagg gacatctgtt 5573tctaaatgtt tattatgtac aatacagaaa aaaattttat aaaattaagc aatgtgaaac 5633tgaattggag agtgataata caagtccttt agtcttaccc agtgaatcat tctgttccat 5693gtctttggac aaccatgacc ttggacaatc atgaaatatg catctcactg gatgcaaaga 5753aaatcagatg gagcatgaat ggtactgtac cggttcatct ggactgcccc agaaaaataa 5813cttcaagcaa acatcctatc aacaacaagg ttgttctgca taccaagctg agcacagaag 5873atgggaacac tggtggagga tggaaaggct cgctcaatca agaaaattct gagactatta 5933ataaataaga ctgtagtgta gatactgagt aaatccatgc acctaaacct tttggaaaat 5993ctgccgtggg ccctccagat agctcatttc attaagtttt tccctccaag gtagaatttg 6053caagagtgac agtggattgc atttcttttg gggaagcttt cttttggtgg ttttgtttat 6113tataccttct taagttttca accaaggttt gcttttgttt tgagttactg gggttatttt 6173tgttttaaat aaaaataagt gtacaataag tgtttttgta ttgaaagctt ttgttatcaa 6233gattttcata cttttacctt ccatggctct ttttaagatt gatactttta agaggtggct 6293gatattctgc aacactgtac acataaaaaa tacggtaagg atactttaca tggttaaggt 6353aaagtaagtc tccagttggc caccattagc tataatggca ctttgtttgt gttgttggaa 6413aaagtcacat tgccattaaa ctttccttgt ctgtctagtt aatattgtga agaaaaataa 6473agtacagtgt gagatactg 649228239PRTHomo sapiens 28Met Ala His Ala Gly Arg Thr Gly Tyr Asp Asn Arg Glu Ile Val Met 1 5 10 15 Lys Tyr Ile His Tyr Lys Leu Ser Gln Arg Gly Tyr Glu Trp Asp Ala 20 25 30 Gly Asp Val Gly Ala Ala Pro Pro Gly Ala Ala Pro Ala Pro Gly Ile 35 40 45 Phe Ser Ser Gln Pro Gly His Thr Pro His Pro Ala Ala Ser Arg Asp 50 55 60 Pro Val Ala Arg Thr Ser Pro Leu Gln Thr Pro Ala Ala Pro Gly Ala 65 70 75 80 Ala Ala Gly Pro Ala Leu Ser Pro Val Pro Pro Val Val His Leu Thr 85 90 95 Leu Arg Gln Ala Gly Asp Asp Phe Ser Arg Arg Tyr Arg Arg Asp Phe 100 105 110 Ala Glu Met Ser Ser Gln Leu His Leu Thr Pro Phe Thr Ala Arg Gly 115 120 125 Arg Phe Ala Thr Val Val Glu Glu Leu Phe Arg Asp Gly

Val Asn Trp 130 135 140 Gly Arg Ile Val Ala Phe Phe Glu Phe Gly Gly Val Met Cys Val Glu 145 150 155 160 Ser Val Asn Arg Glu Met Ser Pro Leu Val Asp Asn Ile Ala Leu Trp 165 170 175 Met Thr Glu Tyr Leu Asn Arg His Leu His Thr Trp Ile Gln Asp Asn 180 185 190 Gly Gly Trp Asp Ala Phe Val Glu Leu Tyr Gly Pro Ser Met Arg Pro 195 200 205 Leu Phe Asp Phe Ser Trp Leu Ser Leu Lys Thr Leu Leu Ser Leu Ala 210 215 220 Leu Val Gly Ala Cys Ile Thr Leu Gly Ala Tyr Leu Gly His Lys 225 230 235 292004DNAHomo sapiensCDS(376)..(1818) 29aacatttcag ccggtgggtg gcggggatta ggcgtgaagc ggttcagcag gcagaggttc 60tcggacgccc tccggcgaag ccacctgttg atgcttttga ctttctgtcc ttgttcctcg 120tcccatctgg agcatttcca attctggttt tgcggagcag caggtctgag cttgtccggc 180gagggtggga gttggtcccg gcggagatcc agtgggaaga gccggcggct gcccgggcaa 240ctcccccact ggaaaggatt ctgaaagaaa tgaagtcagc cctcagaaat gaagttgact 300gcctgctggc tttctgttga ctggcccgga gctgtactgc aagacccttg tgagcttccc 360tagtctaaga gtagg atg tct gct gaa gtc atc cat cag gtt gaa gaa gca 411 Met Ser Ala Glu Val Ile His Gln Val Glu Glu Ala 1 5 10 ctt gat aca gat gag aag gag atg ctg ctc ttt ttg tgc cgg gat gtt 459Leu Asp Thr Asp Glu Lys Glu Met Leu Leu Phe Leu Cys Arg Asp Val 15 20 25 gct ata gat gtg gtt cca cct aat gtc agg gac ctt ctg gat att tta 507Ala Ile Asp Val Val Pro Pro Asn Val Arg Asp Leu Leu Asp Ile Leu 30 35 40 cgg gaa aga ggt aag ctg tct gtc ggg gac ttg gct gaa ctg ctc tac 555Arg Glu Arg Gly Lys Leu Ser Val Gly Asp Leu Ala Glu Leu Leu Tyr 45 50 55 60 aga gtg agg cga ttt gac ctg ctc aaa cgt atc ttg aag atg gac aga 603Arg Val Arg Arg Phe Asp Leu Leu Lys Arg Ile Leu Lys Met Asp Arg 65 70 75 aaa gct gtg gag acc cac ctg ctc agg aac cct cac ctt gtt tcg gac 651Lys Ala Val Glu Thr His Leu Leu Arg Asn Pro His Leu Val Ser Asp 80 85 90 tat aga gtg ctg atg gca gag att ggt gag gat ttg gat aaa tct gat 699Tyr Arg Val Leu Met Ala Glu Ile Gly Glu Asp Leu Asp Lys Ser Asp 95 100 105 gtg tcc tca tta att ttc ctc atg aag gat tac atg ggc cga ggc aag 747Val Ser Ser Leu Ile Phe Leu Met Lys Asp Tyr Met Gly Arg Gly Lys 110 115 120 ata agc aag gag aag agt ttc ttg gac ctt gtg gtt gag ttg gag aaa 795Ile Ser Lys Glu Lys Ser Phe Leu Asp Leu Val Val Glu Leu Glu Lys 125 130 135 140 cta aat ctg gtt gcc cca gat caa ctg gat tta tta gaa aaa tgc cta 843Leu Asn Leu Val Ala Pro Asp Gln Leu Asp Leu Leu Glu Lys Cys Leu 145 150 155 aag aac atc cac aga ata gac ctg aag aca aaa atc cag aag tac aag 891Lys Asn Ile His Arg Ile Asp Leu Lys Thr Lys Ile Gln Lys Tyr Lys 160 165 170 cag tct gtt caa gga gca ggg aca agt tac agg aat gtt ctc caa gca 939Gln Ser Val Gln Gly Ala Gly Thr Ser Tyr Arg Asn Val Leu Gln Ala 175 180 185 gca atc caa aag agt ctc aag gat cct tca aat aac ttc agg ctc cat 987Ala Ile Gln Lys Ser Leu Lys Asp Pro Ser Asn Asn Phe Arg Leu His 190 195 200 aat ggg aga agt aaa gaa caa aga ctt aag gaa cag ctt ggc gct caa 1035Asn Gly Arg Ser Lys Glu Gln Arg Leu Lys Glu Gln Leu Gly Ala Gln 205 210 215 220 caa gaa cca gtg aag aaa tcc att cag gaa tca gaa gct ttt ttg cct 1083Gln Glu Pro Val Lys Lys Ser Ile Gln Glu Ser Glu Ala Phe Leu Pro 225 230 235 cag agc ata cct gaa gag aga tac aag atg aag agc aag ccc cta gga 1131Gln Ser Ile Pro Glu Glu Arg Tyr Lys Met Lys Ser Lys Pro Leu Gly 240 245 250 atc tgc ctg ata atc gat tgc att ggc aat gag aca gag ctt ctt cga 1179Ile Cys Leu Ile Ile Asp Cys Ile Gly Asn Glu Thr Glu Leu Leu Arg 255 260 265 gac acc ttc act tcc ctg ggc tat gaa gtc cag aaa ttc ttg cat ctc 1227Asp Thr Phe Thr Ser Leu Gly Tyr Glu Val Gln Lys Phe Leu His Leu 270 275 280 agt atg cat ggt ata tcc cag att ctt ggc caa ttt gcc tgt atg ccc 1275Ser Met His Gly Ile Ser Gln Ile Leu Gly Gln Phe Ala Cys Met Pro 285 290 295 300 gag cac cga gac tac gac agc ttt gtg tgt gtc ctg gtg agc cga gga 1323Glu His Arg Asp Tyr Asp Ser Phe Val Cys Val Leu Val Ser Arg Gly 305 310 315 ggc tcc cag agt gtg tat ggt gtg gat cag act cac tca ggg ctc ccc 1371Gly Ser Gln Ser Val Tyr Gly Val Asp Gln Thr His Ser Gly Leu Pro 320 325 330 ctg cat cac atc agg agg atg ttc atg gga gat tca tgc cct tat cta 1419Leu His His Ile Arg Arg Met Phe Met Gly Asp Ser Cys Pro Tyr Leu 335 340 345 gca ggg aag cca aag atg ttt ttt att cag aac tat gtg gtg tca gag 1467Ala Gly Lys Pro Lys Met Phe Phe Ile Gln Asn Tyr Val Val Ser Glu 350 355 360 ggc cag ctg gag gac agc agc ctc ttg gag gtg gat ggg cca gcg atg 1515Gly Gln Leu Glu Asp Ser Ser Leu Leu Glu Val Asp Gly Pro Ala Met 365 370 375 380 aag aat gtg gaa ttc aag gct cag aag cga ggg ctg tgc aca gtt cac 1563Lys Asn Val Glu Phe Lys Ala Gln Lys Arg Gly Leu Cys Thr Val His 385 390 395 cga gaa gct gac ttc ttc tgg agc ctg tgt act gcg gac atg tcc ctg 1611Arg Glu Ala Asp Phe Phe Trp Ser Leu Cys Thr Ala Asp Met Ser Leu 400 405 410 ctg gag cag tct cac agc tca cca tcc ctg tac ctg cag tgc ctc tcc 1659Leu Glu Gln Ser His Ser Ser Pro Ser Leu Tyr Leu Gln Cys Leu Ser 415 420 425 cag aaa ctg aga caa gaa aga aaa cgc cca ctc ctg gat ctt cac att 1707Gln Lys Leu Arg Gln Glu Arg Lys Arg Pro Leu Leu Asp Leu His Ile 430 435 440 gaa ctc aat ggc tac atg tat gat tgg aac agc aga gtt tct gcc aag 1755Glu Leu Asn Gly Tyr Met Tyr Asp Trp Asn Ser Arg Val Ser Ala Lys 445 450 455 460 gag aaa tat tat gtc tgg ctg cag cac act ctg aga aag aaa ctt atc 1803Glu Lys Tyr Tyr Val Trp Leu Gln His Thr Leu Arg Lys Lys Leu Ile 465 470 475 ctc tcc tac aca taa gaaaccaaaa ggctgggcgt agtggctcac acctgtaatc 1858Leu Ser Tyr Thr 480 ccagcacttt gggaggccaa ggagggcaga tcacttcagg tcaggagttc gagaccagcc 1918tggccaacat ggtaaacgct gtccctagta aaaatacaaa aattaaaaaa aaaaaaaaaa 1978aaaaaaaaaa aaaaaaaaaa aaaaaa 200430480PRTHomo sapiens 30Met Ser Ala Glu Val Ile His Gln Val Glu Glu Ala Leu Asp Thr Asp 1 5 10 15 Glu Lys Glu Met Leu Leu Phe Leu Cys Arg Asp Val Ala Ile Asp Val 20 25 30 Val Pro Pro Asn Val Arg Asp Leu Leu Asp Ile Leu Arg Glu Arg Gly 35 40 45 Lys Leu Ser Val Gly Asp Leu Ala Glu Leu Leu Tyr Arg Val Arg Arg 50 55 60 Phe Asp Leu Leu Lys Arg Ile Leu Lys Met Asp Arg Lys Ala Val Glu 65 70 75 80 Thr His Leu Leu Arg Asn Pro His Leu Val Ser Asp Tyr Arg Val Leu 85 90 95 Met Ala Glu Ile Gly Glu Asp Leu Asp Lys Ser Asp Val Ser Ser Leu 100 105 110 Ile Phe Leu Met Lys Asp Tyr Met Gly Arg Gly Lys Ile Ser Lys Glu 115 120 125 Lys Ser Phe Leu Asp Leu Val Val Glu Leu Glu Lys Leu Asn Leu Val 130 135 140 Ala Pro Asp Gln Leu Asp Leu Leu Glu Lys Cys Leu Lys Asn Ile His 145 150 155 160 Arg Ile Asp Leu Lys Thr Lys Ile Gln Lys Tyr Lys Gln Ser Val Gln 165 170 175 Gly Ala Gly Thr Ser Tyr Arg Asn Val Leu Gln Ala Ala Ile Gln Lys 180 185 190 Ser Leu Lys Asp Pro Ser Asn Asn Phe Arg Leu His Asn Gly Arg Ser 195 200 205 Lys Glu Gln Arg Leu Lys Glu Gln Leu Gly Ala Gln Gln Glu Pro Val 210 215 220 Lys Lys Ser Ile Gln Glu Ser Glu Ala Phe Leu Pro Gln Ser Ile Pro 225 230 235 240 Glu Glu Arg Tyr Lys Met Lys Ser Lys Pro Leu Gly Ile Cys Leu Ile 245 250 255 Ile Asp Cys Ile Gly Asn Glu Thr Glu Leu Leu Arg Asp Thr Phe Thr 260 265 270 Ser Leu Gly Tyr Glu Val Gln Lys Phe Leu His Leu Ser Met His Gly 275 280 285 Ile Ser Gln Ile Leu Gly Gln Phe Ala Cys Met Pro Glu His Arg Asp 290 295 300 Tyr Asp Ser Phe Val Cys Val Leu Val Ser Arg Gly Gly Ser Gln Ser 305 310 315 320 Val Tyr Gly Val Asp Gln Thr His Ser Gly Leu Pro Leu His His Ile 325 330 335 Arg Arg Met Phe Met Gly Asp Ser Cys Pro Tyr Leu Ala Gly Lys Pro 340 345 350 Lys Met Phe Phe Ile Gln Asn Tyr Val Val Ser Glu Gly Gln Leu Glu 355 360 365 Asp Ser Ser Leu Leu Glu Val Asp Gly Pro Ala Met Lys Asn Val Glu 370 375 380 Phe Lys Ala Gln Lys Arg Gly Leu Cys Thr Val His Arg Glu Ala Asp 385 390 395 400 Phe Phe Trp Ser Leu Cys Thr Ala Asp Met Ser Leu Leu Glu Gln Ser 405 410 415 His Ser Ser Pro Ser Leu Tyr Leu Gln Cys Leu Ser Gln Lys Leu Arg 420 425 430 Gln Glu Arg Lys Arg Pro Leu Leu Asp Leu His Ile Glu Leu Asn Gly 435 440 445 Tyr Met Tyr Asp Trp Asn Ser Arg Val Ser Ala Lys Glu Lys Tyr Tyr 450 455 460 Val Trp Leu Gln His Thr Leu Arg Lys Lys Leu Ile Leu Ser Tyr Thr 465 470 475 480 3121DNAArtificial SequenceSynthetic 31aguccaggau uauagcccct t 213223DNAArtificial SequenceSynthetic 32aacaucugcc uagaucggcu att 233315DNAArtificial SequenceSynthetic 33catttcccgt aaatc 15341669DNAHomo sapiensCDS(170)..(871) 34ctccctcagc aaggacagca gaggaccagc taagagggag agaagcaact acagaccccc 60cctgaaaaca accctcagac gccacatccc ctgacaagct gccaggcagg ttctcttcct 120ctcacatact gacccacggc tccaccctct ctcccctgga aaggacacc atg agc act 178 Met Ser Thr 1 gaa agc atg atc cgg gac gtg gag ctg gcc gag gag gcg ctc ccc aag 226Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala Leu Pro Lys 5 10 15 aag aca ggg ggg ccc cag ggc tcc agg cgg tgc ttg ttc ctc agc ctc 274Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe Leu Ser Leu 20 25 30 35 ttc tcc ttc ctg atc gtg gca ggc gcc acc acg ctc ttc tgc ctg ctg 322Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe Cys Leu Leu 40 45 50 cac ttt gga gtg atc ggc ccc cag agg gaa gag ttc ccc agg gac ctc 370His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro Arg Asp Leu 55 60 65 tct cta atc agc cct ctg gcc cag gca gtc aga tca tct tct cga acc 418Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser Ser Arg Thr 70 75 80 ccg agt gac aag cct gta gcc cat gtt gta gca aac cct caa gct gag 466Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro Gln Ala Glu 85 90 95 ggg cag ctc cag tgg ctg aac cgc cgg gcc aat gcc ctc ctg gcc aat 514Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu Leu Ala Asn 100 105 110 115 ggc gtg gag ctg aga gat aac cag ctg gtg gtg cca tca gag ggc ctg 562Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser Glu Gly Leu 120 125 130 tac ctc atc tac tcc cag gtc ctc ttc aag ggc caa ggc tgc ccc tcc 610Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly Cys Pro Ser 135 140 145 acc cat gtg ctc ctc acc cac acc atc agc cgc atc gcc gtc tcc tac 658Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala Val Ser Tyr 150 155 160 cag acc aag gtc aac ctc ctc tct gcc atc aag agc ccc tgc cag agg 706Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro Cys Gln Arg 165 170 175 gag acc cca gag ggg gct gag gcc aag ccc tgg tat gag ccc atc tat 754Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu Pro Ile Tyr 180 185 190 195 ctg gga ggg gtc ttc cag ctg gag aag ggt gac cga ctc agc gct gag 802Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu Ser Ala Glu 200 205 210 atc aat cgg ccc gac tat ctc gac ttt gcc gag tct ggg cag gtc tac 850Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly Gln Val Tyr 215 220 225 ttt ggg atc att gcc ctg tga ggaggacgaa catccaacct tcccaaacgc 901Phe Gly Ile Ile Ala Leu 230 ctcccctgcc ccaatccctt tattaccccc tccttcagac accctcaacc tcttctggct 961caaaaagaga attgggggct tagggtcgga acccaagctt agaactttaa gcaacaagac 1021caccacttcg aaacctggga ttcaggaatg tgtggcctgc acagtgaagt gctggcaacc 1081actaagaatt caaactgggg cctccagaac tcactggggc ctacagcttt gatccctgac 1141atctggaatc tggagaccag ggagcctttg gttctggcca gaatgctgca ggacttgaga 1201agacctcacc tagaaattga cacaagtgga ccttaggcct tcctctctcc agatgtttcc 1261agacttcctt gagacacgga gcccagccct ccccatggag ccagctccct ctatttatgt 1321ttgcacttgt gattatttat tatttattta ttatttattt atttacagat gaatgtattt 1381atttgggaga ccggggtatc ctgggggacc caatgtagga gctgccttgg ctcagacatg 1441ttttccgtga aaacggagct gaacaatagg ctgttcccat gtagccccct ggcctctgtg 1501ccttcttttg attatgtttt ttaaaatatt tatctgatta agttgtctaa acaatgctga 1561tttggtgacc aactgtcact cattgctgag cctctgctcc ccaggggagt tgtgtctgta 1621atcgccctac tattcagtgg cgagaaataa agtttgctta gaaaagaa 166935233PRTHomo sapiens 35Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala 1 5 10 15 Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe 20 25 30 Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe 35 40 45 Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro 50 55 60 Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser 65 70 75 80 Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro 85 90 95 Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu 100 105 110 Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser 115 120 125 Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly 130 135 140 Cys Pro Ser Thr His Val

Leu Leu Thr His Thr Ile Ser Arg Ile Ala 145 150 155 160 Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro 165 170 175 Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu 180 185 190 Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu 195 200 205 Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly 210 215 220 Gln Val Tyr Phe Gly Ile Ile Ala Leu 225 230 361386DNAHomo sapiensCDS(141)..(758) 36gccccatctc cttgggctgc ccgtgcttcg tgctttggac taccgcccag cagtgtcctg 60ccctctgcct gggcctcggt ccctcctgca cctgctgcct ggatccccgg cctgcctggg 120cctgggcctt ggttctcccc atg aca cca cct gaa cgt ctc ttc ctc cca agg 173 Met Thr Pro Pro Glu Arg Leu Phe Leu Pro Arg 1 5 10 gtg tgt ggc acc acc cta cac ctc ctc ctt ctg ggg ctg ctg ctg gtt 221Val Cys Gly Thr Thr Leu His Leu Leu Leu Leu Gly Leu Leu Leu Val 15 20 25 ctg ctg cct ggg gcc cag ggg ctc cct ggt gtt ggc ctc aca cct tca 269Leu Leu Pro Gly Ala Gln Gly Leu Pro Gly Val Gly Leu Thr Pro Ser 30 35 40 gct gcc cag act gcc cgt cag cac ccc aag atg cat ctt gcc cac agc 317Ala Ala Gln Thr Ala Arg Gln His Pro Lys Met His Leu Ala His Ser 45 50 55 acc ctc aaa cct gct gct cac ctc att gga gac ccc agc aag cag aac 365Thr Leu Lys Pro Ala Ala His Leu Ile Gly Asp Pro Ser Lys Gln Asn 60 65 70 75 tca ctg ctc tgg aga gca aac acg gac cgt gcc ttc ctc cag gat ggt 413Ser Leu Leu Trp Arg Ala Asn Thr Asp Arg Ala Phe Leu Gln Asp Gly 80 85 90 ttc tcc ttg agc aac aat tct ctc ctg gtc ccc acc agt ggc atc tac 461Phe Ser Leu Ser Asn Asn Ser Leu Leu Val Pro Thr Ser Gly Ile Tyr 95 100 105 ttc gtc tac tcc cag gtg gtc ttc tct ggg aaa gcc tac tct ccc aag 509Phe Val Tyr Ser Gln Val Val Phe Ser Gly Lys Ala Tyr Ser Pro Lys 110 115 120 gcc acc tcc tcc cca ctc tac ctg gcc cat gag gtc cag ctc ttc tcc 557Ala Thr Ser Ser Pro Leu Tyr Leu Ala His Glu Val Gln Leu Phe Ser 125 130 135 tcc cag tac ccc ttc cat gtg cct ctc ctc agc tcc cag aag atg gtg 605Ser Gln Tyr Pro Phe His Val Pro Leu Leu Ser Ser Gln Lys Met Val 140 145 150 155 tat cca ggg ctg cag gaa ccc tgg ctg cac tcg atg tac cac ggg gct 653Tyr Pro Gly Leu Gln Glu Pro Trp Leu His Ser Met Tyr His Gly Ala 160 165 170 gcg ttc cag ctc acc cag gga gac cag cta tcc acc cac aca gat ggc 701Ala Phe Gln Leu Thr Gln Gly Asp Gln Leu Ser Thr His Thr Asp Gly 175 180 185 atc ccc cac cta gtc ctc agc cct agt act gtc ttc ttt gga gcc ttc 749Ile Pro His Leu Val Leu Ser Pro Ser Thr Val Phe Phe Gly Ala Phe 190 195 200 gct ctg tag aacttggaaa aatccagaaa gaaaaaataa ttgatttcaa 798Ala Leu 205 gaccttctcc ccattctgcc tccattctga ccatttcagg ggtcgtcacc acctctcctt 858tggccattcc aacagctcaa gtcttccctg atcaagtcac cggagctttc aaagaaggaa 918ttctaggcat cccaggggac cacacctccc tgaaccatcc ctgatgtctg tctggctgag 978gatttcaagc ctgcctagga attcccagcc caaagctgtt ggtctgtccc accagctagg 1038tggggcctag atccacacac agaggaagag caggcacatg gaggagcttg ggggatgact 1098agaggcaggg aggggactat ttatgaaggc aaaaaaatta aattatttat ttatggagga 1158tggagagagg ggaataatag aagaacatcc aaggagaaac agagacaggc ccaagagatg 1218aagagtgaga gggcatgcgc acaaggctga ccaagagaga aagaagtagg catgagggat 1278cacagggccc cagaaggcag ggaaaggctc tgaaagccag ctgccgacca gagccccaca 1338cggaggcatc tgcaccctcg atgaagccca ataaacctct tttctctg 138637205PRTHomo sapiens 37Met Thr Pro Pro Glu Arg Leu Phe Leu Pro Arg Val Cys Gly Thr Thr 1 5 10 15 Leu His Leu Leu Leu Leu Gly Leu Leu Leu Val Leu Leu Pro Gly Ala 20 25 30 Gln Gly Leu Pro Gly Val Gly Leu Thr Pro Ser Ala Ala Gln Thr Ala 35 40 45 Arg Gln His Pro Lys Met His Leu Ala His Ser Thr Leu Lys Pro Ala 50 55 60 Ala His Leu Ile Gly Asp Pro Ser Lys Gln Asn Ser Leu Leu Trp Arg 65 70 75 80 Ala Asn Thr Asp Arg Ala Phe Leu Gln Asp Gly Phe Ser Leu Ser Asn 85 90 95 Asn Ser Leu Leu Val Pro Thr Ser Gly Ile Tyr Phe Val Tyr Ser Gln 100 105 110 Val Val Phe Ser Gly Lys Ala Tyr Ser Pro Lys Ala Thr Ser Ser Pro 115 120 125 Leu Tyr Leu Ala His Glu Val Gln Leu Phe Ser Ser Gln Tyr Pro Phe 130 135 140 His Val Pro Leu Leu Ser Ser Gln Lys Met Val Tyr Pro Gly Leu Gln 145 150 155 160 Glu Pro Trp Leu His Ser Met Tyr His Gly Ala Ala Phe Gln Leu Thr 165 170 175 Gln Gly Asp Gln Leu Ser Thr His Thr Asp Gly Ile Pro His Leu Val 180 185 190 Leu Ser Pro Ser Thr Val Phe Phe Gly Ala Phe Ala Leu 195 200 205 381776DNAHomo sapiensCDS(96)..(941) 38tttcatttcc tcactgacta taaaagaata gagaaggaag ggcttcagtg accggctgcc 60tggctgactt acagcagtca gactctgaca ggatc atg gct atg atg gag gtc 113 Met Ala Met Met Glu Val 1 5 cag ggg gga ccc agc ctg gga cag acc tgc gtg ctg atc gtg atc ttc 161Gln Gly Gly Pro Ser Leu Gly Gln Thr Cys Val Leu Ile Val Ile Phe 10 15 20 aca gtg ctc ctg cag tct ctc tgt gtg gct gta act tac gtg tac ttt 209Thr Val Leu Leu Gln Ser Leu Cys Val Ala Val Thr Tyr Val Tyr Phe 25 30 35 acc aac gag ctg aag cag atg cag gac aag tac tcc aaa agt ggc att 257Thr Asn Glu Leu Lys Gln Met Gln Asp Lys Tyr Ser Lys Ser Gly Ile 40 45 50 gct tgt ttc tta aaa gaa gat gac agt tat tgg gac ccc aat gac gaa 305Ala Cys Phe Leu Lys Glu Asp Asp Ser Tyr Trp Asp Pro Asn Asp Glu 55 60 65 70 gag agt atg aac agc ccc tgc tgg caa gtc aag tgg caa ctc cgt cag 353Glu Ser Met Asn Ser Pro Cys Trp Gln Val Lys Trp Gln Leu Arg Gln 75 80 85 ctc gtt aga aag atg att ttg aga acc tct gag gaa acc att tct aca 401Leu Val Arg Lys Met Ile Leu Arg Thr Ser Glu Glu Thr Ile Ser Thr 90 95 100 gtt caa gaa aag caa caa aat att tct ccc cta gtg aga gaa aga ggt 449Val Gln Glu Lys Gln Gln Asn Ile Ser Pro Leu Val Arg Glu Arg Gly 105 110 115 cct cag aga gta gca gct cac ata act ggg acc aga gga aga agc aac 497Pro Gln Arg Val Ala Ala His Ile Thr Gly Thr Arg Gly Arg Ser Asn 120 125 130 aca ttg tct tct cca aac tcc aag aat gaa aag gct ctg ggc cgc aaa 545Thr Leu Ser Ser Pro Asn Ser Lys Asn Glu Lys Ala Leu Gly Arg Lys 135 140 145 150 ata aac tcc tgg gaa tca tca agg agt ggg cat tca ttc ctg agc aac 593Ile Asn Ser Trp Glu Ser Ser Arg Ser Gly His Ser Phe Leu Ser Asn 155 160 165 ttg cac ttg agg aat ggt gaa ctg gtc atc cat gaa aaa ggg ttt tac 641Leu His Leu Arg Asn Gly Glu Leu Val Ile His Glu Lys Gly Phe Tyr 170 175 180 tac atc tat tcc caa aca tac ttt cga ttt cag gag gaa ata aaa gaa 689Tyr Ile Tyr Ser Gln Thr Tyr Phe Arg Phe Gln Glu Glu Ile Lys Glu 185 190 195 aac aca aag aac gac aaa caa atg gtc caa tat att tac aaa tac aca 737Asn Thr Lys Asn Asp Lys Gln Met Val Gln Tyr Ile Tyr Lys Tyr Thr 200 205 210 agt tat cct gac cct ata ttg ttg atg aaa agt gct aga aat agt tgt 785Ser Tyr Pro Asp Pro Ile Leu Leu Met Lys Ser Ala Arg Asn Ser Cys 215 220 225 230 tgg tct aaa gat gca gaa tat gga ctc tat tcc atc tat caa ggg gga 833Trp Ser Lys Asp Ala Glu Tyr Gly Leu Tyr Ser Ile Tyr Gln Gly Gly 235 240 245 ata ttt gag ctt aag gaa aat gac aga att ttt gtt tct gta aca aat 881Ile Phe Glu Leu Lys Glu Asn Asp Arg Ile Phe Val Ser Val Thr Asn 250 255 260 gag cac ttg ata gac atg gac cat gaa gcc agt ttt ttc ggg gcc ttt 929Glu His Leu Ile Asp Met Asp His Glu Ala Ser Phe Phe Gly Ala Phe 265 270 275 tta gtt ggc taa ctgacctgga aagaaaaagc aataacctca aagtgactat 981Leu Val Gly 280 tcagttttca ggatgataca ctatgaagat gtttcaaaaa atctgaccaa aacaaacaaa 1041cagaaaacag aaaacaaaaa aacctctatg caatctgagt agagcagcca caaccaaaaa 1101attctacaac acacactgtt ctgaaagtga ctcacttatc ccaagagaat gaaattgctg 1161aaagatcttt caggactcta cctcatatca gtttgctagc agaaatctag aagactgtca 1221gcttccaaac attaatgcaa tggttaacat cttctgtctt tataatctac tccttgtaaa 1281gactgtagaa gaaagagcaa caatccatct ctcaagtagt gtatcacagt agtagcctcc 1341aggtttcctt aagggacaac atccttaagt caaaagagag aagaggcacc actaaaagat 1401cgcagtttgc ctggtgcagt ggctcacacc tgtaatccca acattttggg aacccaaggt 1461gggtagatca cgagatcaag agatcaagac catagtgacc aacatagtga aaccccatct 1521ctactgaaag tacaaaaatt agctgggtgt gttggcacat gcctgtagtc ccagctactt 1581gagaggctga ggcaagagaa ttgtttgaac ccgggaggca gaggttgcag tgtggtgaga 1641tcatgccact acactccagc ctggcgacag agcgagactt ggtttcaaaa aaaaaaaaaa 1701aaaaaacttc agtaagtacg tgttattttt ttcaataaaa ttctattaca gtatgtcaaa 1761aaaaaaaaaa aaaaa 177639281PRTHomo sapiens 39Met Ala Met Met Glu Val Gln Gly Gly Pro Ser Leu Gly Gln Thr Cys 1 5 10 15 Val Leu Ile Val Ile Phe Thr Val Leu Leu Gln Ser Leu Cys Val Ala 20 25 30 Val Thr Tyr Val Tyr Phe Thr Asn Glu Leu Lys Gln Met Gln Asp Lys 35 40 45 Tyr Ser Lys Ser Gly Ile Ala Cys Phe Leu Lys Glu Asp Asp Ser Tyr 50 55 60 Trp Asp Pro Asn Asp Glu Glu Ser Met Asn Ser Pro Cys Trp Gln Val 65 70 75 80 Lys Trp Gln Leu Arg Gln Leu Val Arg Lys Met Ile Leu Arg Thr Ser 85 90 95 Glu Glu Thr Ile Ser Thr Val Gln Glu Lys Gln Gln Asn Ile Ser Pro 100 105 110 Leu Val Arg Glu Arg Gly Pro Gln Arg Val Ala Ala His Ile Thr Gly 115 120 125 Thr Arg Gly Arg Ser Asn Thr Leu Ser Ser Pro Asn Ser Lys Asn Glu 130 135 140 Lys Ala Leu Gly Arg Lys Ile Asn Ser Trp Glu Ser Ser Arg Ser Gly 145 150 155 160 His Ser Phe Leu Ser Asn Leu His Leu Arg Asn Gly Glu Leu Val Ile 165 170 175 His Glu Lys Gly Phe Tyr Tyr Ile Tyr Ser Gln Thr Tyr Phe Arg Phe 180 185 190 Gln Glu Glu Ile Lys Glu Asn Thr Lys Asn Asp Lys Gln Met Val Gln 195 200 205 Tyr Ile Tyr Lys Tyr Thr Ser Tyr Pro Asp Pro Ile Leu Leu Met Lys 210 215 220 Ser Ala Arg Asn Ser Cys Trp Ser Lys Asp Ala Glu Tyr Gly Leu Tyr 225 230 235 240 Ser Ile Tyr Gln Gly Gly Ile Phe Glu Leu Lys Glu Asn Asp Arg Ile 245 250 255 Phe Val Ser Val Thr Asn Glu His Leu Ile Asp Met Asp His Glu Ala 260 265 270 Ser Phe Phe Gly Ala Phe Leu Val Gly 275 280 401909DNAHomo sapiensCDS(158)..(1003) 40gaggtgtttc ccttagctat ggaaactcta taagagagat ccagcttgcc tcctcttgag 60cagtcagcaa cagggtcccg tccttgacac ctcagcctct acaggactga gaagaagtaa 120aaccgtttgc tggggctggc ctgactcacc agctgcc atg cag cag ccc ttc aat 175 Met Gln Gln Pro Phe Asn 1 5 tac cca tat ccc cag atc tac tgg gtg gac agc agt gcc agc tct ccc 223Tyr Pro Tyr Pro Gln Ile Tyr Trp Val Asp Ser Ser Ala Ser Ser Pro 10 15 20 tgg gcc cct cca ggc aca gtt ctt ccc tgt cca acc tct gtg ccc aga 271Trp Ala Pro Pro Gly Thr Val Leu Pro Cys Pro Thr Ser Val Pro Arg 25 30 35 agg cct ggt caa agg agg cca cca cca cca ccg cca ccg cca cca cta 319Arg Pro Gly Gln Arg Arg Pro Pro Pro Pro Pro Pro Pro Pro Pro Leu 40 45 50 cca cct ccg ccg ccg ccg cca cca ctg cct cca cta ccg ctg cca ccc 367Pro Pro Pro Pro Pro Pro Pro Pro Leu Pro Pro Leu Pro Leu Pro Pro 55 60 65 70 ctg aag aag aga ggg aac cac agc aca ggc ctg tgt ctc ctt gtg atg 415Leu Lys Lys Arg Gly Asn His Ser Thr Gly Leu Cys Leu Leu Val Met 75 80 85 ttt ttc atg gtt ctg gtt gcc ttg gta gga ttg ggc ctg ggg atg ttt 463Phe Phe Met Val Leu Val Ala Leu Val Gly Leu Gly Leu Gly Met Phe 90 95 100 cag ctc ttc cac cta cag aag gag ctg gca gaa ctc cga gag tct acc 511Gln Leu Phe His Leu Gln Lys Glu Leu Ala Glu Leu Arg Glu Ser Thr 105 110 115 agc cag atg cac aca gca tca tct ttg gag aag caa ata ggc cac ccc 559Ser Gln Met His Thr Ala Ser Ser Leu Glu Lys Gln Ile Gly His Pro 120 125 130 agt cca ccc cct gaa aaa aag gag ctg agg aaa gtg gcc cat tta aca 607Ser Pro Pro Pro Glu Lys Lys Glu Leu Arg Lys Val Ala His Leu Thr 135 140 145 150 ggc aag tcc aac tca agg tcc atg cct ctg gaa tgg gaa gac acc tat 655Gly Lys Ser Asn Ser Arg Ser Met Pro Leu Glu Trp Glu Asp Thr Tyr 155 160 165 gga att gtc ctg ctt tct gga gtg aag tat aag aag ggt ggc ctt gtg 703Gly Ile Val Leu Leu Ser Gly Val Lys Tyr Lys Lys Gly Gly Leu Val 170 175 180 atc aat gaa act ggg ctg tac ttt gta tat tcc aaa gta tac ttc cgg 751Ile Asn Glu Thr Gly Leu Tyr Phe Val Tyr Ser Lys Val Tyr Phe Arg 185 190 195 ggt caa tct tgc aac aac ctg ccc ctg agc cac aag gtc tac atg agg 799Gly Gln Ser Cys Asn Asn Leu Pro Leu Ser His Lys Val Tyr Met Arg 200 205 210 aac tct aag tat ccc cag gat ctg gtg atg atg gag ggg aag atg atg 847Asn Ser Lys Tyr Pro Gln Asp Leu Val Met Met Glu Gly Lys Met Met 215 220 225 230 agc tac tgc act act ggg cag atg tgg gcc cgc agc agc tac ctg ggg 895Ser Tyr Cys Thr Thr Gly Gln Met Trp Ala Arg Ser Ser Tyr Leu Gly 235 240 245 gca gtg ttc aat ctt acc agt gct gat cat tta tat gtc aac gta tct 943Ala Val Phe Asn Leu Thr Ser Ala Asp His Leu Tyr Val Asn Val Ser 250 255 260 gag ctc tct ctg gtc aat ttt gag gaa tct cag acg ttt ttc ggc tta 991Glu Leu Ser Leu Val Asn Phe Glu Glu Ser Gln Thr Phe Phe Gly Leu 265 270 275 tat aag ctc taa gagaagcact ttgggattct ttccattatg attctttgtt 1043Tyr Lys Leu 280 acaggcaccg agaatgttgt attcagtgag ggtcttctta catgcatttg aggtcaagta 1103agaagacatg aaccaagtgg

accttgagac cacagggttc aaaatgtctg tagctcctca 1163actcacctaa tgtttatgag ccagacaaat ggaggaatat gacggaagaa catagaactc 1223tgggctgcca tgtgaagagg gagaagcatg aaaaagcagc taccaggtgt tctacactca 1283tcttagtgcc tgagagtatt taggcagatt gaaaaggaca ccttttaact cacctctcaa 1343ggtgggcctt gctacctcaa gggggactgt ctttcagata catggttgtg acctgaggat 1403ttaagggatg gaaaaggaag actagaggct tgcataataa gctaaagagg ctgaaagagg 1463ccaatgcccc actggcagca tcttcacttc taaatgcata tcctgagcca tcggtgaaac 1523taacagataa gcaagagaga tgttttgggg actcatttca ttcctaacac agcatgtgta 1583tttccagtgc aattgtaggg gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtatgactaa 1643agagagaatg tagatattgt gaagtacata ttaggaaaat atgggttgca tttggtcaag 1703attttgaatg cttcctgaca atcaactcta atagtgctta aaaatcattg attgtcagct 1763actaatgatg ttttcctata atataataaa tatttatgta gatgtgcatt tttgtgaaat 1823gaaaacatgt aataaaaagt atatgttagg atacaaaaaa aaaaaaaaaa aaaaaaaaaa 1883aaaaaaaaaa aaaaaaaaaa aaaaaa 190941281PRTHomo sapiens 41Met Gln Gln Pro Phe Asn Tyr Pro Tyr Pro Gln Ile Tyr Trp Val Asp 1 5 10 15 Ser Ser Ala Ser Ser Pro Trp Ala Pro Pro Gly Thr Val Leu Pro Cys 20 25 30 Pro Thr Ser Val Pro Arg Arg Pro Gly Gln Arg Arg Pro Pro Pro Pro 35 40 45 Pro Pro Pro Pro Pro Leu Pro Pro Pro Pro Pro Pro Pro Pro Leu Pro 50 55 60 Pro Leu Pro Leu Pro Pro Leu Lys Lys Arg Gly Asn His Ser Thr Gly 65 70 75 80 Leu Cys Leu Leu Val Met Phe Phe Met Val Leu Val Ala Leu Val Gly 85 90 95 Leu Gly Leu Gly Met Phe Gln Leu Phe His Leu Gln Lys Glu Leu Ala 100 105 110 Glu Leu Arg Glu Ser Thr Ser Gln Met His Thr Ala Ser Ser Leu Glu 115 120 125 Lys Gln Ile Gly His Pro Ser Pro Pro Pro Glu Lys Lys Glu Leu Arg 130 135 140 Lys Val Ala His Leu Thr Gly Lys Ser Asn Ser Arg Ser Met Pro Leu 145 150 155 160 Glu Trp Glu Asp Thr Tyr Gly Ile Val Leu Leu Ser Gly Val Lys Tyr 165 170 175 Lys Lys Gly Gly Leu Val Ile Asn Glu Thr Gly Leu Tyr Phe Val Tyr 180 185 190 Ser Lys Val Tyr Phe Arg Gly Gln Ser Cys Asn Asn Leu Pro Leu Ser 195 200 205 His Lys Val Tyr Met Arg Asn Ser Lys Tyr Pro Gln Asp Leu Val Met 210 215 220 Met Glu Gly Lys Met Met Ser Tyr Cys Thr Thr Gly Gln Met Trp Ala 225 230 235 240 Arg Ser Ser Tyr Leu Gly Ala Val Phe Asn Leu Thr Ser Ala Asp His 245 250 255 Leu Tyr Val Asn Val Ser Glu Leu Ser Leu Val Asn Phe Glu Glu Ser 260 265 270 Gln Thr Phe Phe Gly Leu Tyr Lys Leu 275 280 4243DNAArtificial SequenceSynthetic 42taggcagtgg tttgacgtcc gcatgttggg aatagccacg cct 43439PRTArtificial SequenceSynthetic 43Arg Arg Arg Arg Arg Arg Arg Arg Arg 1 5 4413PRTArtificial SequenceSynthetic 44Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln 1 5 10 4512PRTArtificial SequenceSynthetic 45Ala Tyr Ala Arg Ala Ala Ala Arg Gln Ala Arg Ala 1 5 10 4634PRTArtificial SequenceSynthetic 46Asp Ala Ala Thr Ala Thr Arg Gly Arg Ser Ala Ala Ser Arg Pro Thr 1 5 10 15 Glu Arg Pro Arg Ala Pro Ala Arg Ser Ala Ser Arg Pro Arg Arg Pro 20 25 30 Val Glu 4727PRTArtificial SequenceSynthetic 47Gly Trp Thr Leu Asn Ser Ala Gly Tyr Leu Leu Gly Leu Ile Asn Leu 1 5 10 15 Lys Ala Leu Ala Ala Leu Ala Lys Lys Ile Leu 20 25 4812PRTArtificial SequenceSynthetic 48Pro Leu Ser Ser Ile Phe Ser Arg Ile Gly Asp Pro 1 5 10 4916PRTArtificial SequenceSynthetic 49Ala Ala Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro 1 5 10 15 5012PRTArtificial SequenceSynthetic 50Ala Ala Val Leu Leu Pro Val Leu Leu Ala Ala Pro 1 5 10 5115PRTArtificial SequenceSynthetic 51Val Thr Val Leu Ala Leu Gly Ala Leu Ala Gly Val Gly Val Gly 1 5 10 15 5221PRTArtificial SequenceSynthetic 52Gly Ala Leu Phe Leu Gly Trp Leu Gly Ala Ala Gly Ser Thr Met Gly 1 5 10 15 Ala Trp Ser Gln Pro 20 5327PRTArtificial SequenceSynthetic 53Gly Trp Thr Leu Asn Ser Ala Gly Tyr Leu Leu Gly Leu Ile Asn Leu 1 5 10 15 Lys Ala Leu Ala Ala Leu Ala Lys Lys Ile Leu 20 25 5418PRTArtificial SequenceSynthetic 54Lys Leu Ala Leu Lys Leu Ala Leu Lys Ala Leu Lys Ala Ala Leu Lys 1 5 10 15 Leu Ala 5521PRTArtificial SequenceSynthetic 55Lys Glu Thr Trp Trp Glu Thr Trp Trp Thr Glu Trp Ser Gln Pro Lys 1 5 10 15 Lys Lys Arg Lys Val 20 5616PRTArtificial SequenceSynthetic 56Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Gly Cys 1 5 10 15 5716PRTArtificial SequenceSynthetic 57Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Ala Ala Gly Cys 1 5 10 15 5816PRTArtificial SequenceSynthetic 58Ala Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Gly Cys 1 5 10 15 5916PRTArtificial SequenceSynthetic 59Lys Ala Phe Ala Ala Leu Ala Ala Arg Leu Tyr Arg Lys Ala Gly Cys 1 5 10 15 6016PRTArtificial SequenceSynthetic 60Lys Ala Phe Ala Lys Leu Ala Ala Gln Leu Tyr Arg Lys Ala Gly Cys 1 5 10 15 6116PRTArtificial SequenceSynthetic 61Ala Gly Gly Gly Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg 1 5 10 15

Claims

1. A composition comprising a first ligand that is specific for binding to a tumor cell, and a second ligand that is specific for binding to a death receptor on the tumor cell, wherein the first and second ligands are bound to a nucleic acid nanostructure.

2. The composition of claim 1, wherein the first ligand is a first aptamer and the second ligand is a second aptamer.

3. The composition of claim 2, wherein the first aptamer is specific for binding to a tumor antigen on the surface of the tumor cell.

4. The composition of claim 3, wherein the tumor antigen is CD20.

5. The composition of claim 2, wherein the death receptor is TRAIL Receptor 1 (TRAIL-R1), TRAIL Receptor 2 (TRAIL-R2) or tumor necrosis factor receptor (TNFR).

6. The composition of claim 2, wherein the distance between the first aptamer and the second aptamer on the nucleic acid nanostructure is about 10 nm to about 15 nm.

7. The composition of claim 2, wherein the first aptamer comprises a plurality of first aptamers, and the second aptamer comprises a plurality of second aptamers.

8. The composition of claim 7 wherein the plurality of first aptamers is present on the nucleic acid nanostructure at a density of 5-10 aptamers per nucleic acid nanostructure, and the plurality of second aptamers is present on the nucleic acid nanostructure at a density of 5-10 aptamers per nucleic acid nanostructure.

9. The composition of claim 8 wherein the distance between each aptamer of the plurality of first aptamers and the distance between each aptamer of the plurality of second aptamers on the nucleic acid nanostructure is about 5 nm to about 8 nm.

10. The composition of claim 9, wherein the ratio of first aptamers to second aptamers on the nucleic acid nanostructure is 1:1.

11. The composition of claim 2, wherein the first aptamer comprises a dimer, trimer, tetramer, or pentamer of an aptamer that is specific for a tumor cell.

12.-22. (canceled)

23. The composition of claim 2, wherein the nucleic acid nanostructure comprises a nucleic acid tile.

24. The composition of claim 23, wherein the nucleic acid nanostructure comprises a plurality of nucleic acid tiles.

25. The composition of claim 24, wherein the plurality of nucleic acid tiles forms a nucleic acid tiling array.

26. The composition of claim 2, further comprising a pharmaceutically acceptable carrier.

27. A method of treating a tumor in a mammal comprising administering to a mammal in need thereof an amount effective to treat the tumor of a nucleic acid nanostructure that comprises a first ligand that is specific for a tumor cell, and a second ligand that is specific for a death receptor on the tumor cell, wherein the first and second ligands are bound to a nucleic acid nanostructure.

28.-37. (canceled)