Methods And Compositions For Modulating T Cell And/or B Cell Activation

Abstract

The present invention provides methods of reducing or enhancing T cell activation and/or B cell activation in a subject, comprising administering to a subject an effective amount of an inhibitor or enhancer, respectively, of Semaphorin 6D (Sema6D) activity on T cells and/or B cells.

Description

STATEMENT OF PRIORITY

[0001] This application claims the benefit, under 35 U.S.C. .sctn. 119(e), of U.S. Provisional Application No. 60/785,310, filed Mar. 23, 2006, the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0003] The present invention relates to regulating immune responses by modulating T cell activation and/or B cell activation.

BACKGROUND ART

[0004] The immune system is comprised of a complex network of autonomous cells working together to manage a chaotic situation. The regulation of the immune network is equally complex, characterized by hubs of activation control. The dendritic cell (DC) represents one hub of immune control via its unique abilities to regulate activation of CD4.sup.+ T cells. In turn, CD4.sup.+ T cells are able to affect the activity of a wide variety of immune cells of both the adaptive and innate categories. During an initial interaction, DCs present antigen (Ag) in the context of MHC class II molecules for recognition by CD4.sup.+ T cells via their T cell receptor (TCR). Binding of Ag by the TCR represents signal one, but further stimulation derived from costimulatory signals is required for fill activation of T cells via DCs. Many co-stimulatory receptor-ligand pairs have been identified between T cells and DCs. The prototypical costimulation interacting pairs on T cells and DCs are CD154-CD40 and CD28-B7 (T-DC respectively). Since their identification, experimental manipulation of these receptors and ligands has proven to be a powerful tool in modulating a wide variety of immune responses ranging from transplant tolerance and autoimmunity to tumor rejection (1-7).

[0005] The present invention overcomes previous shortcomings in the art by demonstrating that PlexA1 expressed on DCs and Sema6D expressed on T cells (e.g., CD4.sup.+ T cells) and on B cells, represent a novel receptor-ligand costimulation pair, capable of regulating immune system activity.

SUMMARY OF THE INVENTION

[0006] The present invention provides a method of reducing T cell activation in a subject, comprising administering to the subject an effective amount of an inhibitor of Semaphorin 6D (Sema6D) activity on T cells.

[0007] Further provided herein is a method of increasing T cell activation in a subject, comprising administering to the subject an effective amount of an enhancer of Semaphorin 6D (Sema6D) activity on T cells.

[0008] In addition, the present invention provides a method of identifying an activated T cell, comprising detecting Sema6D on the surface of the T cell.

[0009] The present invention also provides a method of monitoring T cell activation over time, comprising detecting Sema6D on the surface of a T cell over time and measuring changes in the amount of Sema6D on the surface of a T cell over time.

[0010] In further embodiments, the present invention provides a method of identifying a substance having the ability to inhibit Sema6D activity, comprising contacting the substance with T cells under conditions wherein Sema6D activity can occur and measuring the amount of Sema6D activity in the presence and in the absence of the substance; whereby a decrease in Sema6D activity in the presence of the substance as compared to the amount of Sema6D activity in the absence of the substance identifies a substance having the ability to inhibit Sema6D activity.

[0011] Additionally provided is a method of identifying a substance having the ability to enhance Sema6D activity, comprising contacting the substance with T cells under conditions whereby Sema6D activity can occur and measuring the amount of Sema6D activity in the presence and in the absence of the substance; whereby an increase in Sema6D activity in the presence of the substance as compared to the amount of Sema6D activity in the absence of the substance identifies a substance having the ability to enhance Sema6D activity.

[0012] Further provided herein is a method of reducing B cell activation in a subject, comprising administering to a subject in need of reduced B cell activation an effective amount of an inhibitor of Semaphorin 6D (Sema6D) activity on B cells.

[0013] In further embodiments, the present invention provides a method of increasing B cell activation in a subject, comprising administering to a subject in need of increased B cell activation an effective amount of an enhancer of Semaphorin 6D (Sema6D) activity on B cells.

[0014] Also provided herein is a method of identifying an activated B cell, comprising detecting Sema6D on the surface of the B cell and a method of identifying an activated B cell, comprising detecting messenger RNA encoding Sema6D in the B cell.

[0015] Additional embodiments include a method of monitoring B cell activation over time, comprising detecting Sema6D on the surface of a B cell over time and measuring changes in the amount of Sema6D on the surface of a B cell over time, as well as a method of monitoring B cell activation over time, comprising detecting messenger RNA encoding Sema6D in a B cell over time and measuring changes in the amount of messenger RNA encoding Sema6D in the B cell over time.

[0016] Additionally provided herein is a method of identifying a substance having an inhibitory effect on Sema6D activity and/or having an inhibitory effect on B cell activation, comprising contacting the substance with B cells under conditions whereby Sema6D activity and/or B cell activation can occur and measuring the amount of Sema6D activity and/or B cell activation in the presence and in the absence of the substance; whereby a decrease in Sema6D activity and/or B cell activation in the presence of the substance as compared to the amount of Sema6D activity and or/B cell activation in the absence of the substance identifies a substance having the ability to inhibit Sema6D activity and/or B cell activation.

[0017] Furthermore, the present invention provides a method of identifying a substance having an enhancing effect on Sema6D activity and/or B cell activation, comprising contacting the substance with B cells under conditions whereby Sema6D activity and/or B cell activation can occur and measuring the amount of Sema6D activity and/or B cell activation in the presence and in the absence of the substance; whereby an increase in Sema6D activity and/or B cell activation in the presence of the substance as compared to the amount of Sema6D activity and/or B cell activation in the absence of the substance identifies a substance having the ability to enhance Sema6D activity and/or B cell activation.

[0018] It is further contemplated herein that the present invention provides a method of treating a B cell-related disorder and/or a T cell related disorder and/or other white blood cell-related disorder in a subject, comprising administering to the subject a therapeutic amount of an inhibitor of Semaphorin 6D (Sema6D) activity on B cells, T cells and/or other white blood cells.

[0019] Various other objectives and advantages of the present invention will become apparent from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows expression of Sema6D mRNA in the immune system. (a) SymAtlas gene array mouse cell and tissue expression of Sema6D mRNA. (b) SymAtlas gene array human cell and tissue expression of Sema6D mRNA. (c) SymAtlas gene array human cancer cell expression of Sema6D mRNA.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention will now be described with reference to the following embodiments. As is apparent by these descriptions, this invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment can be deleted from that embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0023] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0024] Except as otherwise indicated, standard methods can be used for the production of viral and non-viral vectors, manipulation of nucleic acid sequences, production of transformed cells, and the like according to the present invention. Such techniques are known to those skilled in the art. See, e.g., SAMBROOK et al., MOLECULAR CLONING: A LABORATORY MANUAL 2nd Ed. (Cold Spring Harbor, N.Y., 1989); F. M. AUSUBEL et al. CURRENT PROTOCOLS 1N MOLECULAR BIOLOGY (Green Publishing Associates, Inc. and John Wiley & Sons, Inc., New York).

[0025] The present invention is based on the unexpected discovery that the semaphorin 6D protein on a T cell (e.g., CD4.sup.+ T cell) surface is a ligand for the Plexin-A1 (PlexA1) receptor protein on antigen-presenting cells, thereby providing the first identification of a ligand for a Plexin-A1 receptor on an immune system cell. Thus, in one embodiment, the present invention provides a method of reducing or inhibiting T cell activation in a subject, comprising administering to the subject (e.g., a subject in need of reduced T cell activation) an effective amount of an inhibitor of Semaphorin 6D (Sema6D) activity on CD4.sup.+ T cells.

[0026] The present invention additionally provides a method of reducing or inhibiting B cell activation in a subject, comprising administering to a subject in need of reduced B cell activation an effective amount of an inhibitor of Semaphorin 6D (Sema6D) activity on B cells.

[0027] In the methods of this invention whereby T cell activation and/or B cell activation is reduced or inhibited, a subject of these methods can include a subject having, or at risk of having, an autoimmune disorder or disease, a transplant recipient, a subject having an inflammatory response or at risk of having an inflammatory response, a subject having an allergic response or at risk of having an allergic response and any subject in whom it is desirable to suppress an immune response associated with T cell activation and/or B cell activation, as known in the art.

[0028] According to the methods of this invention, an inhibitor of Sema6D activity can be, but is not limited to an antibody or antibody fragment that specifically binds Sema6D, a fusion protein comprising the extracellular domain of the Sema6D protein and an immunoglobulin fragment, an antibody or antibody fragment that specifically binds PlexA1, small molecule mimetics that block the binding of Sema6D to PlexA1 and any substance that inhibits binding of Sema6D to PlexA1 as now known or later identified.

[0029] Also included in the methods described herein is a substance that reduces or inhibits Sema6D activity and/or PlexA1 activity at the transcriptional, post-transcriptional, translational and/or post-translational level. For example, the transcription factor class II transactivator (CIITA) can activate the PlexA1 gene expression in immune dendritic cells (Nature Immunol. 4(9):891-8 2003) and this method of activation is not likely to occur in other tissues with PlexA1 such as neurons and heart cells, since CIITA is not expressed in these other cells. It would be possible to alter CIITA to induce a change in PlexA1 expression predominantly in immune dendritic cells.

[0030] In further embodiments of this invention, the inhibitor of Sema6D activity and/or inhibitor of PlexA1 activity is administered in combination (either before, after and/or simultaneously) with another anti-T cell therapeutic and/or anti-B cell therapeutic, either simultaneously, before and/or after administration of the inhibitor of Sema6D activity and/or inhibitor of PlexA1 activity. Nonlimiting examples of an anti-T cell therapeutic include an antibody or fragment thereof or other ligand or fragment thereof that specifically binds and/or inhibits activity of CD3 protein, CD40 protein, B7 family proteins, and/or CD28 family proteins; cyclosporine; FK504; steroids; and/or substances that target MHC-1 and/or MHC-II molecules, immunosuppressive drugs, interferons, corticosteroids, azathioprine, cyclophosphamide, etc. Also included are anti-T cell therapeutics that reduce or inhibit CD3 (e.g., OKT.RTM.3 monoclonal antibody), CD40, B7 and/or CD28 activity in T cells at the transcriptional, post-transcriptional, translational and/or post-translational level (e.g., an antisense nucleic acid that binds a coding sequence of the Sema6D protein, an interfering RNA that inhibits or suppresses transcription and/or translation of the Sema6D protein, a ribozyme, etc.), therapies that target T cell activation transcription factors, such as inhibitors of I.kappa.B kinase (IKK), which would also inhibit the transcription factor, Nuclear Factor kappa light chain enhancer in B cells (NF-.kappa.b), or cyclosporine, which inhibits the calcineurin pathway important for the activation of the transcription factor, Nuclear Factor of Activated T cells). Also included are Basiliximab (anti-CD25), Alefacept (LFA3-Ig fusion; blocks CD2), Daclizumab (Anti-CD25), Tysabri (anti-VLA4) and anti-CLA4 Ab. Other inhibitors that can be used in the methods of this invention include but are not limited to Omalizumab (Anti-IgE mab; targets mast cells and basophils) and Lumiliximab (anti-CD23; targets mast cells and basophils).

[0031] Nonlimiting examples of an anti-B cell therapeutic include an antibody or fragment thereof or other ligand or fragment thereof that specifically binds and/or inhibits activity of CD20 protein (e.g., Rituximab.RTM. monoclonal antibody), immunosuppressive drugs, interferons, corticosteroids, azathioprine, cyclophosphamide, CTLA4-IG (targets CD80/86 on DCs and B cells), Belimumab (targets Blys (BAFF) interactions with receptors on B cells), and Natalizumab or Tysabri (Anti-VLA4; targets T cells and B cells),

[0032] Further provided is a method of increasing T cell and/or B cell activation in a subject, comprising administering to the subject (e.g., a subject in need of increased T cell activation and/or increased B cell activation) an effective amount of an enhancer of Semaphorin 6D (Sema6D) activity on T cells and/or B cells.

[0033] In the methods provided herein for enhancing T cell activation and/or B cell activation, a subject can be a subject having an infection or at risk of having an infection, a subject having a suppressed immune system or suppressed immune response or at risk of having a suppressed immune system or suppressed immune response, as known in the art. Examples of infections that cause immunosuppression include but are not limited to human immunodeficiency virus infection, cytomegalovirus infection, vaccinia virus infection, and F. tularenesis bacterial infection. Conditions under which immune suppression occurs include severe immunodeficiencies, advanced age, chemotherapy, radiation therapy, irradiation and upon severe burn. In additional embodiments, the enhancer of T cell activation and/or B cell activation can be administered in combination (either before, after and/or simultaneously) with a T cell activation therapeutic and/or a B cell activation therapeutic. Nonlimiting examples of a T cell activation and/or a B cell activation therapeutic of this invention include vaccines such as peptides, DNA and glycoproteins and adjuvants such as toll-like receptor agonists, and the Bacillus Calmette-Guerin.

[0034] It is further contemplated herein that T cell activation and/or B cell activation can be reduced, inhibited or enhanced in methods employing ex vivo T cells and/or B cells and/or antigen presenting cells that have been removed from a subject and are subsequently administered to the same subject or a different subject of the same species. Thus, the present invention provides a method of enhancing T cell activation and/or B cell activation, comprising contacting a T cell and/or a B cell with an enhancer of Sema6D activity and/or an enhancer of PlexA1 activity in the presence of an antigen presenting cell having PlexA1 on the surface, under conditions whereby T cell activation and/or B cell activation can occur and then administering the activated T cell and/or activated B cell and/or antigen presenting cell to a subject. Further provided is a method of reducing T cell activation and/or B cell activation, comprising contacting a T cell and/or B cell with an inhibitor of Sema6D activity and/or an inhibitor of PlexA1 activity in the presence of an antigen presenting cell having PlexA1 on the surface, under conditions whereby inhibition of T cell activation and/or inhibition of B cell activation can occur and then administering the T cell and/or B cell and/or antigen presenting cell to a subject.

[0035] In other embodiments, the present invention provides a method of identifying an activated T cell or activated B cell, comprising detecting Sema6D on the surface of the T cell or B cell. Further provided herein is a method of identifying an activated T cell or activated B cell, comprising detecting messenger RNA encoding Sema6D in the T cell or B cell.

[0036] In methods of this invention wherein Sema6D is detected on the surface of a T cell or a B cell, such detection can be carried out according to methods standard in the art for detecting a protein on the surface, of a cell and such methods can be qualitative and/or quantitative. Furthermore, in methods of this invention wherein an amount of messenger RNA encoding Sema6D is detected, such detection can be carried out according to standard methods for detecting nucleic acid in a cell (e.g., polymerase chain reaction (PCR) and other nucleic acid amplification protocols, real-time PCR, RNase protection, in situ hybridization, Northern blots, etc.) and such methods can be qualitative and/or quantitative.

[0037] Thus, in some embodiments, the identification of an activated T cell or activated B cell can be carried out by identifying an increase in the amount of Sema6D on the surface of a cell relative to a cell that is not activated. An amount of Sema6D on a T cell or B cell that is not activated can be determined by identifying T cells or B cells that are not activated (as determined by features other than the absence of Sema6D, such as the absence of CD69, CD25, HLA-DR, CD62L, CD154 and/or CD44CD25, IL-2 production, ZAP70, LAT and Lck phosphorylation in T cells) and measuring the amount of Sema6D on the surface of said non-activated cells to establish a baseline amount of Sema6D. Thus, an activated T cell or activated B cell would be identified as having an amount of Sema6D on the surface that is increased relative to the baseline amount.

[0038] Thus, in some embodiments, the increase in Sema6D protein can be an increase of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 300%, etc., relative to the amount of Sema6D protein on the surface of a nonactivated T cell or nonactivated B cell.

[0039] In addition, the increase in Sema6D protein can be at least about 0.1 fold, 0.2 fold, 0.5 fold, 1.0 fold, 1.5 fold, 2.0 fold, 2.5 fold, 3.0 fold, 3.5 fold, 4.0 fold, 4.5 fold, 5.0 fold, 5.5 fold, 6.0 fold, 6.5 fold, 7.0 fold, 7.5 fold, 8.0 fold, 8.5 fold, 9.0 fold, 9.5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, etc., relative to the amount of Sema6D protein on the surface of a nonactivated T cell or nonactivated B cell.

[0040] In other embodiments, the increase in Sema6D activity can be an increase of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 300%; etc., relative to the amount of Sema6D protein on the surface of a nonactivated T cell or non activated B cell.

[0041] In addition, the increase in Sema6D activity can be at least about 0.1 fold, 0.2 fold, 0.5 fold, 1.0 fold, 1.5 fold, 2.0 fold, 2.5 fold, 3.0 fold, 3.5 fold, 4.0 fold, 4.5 fold, 5.0 fold, 5.5 fold, 6.0 fold, 6.5 fold, 7.0 fold, 7.5 fold, 8.0 fold, 8.5 fold, 9.0 fold, 9.5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, etc., relative to the amount of Sema6D protein on the surface of a nonactivated T cell or nonactivated B cell.

[0042] Furthermore, in methods wherein the amount of mRNA encoding Sema6D is measured to identify an activated T cell or activated B cell, a baseline amount of mRNA in a nonactivated T cell or nonactivated B cell can be determined and an activated T cell or activated B cell can be identified by measuring the amount of mRNA relative to the baseline amount.

[0043] Thus, the increase in Sema6D mRNA can be of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 300%, etc., relative to the amount of Sema6D mRNA in a nonactivated T cell or nonactivated B cell.

[0044] In addition, the increase in Sema6D mRNA can be at least about 0.1 fold, 0.2 fold, 0.5 fold, 1.0 fold, 1.5 fold, 2.0 fold, 2.5 fold, 3.0 fold, 3.5 fold, 4.0 fold, 4.5 fold, 5.0 fold, 5.5 fold, 6.0 fold, 6.5 fold, 7.0 fold, 7.5 fold, 8.0 fold, 8.5 fold, 9.0 fold, 9.5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, etc., relative to the amount of Sema6D mRNA in a nonactivated T cell or nonactivated B cell.

[0045] Additionally, in methods of this invention wherein T cell activation and/or B cell activation is inhibited, such inhibition can be detected by identifying a decrease in Sema6D protein on the surface of a T cell and/or B cell and/or by identifying a decrease in mRNA encoding Sema6D protein in a T cell and/or B cell. Such inhibition can be detected by identifying a decrease in Sema6D protein and/or mRNA relative to the amount of Sema6D protein and/or mRNA present in a T cell identified as an activated T cell and/or in a B cell identified as an activate B cell. Typical surface and biochemical activation markers on T cells include but are not limited to CD69, CD25, HLA-DR, CD62L, CD154 and/or the production of IL-2, calcium mobilization, ZAP-70 phosphorylation, LAT phosphorylation, Lck phosphorylation and c-abl kinase activation. Immunologic assays measuring T cell and/or B cell proliferation and cytotoxicity (defined as the ability to kill target cells) can also be used.

[0046] Thus, in some embodiments, the inhibition or reduction of T cell activation or B cell activation can be a decrease in Sema6D protein and/or mRNA of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%. 8%, 9%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, etc., relative to the amount of Sema6D protein and/or mRNA in an activated T cell or activated B cell.

[0047] In addition, the inhibition or reduction of T cell activation or B cell activation can be a decrease of Sema6D protein and/or mRNA of at least about 0.1 fold, 0.2 fold, 0.5 fold, 1.0 fold, 1.5 fold, 2.0 fold, 2.5 fold, 3.0 fold, 3.5 fold, 4.0 fold, 4.5 fold, 5.0 fold, 5.5 fold, 6.0 fold, 6.5 fold, 7.0 fold, 7.5 fold, 8.0 fold, 8.5 fold, 9.0 fold, 9.5 fold, 10 fold, 20 fold, 30 fold, 40 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, etc., relative to the amount of Sema6D protein and/or mRNA in an activated T cell or activated B cell.

[0048] The present invention also provides a method of monitoring T cell activation and/or B cell activation over time, comprising detecting Sema6D on the surface of a T cell and/or B cell over time and measuring changes in the amount of Sema6D on the surface of a T cell and/or B cell over time. Additionally provided is a method of monitoring T cell activation and/or B cell activation over time, comprising detecting mRNA encoding Sema6D in a T cell and/or B cell over time and measuring changes in the amount of mRNA encoding Sema6D in the cell over time. Thus a baseline measurement of Sema6D protein and/or mRNA can be performed according to methods known in the art and as described herein and measurements of Sema6D protein and/or mRNA can be carried out at any time interval (e.g., minutes, hours, days, etc.) and under conditions whereby T cell activation and/or B cell activation can be modulated. Changes in the amount of Sema6D protein and/or mRNA can be detected, whereby an increase or decrease in the amount of Sema6D protein and/or mRNA can identify an increase or decrease, respectively in the activation of a T cell and/or B cell over time.

[0049] The present invention further provides screening methods, including a method of identifying a substance having the ability to inhibit Sema6D activity, comprising contacting the substance with T cells and/or B cells expressing Sema6D under conditions whereby Sema6D activity can occur and measuring the amount of Sema6D activity in the presence and in the absence of the substance; whereby a decrease in Sema6D activity in the presence of the substance as compared to the amount of Sema6D activity in the absence of the substance identifies a substance having the ability to inhibit Sema6D activity.

[0050] Further provided herein is a method of identifying a substance having the ability to enhance Sema6D activity, comprising contacting the substance with T cells and/or B cells expressing Sema6D under conditions whereby Sema6D activity can occur and measuring the amount of Sema6D activity in the presence and in the absence of the substance; whereby an increase in Sema6D activity in the presence of the substance as compared to the amount of Sema6D activity in the absence of the substance identifies a substance having the ability to enhance Sema6D activity.

[0051] In the screening methods of this invention, Sema6D activity indicates activation of T cells, as determined by measurement of T cell activation markers such as CD25, CD69, CD62L, CD154, CD44, HLA-DR, IL-2 production, calcium mobilization, phosphorylation of LAT, ZAP70, lck, c-Abl etc., in response to a substance that can bind and activate through the Sema6D molecule. An example would be a fusion protein consisting of the extramembrane domain of PlexA1 coupled with the Fc portion of immunoglobulin as described herein.

[0052] Sema6D activity can be measured by, for example, identifying the T cell and/or B cell activation status of a T cell and/or B cell in the absence of a test substance and measuring the T cell and/or B cell activation status of the T cell and/or B cell in the presence of the substance, whereby an increase in T cell and/or B cell activation in the presence of the substance identifies the substance as having the ability to enhance Sema6D activity and whereby a decrease in T cell and/or B cell activation in the presence of the substance identifies a substance having the ability to inhibit Sema6D activity. The activation status of a T cell can be measured by methods standard in the art, including but not limited to, measuring an increase in the production and/or expression of CD69, CD25, HLA-DR, CD62L, CD154 and/or CD44, either singly or in any combination, in the T cell, according to art-known methods. T cell activation status can also be determined by employing art-known methods for detecting cytotoxic T cell responses, T helper responses and/or IL-2 production. The activation status of a B cell can be measured by methods standard in the art.

[0053] In some embodiments, the screening methods of this invention can include the step of contacting the T cells and/or B cells with a known inhibitor of Sema6D activity, such as an antibody that specifically binds a Sema6D protein or a fusion protein of this invention comprising the extracellular domain of a Sema6D protein and an immunoglobulin fragment and establishing a baseline amount of T cell and/or B cell activation and then contacting the T cell and/or B cell with the substance to be screened and identifying a change in the T cell and/or B cell activation status to identify a substance that either inhibits or enhances Sema6D activity. Typical surface and biochemical activation markers on T cells include but are not limited to CD69, CD25, HLA-DR, CD62L, CD154 and/or the production of IL-2, calcium mobilization, ZAP-70 phosphorylation, LAT phosphorylation, and Lck phosphorylation. T cell proliferation and cytotoxicity (defined as the ability to kill target cells) can also be measured. Sema6D activity can be measured by the methods described herein.

[0054] In some embodiments of this invention, substances can be screened for the ability to inhibit or enhance Sema6D activity by affecting the ability of Sema6D to bind PlexA1. This inhibition or enhancement of binding activity can be detected by any of a variety of art-recognized methods for evaluating binding activity. As one example, the substance to be tested and a PlexA1 protein or an active fragment thereof can be contacted in the presence of T cells and/or B cells having Sema6D on the surface. The amount of binding of PlexA1 to the cells in the presence of the substance and the amount of binding of PlexA1 to the cells in the absence of the substance can be determined and a decrease or increase in the amount of binding in the presence of the substance identifies the substance as having the ability to inhibit or enhance binding, respectively and thus inhibit or enhance Sema6D activity, respectively.

[0055] In some embodiments, binding of the PlexA1 protein to a T cell or B cell can be measured by attaching a detectable moiety to the PlexA1 polypeptide or fragment (e.g., a fluorescence moiety, histochemically detectable moiety, radioactive moiety, etc.). The amount of detectable moiety can be measured in the presence and absence of the substance to be tested and the amounts can be compared to determine inhibition or enhancement. T cell activation can be measured by methods not limited to the following: detection and/or quantitation of cell surface markers such as CD69, CD25, HLA-DR, CD62L, CD154 and/or the production of IL-2, calcium mobilization, ZAP-70 phosphorylation, LAT phosphorylation, Lck phosphorylation; NF-.kappa.B activation, MEK activation, NFAT activation, Ap-1 activation; T cell proliferation and cytotoxicity (defined as the ability to kill target cells).

[0056] Substances suitable for screening according to the above methods include small molecules, natural products, peptides, nucleic acids, etc. Sources for compounds include natural product extracts, collections of synthetic compounds, and compound libraries generated by combinatorial chemistry. Libraries of compounds are well known in the art. Small molecule libraries can be obtained from various commercial entities, for example, SPECS and BioSPEC B.V. (Rijswijk, the Netherlands), Chembridge Corporation (San Diego, Calif.), Comgenex USA Inc., (Princeton, N.J.), Maybridge Chemical Ltd. (Cornwall, UK), and Asinex (Moscow, Russia). One representative example is known as DIVERSet.TM., available from ChemBridge Corporation, 16981 Via Tazon, Suite G, San Diego, Calif. 92127. DIVERSet.TM. contains between 10,000 and 50,000 drug-like, hand-synthesized small molecules. The compounds are pre-selected to form a "universal" library that covers the maximum pharmacophore diversity with the minimum number of compounds and is suitable for either high throughput or lower throughput screening. For descriptions of additional libraries, see, for example, Tan et al. "Stereoselective Synthesis of Over Two Million Compounds Having Structural Features Both Reminiscent of Natural Products and Compatible with Miniaturized Cell-Based Assays" Am. Chem Soc. 120, 8565-8566, 1998; Floyd et al. Prog Med Chem 36:91-168, 1999. Numerous libraries are commercially available, e.g., from AnalytiCon USA Inc., P.O. Box 5926, Kingwood, Tex. 77325; 3-Dimensional Pharmaceuticals, Inc., 665 Stockton Drive, Suite 104, Exton, Pa. 19341-1151; Tripos, Inc., 1699 Hanley Rd., St. Louis, Mo., 63144-2913, etc. In certain embodiments of the invention the methods are performed in a high-throughput format using techniques that are well known in the art, e.g., in multiwell plates, using robotics for sample preparation and dispensing, etc. Representative examples of various screening methods may be found, for example, in U.S. Pat. Nos. 5,985,829, 5,726,025, 5,972,621, and 6,015,692. The skilled practitioner will readily be able to modify and adapt these methods as appropriate.

[0057] The present invention further provides compositions, such as a fusion protein comprising the extracellular domain of a Sema6D protein or an active portion or fragment thereof and any active or functional fragment of an immunoglobulin molecule, as would be well known in the art. Also provided is a fusion protein comprising a transmembrane domain or an active portion or fragment thereof of a Sema6D protein and/or an intracellular domain or an active portion or fragment thereof of a Sema6D protein and an active or functional fragment of an immunoglobulin molecule. The present invention further provides a composition comprising a fusion protein of this invention in a pharmaceutically acceptable carrier. Additionally provided is a composition comprising an antibody or other ligand that specifically binds a Sema6D protein in a pharmaceutically acceptable carrier. Further provided herein is a nucleotide sequence encoding a fusion protein of this invention, which nucleotide sequence can be present in a composition comprising a pharmaceutically acceptable carrier. These compositions can be delivered to a subject of this invention in methods as described herein and in methods of treating disorders and diseases as described herein associated with increased or decreased T cell and/or B cell activation.

[0058] Thus, in further embodiments, the present invention provides a method of treating a T-cell-related disorder, B cell-related disorder and/or other white blood cell related disease or disorder in a subject, comprising administering to the subject a therapeutic amount of an inhibitor of Semaphorin 6D (Sema6D) activity on T cells, B cells and/or other white blood cells.

[0059] Nonlimiting examples of the diseases and disorders that can be treated according to the methods of this invention include but are not limited to leukemia (e.g., lymphoblastic leukemia, chronic myelogenous leukemia; promyelocytic leukemia, etc.; FIG. 1), lymphoma (e.g., B cell lymphomas, T cell lymphomas, Burkitts lymphoma, etc.), autoimmune diseases and disorders, inflammatory disorders and diseases, transplant rejection, psoriasis, asthmatic and allergic disorders and any combination thereof.

[0060] Nonlimiting examples of autoimmune disorders and diseases that can be treated and/or prevented by the methods of this invention include arthritis (e.g., rheumatoid arthritis or RA), multiple sclerosis (MS), diabetes (e.g., insulin dependent diabetes mellitus or IDDM), systemic lupus erythematosus (SLE), allergic reactions, asthmatic reaction, myasthenia gravis, Crohns' disease, regional enteritis, vasculitis, ulcerative colitis, Sjogren's syndrome, ankylosing spondylitis, polymyositis and any other autoimmune disorder now known or later identified.

[0061] An inflammatory disease or disorder of this invention can include but is not limited to inflammation of any organ, e.g., skin, heart, gastrointestinal tract, central nervous system, liver, pancreas, ovary, lung, eye, ear, throat, etc., such as, e.g., in psoriasis and general tissue fibrosis.

[0062] Additionally provided is a method of reducing the likelihood of transplant rejection (or increasing the likelihood of successful transplantation) in a transplant recipient, comprising administering to the transplant recipient an effective amount of an inhibitor of T cell and/or B cell activation of this invention. The reduction in the likelihood of transplant rejection or increase in the likelihood of successful transplantation is in comparison to the likelihood of transplant rejection or likelihood of successful transplantation in a transplant recipient that did not receive an inhibitor of T cell and/or B cell activation, as such likelihood would be known and/or determined according to art-known standards. Furthermore, the inhibitor of these methods can be administered to the transplant recipient at any time relative to the transplantation (i.e., before, after and/or simultaneously, in any combination).

[0063] In further embodiments, the present invention provides nucleic acids that inhibit T cell and/or B cell activation and nucleic acids that enhance T cell and/or B cell activation. These nucleic acids can be present in a composition comprising a pharmaceutically acceptable carrier. These nucleic acids can be present in vectors, plasmids, and/or other vehicles for delivery of nucleic acids to cells to carry out the methods of this invention, as described herein. These nucleic acids can encode inhibitors and enhancers of T cell and/or B cell activation and/or these nucleic acids can act directly to inhibit or enhance T cell and/or B cell activation, for example, by inhibiting or enhancing Sema6D activity at the nucleic acid level.

[0064] Also provided herein is a method of treating a disorder or disease associated with decreased T cell and/or B cell activation, comprising administering to the subject an effective amount of an enhancer of T cell and/or B cell activation as described herein.

[0065] In the methods provided herein for enhancing T cell and/or B cell activation in a subject, such an enhancement can be identified by comparison with T cell and/or B cell activation in a subject that did not receive the enhancer of this invention. Such comparative studies can be carried out according to well known protocols in the art for detecting and/or measuring T cell and/or B cell activation, and as described herein.

[0066] Thus, the present invention further provides a method of initiating, inducing and/or enhancing a T cell-mediated immune response and/or a B cell-mediated immune response in a subject, comprising administering to the subject an effective amount of an enhancer of Semaphorin 6D (Sema6D) activity on T cells and/or B cells.

[0067] The subject of this invention can be any subject in need of the immunomodulating effects of the methods of this invention. Such a subject can be any type of animal that is susceptible to diseases and disorders associated with increased T cell and/or B cell activation or decreased T cell and/or B cell activation and/or that can be treated by increasing or decreasing T cell and/or B cell activation according to the methods of this invention, as well as any animal to whom the compositions of this invention can be administered according to the methods of this invention. For example, an animal of this invention can be a mammal, a bird or a reptile. In certain embodiments, the subject of this invention is a human.

[0068] As noted above, the compositions of this invention can be administered to a cell of a subject or to a subject either in vivo or ex vivo. For administration to a cell of the subject in vivo, as well as for administration to the subject, the compositions of this invention can be administered orally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, subcutaneous injection, transdermally, extracorporeally, topically, by transdermal patch, or the like.

[0069] The exact amount of the composition required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the particular composition used, its mode of administration, the condition being treated and the like. Thus, it is not possible to specify an exact amount for every composition of this invention. However, an effective amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.

[0070] As an example, one or more doses of between about 0.1 .mu.g/kg and about 1000 mg/kg of an inhibitor and/or biologically active fragment of this invention can be administered orally and/or parenterally to a subject in whom it is desirable to decrease T cell activation, at hourly, daily and/or weekly intervals until an evaluation of the subject's clinical parameters indicate that the subject's condition has improved and/or the subject demonstrates the desired response.

[0071] If ex vivo methods are employed, cells or tissues can be removed and maintained outside the subject's body according to standard protocols well known in the art. The compositions of this invention can be introduced into the cells via known mechanisms for uptake of materials into cells (e.g., phagocytosis, pulsing onto class I MHC-expressing cells, liposomes, etc.). The cells can then be infused (e.g., in a pharmaceutically acceptable carrier) or transplanted back into the same subject or a different subject per standard methods for the cell or tissue type. Standard methods are known for transplantation or infusion of various cells into a subject.

[0072] The pharmaceutical compositions of this invention include those suitable for oral, rectal, topical, inhalation (e.g., via an aerosol) buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, intraarticular, intrapleural, intraperitoneal, intracerebral, intraarterial, or intravenous), topical (i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration, although the most suitable route in any given case will depend, as is well known in the art, on such factors as the species, age, gender and overall condition of the subject, the nature and severity of the condition being treated and/or on the nature of the particular composition (i.e., dosage, formulation) that is being administered.

[0073] Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tables, each containing a predetermined amount of the composition of this invention; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Oral delivery can be performed by complexing a composition of the present invention to a carrier capable of withstanding degradation by digestive enzymes in the gut of an animal. Examples of such carriers include plastic capsules or tablets, as known in the art. Such formulations are prepared by any suitable method of pharmacy, which includes the step of bringing into association the composition and a suitable carrier (which may contain one or more accessory ingredients as noted above). In general, the pharmaceutical composition according to embodiments of the present invention are prepared by uniformly and intimately admixing the composition with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet can be prepared by compressing or molding a powder or granules containing the composition, optionally with one or more accessory ingredients. Compressed tablets are prepared by compressing, in a suitable machine, the composition in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets are made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.

[0074] Pharmaceutical compositions suitable for buccal (sub-lingual) administration include lozenges comprising the composition of this invention in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the composition in an inert base such as gelatin and glycerin or sucrose and acacia.

[0075] Pharmaceutical compositions of this invention suitable for parenteral administration can comprise sterile aqueous and non-aqueous injection solutions of the composition of this invention, which preparations are preferably isotonic with the blood of the intended recipient. These preparations can contain anti-oxidants, buffers, bacteriostats and solutes, which render the composition isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions, solutions and emulsions can include suspending agents and thickening agents. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

[0076] The compositions can be presented in unit\dose or multi-dose containers, for example, in sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.

[0077] Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described. For example, an injectable, stable, sterile composition of this invention in a unit dosage form in a sealed container can be provided. The composition can be provided in the form of a lyophilizate, which can be reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection into a subject. The unit dosage form can be from about 0.1 .mu.g to about 10 grams of the composition of this invention. When the composition is substantially water-insoluble, a sufficient amount of emulsifying agent, which is physiologically acceptable, can be included in sufficient quantity to emulsify the composition in an aqueous carrier. One such useful emulsifying agent is phosphatidyl choline.

[0078] Pharmaceutical compositions suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by admixing the composition with one or more conventional solid carriers, such as for example, cocoa butter and then shaping the resulting mixture.

[0079] Pharmaceutical compositions of this invention suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers that can be used include, but are not limited to, petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. In some embodiments, for example, topical delivery can be performed by mixing a pharmaceutical composition of the present invention with a lipophilic reagent (e.g., DMSO) that is capable of passing into the skin.

[0080] Pharmaceutical compositions suitable for transdermal administration can be in the form of discrete patches adapted to remain in intimate contact with the epidermis of the subject for a prolonged period of time. Compositions suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3:318 (1986)) and typically take the form of an optionally buffered aqueous solution of the composition of this invention. Suitable formulations can comprise citrate or bis\tris buffer (pH 6) or ethanol/water and can contain from 0.1 to 0.2M active ingredient.

[0081] Furthermore, the compositions of this invention can be administered orally, intranasally, parenterally (e.g., intravenously), by intramuscular injection, by intraperitoneal injection, transdermally, extracorporeally, topically or the like. In the methods described herein which include the administration and uptake of exogenous DNA into the cells of a subject (i.e., gene transduction or transfection), the nucleic acids of the present invention can be in the form of naked. DNA or the nucleic acids can be in a vector for delivering the nucleic acids to the cells for expression of the polypeptides and/or fragments of this invention. The vector can be a commercially available preparation or can be constructed in the laboratory according to methods well known in the art.

[0082] Delivery of a nucleic acid or vector to cells can be via a variety of mechanisms. As one example, delivery can be via a liposome, using commercially available liposome preparations such as LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden, Germany) and TRANSFECTAM (Promega Biotec, Inc., Madison, Wis.), as well as other liposomes developed according to procedures standard in the art. In addition, the nucleic acid or vector of this invention can be delivered in vivo by electroporation, the technology for which is available from Genetronics, Inc. (San Diego, Calif.) as well as by means of a SONOPORATION machine (ImaRx Pharmaceutical Corp., Tucson, Ariz.).

[0083] As one example, vector delivery can be via a viral system, such as a retroviral vector system, which can package a recombinant retroviral genome. The recombinant retrovirus can then be used to infect and thereby deliver to the infected cells nucleic acid encoding the polypeptide and/or fragment of this invention. The exact method of introducing the exogenous nucleic acid into mammalian cells is, of course, not limited to the use of retroviral vectors. Other techniques are widely available for this procedure including the use of adenoviral vectors, alphaviral vectors, adeno-associated viral (AAV) vectors, lentiviral vectors, pseudotyped retroviral vectors and vaccinia viral vectors, as well as any other viral vectors now known or developed in the future. Physical transduction techniques can also be used, such as liposome delivery and receptor-mediated and other endocytosis mechanisms. This invention can be used in conjunction with any of these or other commonly used gene transfer methods.

[0084] As one example, if the nucleic acid of this invention is delivered to the cells of a subject in an adenovirus vector, the dosage for administration of adenovirus to humans can range from about 10.sup.7 to 10.sup.9 plaque forming units (pfu) per injection, but can be as high as 10.sup.12, 10.sup.15 and/or 10.sup.20 pfu per injection.

[0085] In some embodiments, a subject will receive a single injection of a viral vector comprising a nucleic acid of this invention. If additional injections are necessary, they can be repeated at daily/weekly/monthly intervals for an indefinite period and/or until the efficacy of the treatment has been established. As set forth herein, the efficacy of treatment can be determined by evaluating the symptoms and clinical parameters described herein and/or by detecting a desired immunological response.

[0086] The exact amount of the nucleic acid or vector required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the particular nucleic acid or vector used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every nucleic acid or vector. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.

[0087] Further provided are isolated nucleic acids comprising, consisting essentially of and/or consisting of nucleotide sequences that encode the proteins and fragments of this invention. In particular, the present invention provides a fusion protein comprising, consisting essentially of, and/or consisting of the amino acid sequence of

TABLE-US-00001 (Sema6D-Ig: primary amino acid sequence (886 aa) SEQ ID NO: 2 (MGFLLLWFCVLFLLVSRLRAVSFPEDDEPLNTVDYHYSRQYPVFRGRPS GNESQHRLDFQLMLKIRDTLYIAGRDQVYTVNLNEIPQTEVIPSKKLTWR SRQQDRENCAMKGKHKDECHNFIKVFVPRNDEMVFVCGTFNAFNPMCRYY RLRTLEYDGEEISGLARCPFDARQTNVALFADGKLYSATVADFLASDAVI YRSMGDGSALRTIKYDSKWIKEPHFLHAIEYGNYVYFFFREIAVEHNNLG KAVYSRVARICKNDMGGSQRVLEKHWTSFLKARLNCSVPGDSFFYFDVLQ SITDIIQINGIPTVVGVFTTQLNSIPGSAVCAFSMDDIEKVFKGRFKEQK TPDSVWTAVPEDKVPKPRPGCCAKHGLAEAYKTSIDFPDDTLAFIKSHPL MDSAVPPIADEPWFTKTRVRYRLTAIEVDRSAGPYQNYTVIFVGSEAGVV LKVLAKTSPFSLNDSVLLEEIEAYNPAKCSAESEEDRKVVSLQLDKDHHA LYVAFSSCVVRIPLSRCERYGSCKKSCIASRDPYCGWLSQGVCERVTLGM LPGGYEQDTEYGNTAHLGDCHDMEVSSSSVTTVASSPEITSKVIDTWRPK LTSSRKFVVQDDPNTSDFTDTISGIPKGVRWEVQSGESNQMVHMNVLITC VFAA): Sema6D seq (652 aa) (GSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK): Ig seq

[0088] Additionally provided is a nucleic acid comprising, consisting essentially of, and/or consisting of a nucleotide sequence that encodes an amino acid sequence comprising, consisting essentially of, and/or consisting of the amino acid sequence or a biologically active fragment of the amino acid sequence of SEQ ID NO:2 above. In a particular embodiment, the nucleic acid of this invention comprises the nucleotide sequence of

TABLE-US-00002 SEQ ID NO: 1: (GCCACCCATGGGGTTCC TTCTGCTTTG GTTCTGCGTG CTGTTCCTTC TGGTCTCCAG GTTACGGGCGGTCAGCTTCC CAGAAGACGA TGAGCCCCTC AACACGGTTG ACTATCACTA TTCAAGGCAATATCCGGTTT TTAGAGGACG CCCTTCAGGC AACGAATCGC AGCACAGGCT GGACTTTCAGCTGATGTTGA AAATTCGAGA CACACTTTAT ATTGCTGGCA GGGATCAAGT CTATACAGTGAACTTAAATG AAATCCCCCA AACAGAGGTG ATACCAAGCA AGAAGCTGAC GTGGAGGTCCAGACAGCAGG ATCGAGAAAATTGTGCTATG AAAGGCAAGC ATAAAGATGA ATGCCACAACTTCATCAAAG TCTTTGTCCC AAGAAATGAT GAGATGGTTT TTGTCTGTGG TACCAATGCTTTCAACCCGA TGTGCAGATA CTATAGGTTG AGAACGTTAG AGTATGATGG GGAAGAAATTAGTGGCCTGG CACGATGCCC GTTTGATGCC CGACAAACCA ATGTCGCCCT CTTTGCTGATGGAAAACTCT ATTCTGCCAC AGTGGCTGAT TTCCTGGCCA GTGATGCTGT CATTTACAGAAGCATGGGAG ATGGATCTGC CCTTCGCACA ATAAAATACG ATTCCAAGTG GATCAAAGAACCACACTTCC TTCATGCCAT AGAATATGGA AACTATGTCT ATTTCTTCTT CAGAGAAATCGCCGTGGAAC ATAATAACTT AGGCAAGGCT GTGTATTCCC GCGTGGCTCG CATTTGTAAAAACGACATGG GTGGCTCACA GCGGGTCCTG GAGAAACACT GGACTTCCTT CCTTAAGGCTCGGCTGAACT GCTCCGTTCC TGGAGATTCC TTTTTCTACT TCGACGTCCT GCAGTCTATAACAGACATAA TCCAAATCAATGGCATCCCC ACTGTGGTTG GGGTCTTCAC CACACAGCTCAACAGCATTCCTGGTTCTGC AGTCTGTGCC TTTAGCATGG ACGACATTGAGAAAGTGTTCAAAGGGCGGT TCAAAGAGCA GAAAACCCCA GACTCTGTTT GGACAGCAGT TCCCGAAGACAAAGTACCAA AACCAAGGCC TGGCTGTTGT GCCAAACACG GCCTCGCAGA AGCTTACAAGACCTCCATCG ACTTTCCAGA TGACACCCTG GCTTTCATCA AGTCCCACCC GCTGATGGACTCTGCCGTCC CACCCATTGC CGATGAGCCC TGGTTCACAA AGACACGGGT CAGGTACAGGTTGACAGCCA TCGAAGTGGA CCGTTCAGCA GGGCCATACC AAAACTACAC AGTCATCTTTGTTGGCTCTG AAGCTGGCGT GGTACTTAAA GTTTTGGCAA AGACCAGTCC TTTCTCTCTGAATGACAGTG TATTACTCGA AGAGATTGAA GCTTATAACC CAGCCAAGTG CAGCGCCGAGAGTGAGGAGG ACAGAAAGGT GGTCTCATTA CAGCTGGACA AGGATCACCA TGCTTTATACGTGGCCTTCT CTAGCTGCGT GGTCCGCATC CCCCTCAGCC GCTGTGAGCG CTACGGATCGTGTAAAAAGT CTTGCATTGC ATCACGTGAC CCGTACTGTG GTTGGTTAAG CCAGGGAGTTTGTGAGAGAG TGACCCTAGG GATGCTCCCT GGAGGATATG AGCAGGACACGGAGTACGGCAACACAGCCC ACCTAGGGGA CTGCCACGAC ATGGAGGTAT CCTCATCTTC TGTTACCACTGTGGCAAGTA GCCCAGAAAT TACATCTAAA GTGATTGATA CCTGGAGACC TAAACTGACGAGCTCCCGGA AATTTGTAGT TCAAGATGAC CCAAATACTT CTGATTTTAC TGATACTATATCAGGTATCC CAAAGGGTGT ACGGTGGGAA GTCCAGTCTG GAGAATCCAA TCAGATGGTCCACATGAATG TCCTCATCAC CTGCGTGTTT GCCGCTGGAT CCGAGCCCAA ATCTTGTGACA AAACTCACAC ATGCCCACCG TGCCCAGCAC CTGAACTCCT GGGGGGACCG TCAGTCTTCC TCTTCCCCCC AAAACCCAAG GACACCCTCA TGATCTCCCG GACCCCTGAG GTCACATGCG TGGTGGTGGA CGTGAGCCAC GAAGACCCTGAGGTCAAGTT CAACTGGTAC GTGGACGGCG TGGAGGTGCA TAATGCCAAG ACAAAGCCGCGGGAGGAGCA GTACAACAGC ACGTACCGTG TGGTCAGCGT CCTCACCGTC CTGCACCAGGACTGGCTGAA TGGCAAGGAG TACAAGTGCA AGGTCTCCAA CAAAGCCCTC CCAGCCCCCATCGAGAAAAC CATCTCCAAA GCCAAAGGGC AGCCCCGAGA ACCACAGGTG TACACCCTGCCCCCATCCCG GGATGAGCTG ACCAAGAACC AGGTCAGCCT GACCTGCCTG GTCAAAGGCTTCTATCCCAG CGACATCGCC GTGGAGTGGG AGAGCAATGG GCAGCCGGAG AACAACTACAAGACCACGCC TCCCGTGCTG GACTCCGACG GCTCCTTCTT CCTCTACAGC AAGCTCACCGTGGACAAGAG CAGGTGGCAG CAGGGGAACG TCTTCTCATG CTCCGTGATG CATGAGGCTCTGCACAACCA CTACACGCAG AAGAGCCTCT CCCTGTCTCC GGGTAAATGA).

[0089] Further provided herein is a nucleic acid that is the complement of each and any of the nucleic acids of this invention.

[0090] A variety of protocols for detecting the presence of and/or measuring the amount of Sema6D protein, using, e.g., polyclonal and/or monoclonal antibodies specific for the Sema6D protein, are known in the art. Examples of such protocols include, but are not limited to, enzyme immunoassays (EIA), agglutination assays, immunoblots (Western blot; dot/slot blot, etc.), radioimmunoassays (RIA), immunodiffusion assays, chemiluminescence assays, antibody library screens, expression arrays, enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA), immunoprecipitation, Western blotting, competitive binding assays, immunofluorescence, immunohistochemical staining precipitation/flocculation assays and fluorescence-activated cell sorting (FACS). These and other assays are described, among other places, in Hampton et al. (Serological Methods, a Laboratory Manual, APS Press, St Paul, Minn. (1990)) and Maddox et al. (J. Exp. Med. 158:1211-1216 (1993)).

[0091] Furthermore, a number of assays for identification, detection and/or amplification of nucleic acid sequences (e.g., Sema6D mRNA) are well known in the art. For example, various protocols can be employed in the methods of this invention to amplify nucleic acid. As used herein, the term "oligonucleotide-directed amplification procedure" refers to template-dependent processes that result in an increase in the concentration of a specific nucleic acid molecule relative to its initial concentration, or in an increase in the concentration of a detectable signal, such as amplification. As used herein, the term "oligonucleotide directed mutagenesis procedure" is intended to refer to a process that involves the template-dependent extension of a primer molecule. The term "template dependent process" refers to nucleic acid synthesis of a RNA or a DNA molecule wherein the sequence of the newly synthesized strand of nucleic acid is dictated by the well-known rules of complementary base pairing. Typically, vector mediated methodologies involve the introduction of the nucleic acid fragment into a DNA or RNA vector, the clonal amplification of the vector, and the recovery of the amplified nucleic acid fragment. Examples of such methodologies are provided in U.S. Pat. No. 4,237,224 (incorporated herein by reference in its entirety). Nucleic acids, used as a template for amplification methods can be isolated from cells according to standard methodologies (Sambrook et al., 1989). The nucleic acid can be genomic DNA or fractionated or whole cell RNA. Where RNA is used, it may be desired to convert the RNA to a complementary DNA. In one embodiment, the RNA can be whole cell RNA and is used directly as the template for amplification.

[0092] Pairs of primers that selectively hybridize to nucleic acids corresponding to the Sema6D gene or coding sequence are contacted with the nucleic acid under conditions that permit selective hybridization. The term "primer," as defined herein, is meant to encompass any nucleic acid that is capable of priming the synthesis of a nascent nucleic acid in a template dependent process. Typically, primers are oligonucleotides from ten to twenty bases in length, but shorter (e.g., 6, 7, 8, or 9 bases) or longer (e.g., 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50 bases) sequences can be employed. Primers can in double-stranded or single-stranded form, although the single-stranded form is commonly used.

[0093] Once hybridized, the nucleic acid: primer hybridization complex is contacted with one or more enzymes that facilitate template-dependent nucleic acid synthesis. Multiple rounds of amplification, also referred to as "cycles," are conducted until a sufficient amount of amplification product is produced.

[0094] Next, the amplification product is detected. In some embodiments, the detection can be performed by visual means. Alternatively, the detection can involve indirect identification of the product via chemiluminescence, radioactive scintigraphy of incorporated radiolabel or fluorescence or chemiluminescence label or even via a system using electrical or thermal impulse signals (e.g., Affymax technology).

[0095] A number of template dependent processes are available to amplify the sequences present in a given template sample. One of the best-known amplification methods is the polymerase chain reaction (referred to as PCR), which is described in detail in U.S. Pat. Nos. 4,683,195, 4,683,202 and 4,800,159, each incorporated herein by reference in its entirety.

[0096] Briefly, in PCR, two primer sequences are prepared that are complementary to regions on opposite complementary strands of the target sequence. An excess of deoxynucleoside triphosphates is added to a reaction mixture along with a DNA polymerase, e.g., a Taq polymerase. If the particular target sequence is present in a sample, the primers will bind to the target sequence and the polymerase will cause the primers to be extended along the sequence by adding on nucleotides. By raising and lowering the temperature of the reaction mixture, the extended primers will dissociate from the target sequence to form reaction products, excess primers will bind to the target sequence and to the reaction products and the process is repeated.

[0097] A reverse transcriptase PCR amplification procedure can be performed in order to quantify the amount of mRNA amplified. Methods of reverse transcribing RNA into cDNA are well known in the art (e.g., Sambrook et al., 1989). Alternative methods for reverse transcription employ thermostable, RNA-dependent DNA polymerases. These methods are described, for example, in PCT Publication No. WO 90/07641, filed Dec. 21, 1990, incorporated herein by reference in its entirety. Polymerase chain reaction methodologies are well known in the art.

[0098] Another method for nucleic acid amplification is the ligase chain reaction ("LCR"), disclosed in Eur. Pat. Appl. No. 320308, incorporated herein by reference in its entirety. In LCR, two complementary probe pairs are prepared and in the presence of the target sequence, each pair will bind to opposite complementary strands of the target such that they abut. In the presence of a ligase, the two probe pairs will link to form a single unit. By temperature cycling, as in PCR, bound ligated units dissociate from the target and then serve as "target sequences" for ligation of excess probe pairs. U.S. Pat. No. 4,883,750 (incorporated by reference herein in its entirety) describes a method similar to LCR for binding probe pairs to a target sequence.

[0099] Qbeta replicase (Q.beta.R), described in PCT Application No. PCT/US87/00880, (incorporated herein by reference), can also be used as an amplification method in the present invention. In this method, a replicative sequence of RNA that has a region complementary to that of a target is added to a sample in the presence of an RNA polymerase. The polymerase will copy the replicative sequence that can then be detected.

[0100] An isothermal amplification method, in which restriction endonucleases and ligases are used to achieve the amplification of target molecules that contain nucleotide 5'-[alpha-thio]triphosphates in one strand of a restriction site may also be useful in the amplification of nucleic acids in the present invention.

[0101] Strand Displacement Amplification (SDA), described in U.S. Pat. Nos. 5,455,166, 5,648,211, 5,712,124 and 5,744,311, each incorporated herein by reference, is another method of carrying out isothermal amplification of nucleic acids which involves multiple rounds of strand displacement and synthesis, i.e., nick translation. A similar method, called Repair Chain Reaction (RCR), involves annealing several probes throughout a region targeted for amplification, followed by a repair reaction in which only two of the four bases are present.

[0102] The other two bases can be added as biotinylated derivatives for easy detection. A similar approach is used in SDA. Target specific sequences can also be detected using a cyclic probe reaction (CPR). In CPR, a probe having 3' and 5' sequences of non-specific DNA and a middle sequence of specific RNA is hybridized to DNA that is present in a sample. Upon hybridization, the reaction is treated with RNase H, and the products of the probe identified as distinctive products that are released after digestion. The original template is annealed to another cycling probe and the reaction is repeated.

[0103] Still another amplification method, as described in Intl. Pat. Appl. No. PCT/US89/01025, which is incorporated herein by reference in its entirety, may be used in accordance with the present invention. In one embodiment, "modified" primers are used in a PCR-like, template- and enzyme-dependent synthesis. The primers may be modified by labeling with a capture moiety (e.g., biotin) and/or a detectable moiety (e.g., enzyme). In another embodiment, an excess of labeled probes is added to a sample. In the presence of the target sequence, the probe binds and is cleaved catalytically. After cleavage, the target sequence is released intact, available to be bound by excess probe. Cleavage of the labeled probe signals the presence of the target sequence.

[0104] Other nucleic acid amplification procedures include transcription-based amplification systems (TAS), including nucleic acid sequence based amplification (NASBA) and 3SR (PCT Publication No. WO 88/10315, incorporated herein by reference). In NASBA, the nucleic acids can be prepared for amplification by standard phenol/chloroform extraction, heat denaturation of a clinical sample, treatment with lysis buffer and minispin columns for isolation of DNA and RNA or guanidinium chloride extraction of RNA. These amplification techniques involve annealing a primer that has target specific sequences. Following polymerization, DNA/RNA hybrids are digested with RNase H while double stranded DNA molecules are heat denatured again. In either case the single stranded DNA is made fully double stranded by addition of second target specific primer, followed by polymerization. The double-stranded DNA molecules are then multiply transcribed by an RNA polymerase such as T7, T3 or SP6. In an isothermal cyclic reaction, the RNAs are reverse transcribed into single stranded DNA, which is then converted to double-stranded DNA, and then transcribed once again with an RNA polymerase such as T7, T3 or SP6. The resulting products, whether truncated or complete, indicate target specific sequences.

[0105] European Pat. Appl. No. 329822 (incorporated herein by reference in its entirety) discloses a nucleic acid amplification process involving cyclically synthesizing single stranded RNA (ssRNA), ssDNA, and double-stranded DNA (dsDNA), which can be used in accordance with the present invention. The ssRNA is a template for a first primer oligonucleotide, which is elongated by reverse transcriptase (RNA-dependent DNA polymerase). The RNA is then removed from the resulting DNA:RNA duplex by the action of ribonuclease H (RNase H, an RNase specific for RNA in duplex with either DNA or RNA).

[0106] The resultant ssDNA is a template for a second primer, which also includes the sequences of an RNA polymerase promoter (exemplified by T7 RNA polymerase) 5' to its homology to the template. This primer is then extended by DNA polymerase (exemplified by the large Klenow fragment of E. coli DNA polymerase I), resulting in a double-stranded DNA (dsDNA) molecule, having a sequence identical to that of the original RNA between the primers and having additionally, at one end, a promoter sequence. This promoter sequence can be used by the appropriate RNA polymerase to make many RNA copies of the DNA. These copies can then re-enter the cycle, leading to very swift amplification. With proper choice of enzymes, this amplification can be done isothermally without addition of enzymes at each cycle. Because of the cyclical nature of this process, the starting sequence can be chosen to be in the form of either DNA or RNA.

[0107] PCT Application WO 89/06700 (incorporated herein by reference in its entirety) discloses a nucleic acid sequence amplification scheme based on the hybridization of a promoter/primer sequence to a target single-stranded DNA (ssDNA), followed by transcription of many RNA copies of the sequence. This scheme is not cyclic, i.e., new templates are not produced from the resultant RNA transcripts. Other amplification methods include "RACE" and "one-sided PCR" (Frohman, 1990, incorporated by reference herein).

[0108] Methods based on ligation of two (or more) oligonucleotides in the presence of nucleic acid having the sequence of the resulting "di-oligonucleotide," thereby amplifying the dioligonucleotide, can also be used in the amplification step of the present invention.

[0109] Following any amplification, it is desirable to separate the amplification product from the template and the excess primer for the purpose of determining whether specific amplification has occurred. In one embodiment, amplification products can be separated by agarose, agarose-acrylamide or polyacrylamide gel electrophoresis using standard methods (e.g., Sambrook et al., 1989).

[0110] Alternatively, chromatographic techniques can be used to effect separation. There are many kinds of chromatography that can be used in the present invention: such as, for example, adsorption, partition, ion exchange and molecular sieve, as well as many specialized techniques for using them including column, paper, thin-layer and gas chromatography.

[0111] Amplification products must be visualized in order to confirm amplification of the target sequences. One typical visualization method involves staining of a gel with ethidium bromide and visualization under UV light. Alternatively, if the amplification products are integrally labeled with radio- or fluorometrically-labeled nucleotides, the amplification products can then be exposed to x-ray film or visualized under the appropriate stimulating spectra, following separation.

[0112] In some embodiments, visualization is achieved indirectly. Following separation of amplification products, a labeled, nucleic acid probe is brought into contact with the amplified target sequence. The probe preferably is conjugated to a chromophore but may be radiolabeled. In another embodiment, the probe is conjugated to a binding partner, such as an antibody or biotin, and the other member of the binding pair carries a detectable moiety.

[0113] In other embodiments, detection can be by Southern or Northern blotting and hybridization with a labeled probe. The techniques involved in Southern and Northern blotting are well known to those of skill in the art and can be found in many standard books on molecular protocols (e.g., Sambrook et al., 1989). Briefly, amplification products are separated by gel electrophoresis. The gel is then contacted with a membrane, such as nitrocellulose, permitting transfer of the nucleic acid and noncovalent binding. Subsequently, the membrane is incubated with a chromophore-conjugated probe that is capable of hybridizing with a target amplification product. Detection is by exposure of the membrane to x-ray film or ion-emitting detection devices. One example of the foregoing is described in U.S. Pat. No. 5,279,721, incorporated by reference herein, which discloses an apparatus and method for the automated electrophoresis and transfer of nucleic acids. The apparatus permits electrophoresis and blotting without external manipulation of the gel.

[0114] Additionally, a wide variety of labeling and conjugation techniques are known in the art that are used in various nucleic acid detection and amplification assays. Methods for producing labeled hybridization probes and/or PCR or other ligation primers for detecting and/or amplifying nucleic acid sequences can include, for example, oligolabeling, nick translation and end-labeling, as well as other well known methods. Alternatively, nucleic acid sequences encoding the polypeptides of this invention, and/or any functional fragment thereof, can be cloned into a plasmid or vector for detection and amplification. Such plasmids and vectors are well known in the art and are commercially available. It is also contemplated that the methods of this invention can be conducted using a variety of commercially available kits (e.g., Pharmacia & Upjohn; Promega; U.S. Biochemical Corp.). Suitable reporter molecules or labels, which can be used for ease of detection, include, for example, radionuclides, enzymes, fluorescence agents, chemiluminescence agents and chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles and the like as are well known in the art.

[0115] The present invention further includes isolated polypeptides, peptides, proteins, fragments, domains and/or nucleic acid molecules that are substantially equivalent to those described for this invention. As used herein, "substantially equivalent" can refer both to nucleic acid and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitutions, deletions, or additions, the net effect of which does not result in an undesirable adverse functional dissimilarity between reference and subject sequences. In some embodiments, this invention can include substantially equivalent sequences that have an adverse functional dissimilarity. For purposes of the present invention, sequences having equivalent biological activity and equivalent expression characteristics are considered substantially equivalent.

[0116] The invention further provides homologs, as well as methods of obtaining homologs, of the polypeptides and/or fragments of this invention. As used herein, an amino acid sequence or protein is defined as a homolog of a polypeptide or fragment of the present invention if it shares significant homology to one of the polypeptides and/or fragments of the present invention. Significant homology means at least 60%, 65%, 75%, 80%, 85%, 90%, 95%, 98% and/or 100% homology with another amino acid sequence. Specifically, by using the nucleic acids disclosed herein as a probe or as primers, and techniques such as PCR amplification and colony/plaque hybridization, one skilled in the art can identify homologs of the polypeptides and/or fragments of this invention.

[0117] In further embodiments, the nucleic acids encoding the polypeptides and/or fragments of this invention can be part of a recombinant nucleic acid construct comprising any combination of restriction sites and/or functional elements as are well known in the art that facilitate molecular cloning and other recombinant DNA manipulations. Thus, the present invention further provides a recombinant nucleic acid construct comprising a nucleic acid encoding a polypeptide and/or biologically active fragment of this invention.

[0118] The present invention further provides a vector comprising a nucleic acid encoding a polypeptide and/or fragment of this invention. The vector can be an expression vector which contains all of the genetic components required for expression of the nucleic acid in cells into which the vector has been introduced, as are well known in the art. The expression vector can be a commercial expression vector or it can be constructed in the laboratory according to standard molecular biology protocols. The expression vector can comprise viral nucleic acid including, but not limited to, poxvirus, vaccinia virus, adenovirus, retrovirus and/or adeno-associated virus nucleic acid. The nucleic acid or vector of this invention can also be in a liposome or a delivery vehicle, which can be taken up by a cell via receptor-mediated or other type of endocytosis.

[0119] The nucleic acid of this invention can be in a cell, which can be a cell expressing the nucleic acid whereby a polypeptide and/or biologically active fragment of this invention is produced in the cell. In addition, the vector of this invention can be in a cell, which can be a cell expressing the nucleic acid of the vector whereby a polypeptide and/or biologically active fragment of this invention is produced in the cell. It is also contemplated that the nucleic acids and/or vectors of this invention can be present in a host animal (e.g., a transgenic animal), which expresses the nucleic acids of this invention and produces the polypeptides and/or fragments of this invention.

[0120] The nucleic acid encoding the polypeptide and/or fragment of this invention can be any nucleic acid that functionally encodes the polypeptides and/or fragments of this invention. To functionally encode the polypeptides and/or fragments (i.e., allow the nucleic acids to be expressed), the nucleic acid of this invention can include, for example, expression control sequences, such as an origin of replication, a promoter, an enhancer and necessary information processing sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites and transcriptional terminator sequences.

[0121] Nonlimiting examples of expression control sequences that can be present in a nucleic acid of this invention include promoters derived from metallothionine genes, actin genes, immunoglobulin genes, CMV, SV40, adenovirus, bovine papilloma virus, etc. A nucleic acid encoding a selected polypeptide and/or fragment can readily be determined based upon the genetic code for the amino acid sequence of the selected polypeptide and/or fragment and many nucleic acids will encode any selected polypeptide and/or fragment. Modifications in the nucleic acid sequence encoding the polypeptide and/or fragment are also contemplated. Modifications that can be useful are modifications to the sequences controlling expression of the polypeptide and/or fragment to make production of the polypeptide and/or fragment inducible or repressible as controlled by the appropriate inducer or repressor. Such methods are standard in the art. The nucleic acid of this invention can be generated by means standard in the art, such as by recombinant nucleic acid techniques and/or by synthetic nucleic acid synthesis or in vitro enzymatic synthesis.

[0122] The nucleic acids and/or vectors of this invention can be transferred into a host cell (e.g., a prokaryotic or eukaryotic cell) by well-known methods, which vary depending on the type of cell host. For example, calcium chloride transfection is commonly used for prokaryotic cells, whereas calcium phosphate treatment, transduction and/or electroporation can be used for other cell hosts.

[0123] As used herein, "a" or "an" or "the" can mean one or more than one. For example, "a" cell can mean one cell or a plurality of cells.

[0124] Also as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

[0125] Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of .+-.20%, .+-.10%, .+-.5%, .+-.1%, .+-.0.5%, or even .+-.0.1% of the specified amount.

[0126] A T cell of this invention includes but is not limited to CD4+ T cells, T regulatory cells, double positive (CD4+, CD8+) T cells and double negative (CD4-, CD8-) T cells. A B cell of this invention is, e.g., an antibody producing cell and can be for example, a plasma B cell, a memory B cell, a B-1 cell or a B-2 cell.

[0127] As used herein, "T cell activation" or "B cell activation" means a process or activity that causes T cells or B cells to exhibit a phenotype of an activated T cell or B cell, and "activated T cell" or "activated B cell" describes T cells or B cells that can exhibit some of the following phenotypes: T cell activation can be measured by methods not limited to the following: CD69, CD25, HLA-DR, CD62L and/or CD154 expression and/or the production of IL-2, calcium mobilization, ZAP-70 phosphorylation, LAT phosphorylation, Lck phosphorylation, NF-.kappa.B activation, MEK activation, NFAT activation, Ap-1 activation; T cell proliferation and cytotoxicity (defined as the ability to kill target cells). B cell activation can be measured by any methods known in the art to identify antigen-mediated activation, T cell dependent activation, T cell-independent activation, etc.

[0128] Nonlimiting examples of a Sema6D protein of this invention have an amino acid sequence as shown in the Sequence Listing. For example SEQ ID NOs:22, 24, 26, 28, 30 and are examples of human isoforms of a Sema6D protein. Other Sema6D proteins as are known in the art and as described herein are also included in the present invention.

[0129] As used herein, "modulate," "modulates" or "modulation" refers to enhancement (e.g., an increase) or inhibition (e.g., diminished, reduced or suppressed) of the specified activity. The term "enhancement," "enhance," "enhances," or "enhancing" refers to an increase in the specified parameter (e.g., at least about a 1.1-fold, 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold or more increase) and/or an increase in the specified activity of at least about 5%, 10%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95%, 97%, 98%, 99% or 100%. The term "inhibit," "diminish," "reduce" or "suppress" refers to a decrease in the specified parameter (e.g., at least about a 1.1-fold, 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold or more decrease) and/or a decrease or reduction in the specified activity of at least about 5%, 10%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95%, 97%, 98%, 99% or 100%. In particular embodiments, the inhibition or reduction results in little or essentially no detectable activity (at most, an insignificant amount, e.g., less than about 10% or about 5%).

[0130] The term "overexpress," "overexpresses" or "overexpression" as used herein in connection with isolated nucleic acids encoding Sema6D refers to expression that results in higher levels of Sema6D polypeptide than exist in the cell in its native (control) state. Overexpression of Sema6D can result in levels that are 25%, 50%, 100%, 200%, 500%, 1000%, 2000% or higher in the cell. Further, nucleic acid encoding Sema6D can be introduced into a cell that does not produce the specified form of Sema6D (e.g., an isoform) encoded by the transgene or does so only at negligible levels.

[0131] The term "enhance," "enhances," "enhancing" or "enhancement" with respect to T cell or B cell activation refers to an increase in T cell or B cell activation (e.g., at least about a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelve-fold, or even fifteen-fold or more increase), for example, in response to a substance that enhances T cell or B cell activation. Alternatively, these terms can refer to increasing expression of nucleic acid encoding Sema6D in a cell or subject in response to an enhancer as compared with the amount of Sema6D nucleic acid expression in the absence of the enhancer.

[0132] A "fusion polypeptide" is a polypeptide produced when two heterologous nucleotide sequences or fragments thereof coding for two (or more) different polypeptides not found fused together in nature are fused together in the correct translational reading frame. Illustrative fusion polypeptides include, but are not limited to a fusion of the extracellular domain of Sema6D or active fragment thereof to an immunoglobulin fragment as described herein. Ig fragments from human, mouse, rat, goat, rabbit can all be used. In addition, mutations in the Fc binding sequence do not alter the function of the protein, and these can also be used. When used in animals, it is best to use the IgG fusion that is from the same species. For example, using human IgG fusion protein to perform in mice may cause immunogenicity in the long run, although for short term experiments, this is less of a concern.

[0133] As used herein, a "functional" or "active" polypeptide is one that retains at least one biological activity normally associated with that polypeptide. Preferably, a "functional" polypeptide retains all of the activities possessed by the unmodified peptide. By "retains" biological activity, it is meant that the polypeptide retains at least about 50%, 60%, 75%, 85%, 90%, 95%, 97%, 98%, 99%, or more, of the biological activity of the native polypeptide (and can even have a higher level of activity than the native polypeptide). A "non-functional" polypeptide is one that exhibits essentially no detectable biological activity normally associated with the polypeptide (e.g., at most, only an insignificant amount, e.g., less than about 10% or even 5%).

[0134] As used herein, the transitional phrase "consisting essentially of" means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim, "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. See, In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in the original); see also MPEP .sctn. 2111.03. Thus, the term "consisting essentially of" when used in a claim of this invention is not intended to be interpreted to be equivalent to "comprising."

[0135] "Isolated" as used herein means the nucleic acid or protein or protein fragment of this invention is sufficiently free of contaminants or cell components with which nucleic acids or proteins normally occur. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to provide the nucleic acid or protein or protein fragment in a form in which it can be used therapeutically.

[0136] "Epitope" or "antigenic epitope" or "antigenic peptide" as used herein means a specific amino acid sequence which, when present in the proper conformation, provides a reactive site for an antibody or T cell receptor. The identification of epitopes on antigens can be carried out by immunology protocols that are well known in the art. Typically, an epitope or antigenic peptide can be 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45 or 50 amino acids in length.

[0137] As used herein, the term "polypeptide" or "protein" is used to describe a chain of amino acids that correspond to those encoded by a nucleic acid. A polypeptide of this invention can be a peptide, which usually describes a chain of amino acids of from two to about 30 amino acids. The term polypeptide as used herein also describes a chain of amino acids having more than 30 amino acids and can be a fragment or domain of a protein or a full length protein. Furthermore, as used herein, the term polypeptide can refer to a linear chain of amino acids or it can refer to a chain of amino acids that has been processed and folded into a functional protein. It is understood, however, that 30 is an arbitrary number with regard to distinguishing peptides and polypeptides and the terms can be used interchangeably for a chain of amino acids. The polypeptides of the present invention are obtained by isolation and purification of the polypeptides from cells where they are produced naturally, by enzymatic (e.g., proteolytic) cleavage, and/or recombinantly by expression of nucleic acid encoding the polypeptides or fragments of this invention. The polypeptides and/or fragments of this invention can also be obtained by chemical synthesis or other known protocols for producing polypeptides and fragments.

[0138] The amino acid sequences disclosed herein are presented in the amino to carboxy direction, from left to right. Nucleotide sequences are presented herein in the 5' to 3' direction, from left to right. It is intended that the nucleic acids of this invention can be either single or double stranded (i.e., including the complementary nucleic acid). A nucleic acid of this invention can be the complement of a nucleic acid described herein.

[0139] A "biologically active fragment" or "active fragment" or "functional fragment" or "functionally active fragment" as used herein includes a polypeptide of this invention that comprises a sufficient number of amino acids to have one or more of the biological activities of the polypeptides of this invention. Such biological activities can include, but are not limited to, in any combination, binding activity, immunomodulating activity and/or immunogenic activity, as well as any other activity now known or later identified for the polypeptides and/or fragments of this invention. A fragment of a polypeptide of this invention can be produced by methods well known and routine in the art. Fragments of this invention can be produced, for example, by enzymatic or other cleavage of naturally occurring peptides or polypeptides or by synthetic protocols that are well known. Such fragments can be tested for one or more of the biological activities of this invention according to the methods described herein, which are routine methods for testing activities of polypeptides, and/or according to any art-known and routine methods for identifying such activities. Such production and testing to identify biologically active fragments of the polypeptides described herein would be well within the scope of one of ordinary skill in the art and would be routine.

[0140] Fragments of the polypeptides of this invention are preferably at least about ten amino acids in length and retain one or more of the biological activities (e.g., immunomodulating; binding) and/or the immunological activities of the proteins of this invention. Examples of the fragments of this invention include, but are not intended to be limited to, the following fragments identified by the amino acid number as shown in the Sequence Listing herein: Amino acids 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-210, 210-220, 220-230, 230-240, 240-250, 1-25, 1-50, 1-67, 1-75, 1-100, 1-125, 1-135, 1-145, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-250, 68-180, 183-223, 50-100, 100-200, 200-300, 300-400, 400-500, 500-600, 600-650, etc.

[0141] It is understood that this list is exemplary only and that a fragment of this invention can be any amino acid sequence containing any combination of contiguous amino acids that are numbered in the Sequence Listing as amino acids 1 through 652, even if that combination is not specifically recited as an example herein. It is also understood that these fragments can be combined in any order or amount. For example, fragment 1-10 can be combined with fragment 10-20 to produce a fragment of amino acids 1-20. As another example, fragment 1-20 can be combined with fragment 50-60 to produce a single fragment of this invention having 31 amino acids (AA 10-20 and AA 50-60). Also fragments can be present in multiple numbers and in any combination in a fragment of this invention. Thus, for example, fragment 1-150 can be combined with a second fragment 1-150 and/or combined with fragment 400-500 to produce a fragment of this invention.

[0142] The terms "homology," "identity" and "complementarity" as used herein refer to a degree of similarity between two or more sequences. There may be partial homology or complete homology (i.e., identity). A partially complementary sequence that at least partially inhibits an identical sequence from hybridizing to a target nucleic acid is referred to as "substantially homologous." The inhibition of hybridization of the completely complementary sequence to the target sequence can be examined using a hybridization assay (Southern or Northern blot, solution hybridization and the like) under conditions of low stringency. A substantially homologous sequence or hybridization probe will compete for and inhibit the binding of a completely homologous sequence to the target sequence under conditions of low stringency, as this term is known in the art. This is not to say that conditions of low stringency are such that non-specific binding is permitted; low stringency conditions require that the binding of two sequences to one another be a specific (i.e., selective) interaction. The absence of non-specific binding can be tested by the use of a second target sequence that lacks even a partial degree of complementarity (e.g., less than about 30% identity). In the absence of non-specific binding, the probe will not hybridize to the second non-complementary target sequence.

[0143] The term "hybridization" as used herein refers to any process by which a first strand of nucleic acid binds with a second strand of nucleic acid through base pairing. Nucleic acids encoding the polypeptides and/or fragments of this invention can be detected by DNA-DNA or DNA-RNA hybridization and/or amplification using probes, primers and/or fragments of polynucleotides encoding the polypeptides and/or fragments of this invention and/or designed to detect and/or amplify the nucleic acids of this invention.

[0144] The term "hybridization complex" as used herein refers to a complex formed between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary G and C bases and between complementary A and T bases; these hydrogen bonds may be further stabilized by base stacking interactions. The two complementary nucleic acid sequences hydrogen bond in an antiparallel configuration. A hybridization complex may be formed in solution (e.g., C.sub.0t or R.sub.0t analysis) or between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells and/or nucleic acids have been fixed).

[0145] The term "nucleotide sequence" refers to a heteropolymer of nucleotides or the sequence of these nucleotides. The terms "nucleic acid," "oligonucleotide" and "polynucleotide" are also used interchangeably herein to refer to a heteropolymer of nucleotides. Generally, nucleic acid segments provided by this invention may be assembled from fragments of the genome and short oligonucleotide linkers, or from a series of oligonucleotides, or from individual nucleotides, to provide a synthetic nucleic acid which is capable of being expressed in a recombinant transcriptional unit comprising regulatory elements derived from a microbial or viral operon, or a eukaryotic gene. Nucleic acids of this invention can comprise a nucleotide sequence that can be identical in sequence to the sequence which is naturally occurring or, due to the well-characterized degeneracy of the nucleic acid code, can include alternative codons that encode the same amino acid as that which is found in the naturally occurring sequence. Furthermore, nucleic acids of this invention can comprise nucleotide sequences that can include codons which represent conservative substitutions of amino acids as are well known in the art, such that the biological activity of the resulting polypeptide and/or fragment is retained.

[0146] The term "probe" or "primer" includes naturally occurring and/or recombinant and/or chemically synthesized single- and/or double-stranded nucleic acids. They can be labeled for detection by nick translation, Klenow fill-in reaction, PCR and/or other methods well known in the art. Probes and primers of the present invention, their preparation and/or labeling are described in Sambrook et al. 1989. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, NY and Ausubel et al. 1989. Current Protocols in Molecular Biology, John Wiley & Sons, New York N.Y., both of which are incorporated herein by reference in their entirety for these teachings.

[0147] The term "stringent" as used herein refers to hybridization conditions that are commonly understood in the art to define the conditions of the hybridization procedure. Stringency conditions can be low, high or medium, as those terms are commonly know in the art and well recognized by one of ordinary skill. In various embodiments, stringent conditions can include, for example, highly stringent (i.e., high stringency) conditions (e.g., hybridization in 0.5 M NaHPO.sub.4, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65.degree. C., and washing in 0.1.times.SSC/0.1% SDS at about 68.degree. C.), and/or moderately stringent (i.e., medium stringency) conditions (e.g., washing in 0.2.times.SSC/0.1% SDS at about 42.degree. C.).

[0148] "Amplification" as used herein includes the production of multiple copies of a nucleic acid molecule and is generally carried out using polymerase chain reaction (PCR) and/or any other amplification technologies as are well known in the art (Dieffenbach and Dveksler. 1995. PCR Primer, a Laboratory Manual, Cold Spring Harbor Press, Plainview, N.Y.).

[0149] "Effective amount" as used herein refers to an amount of a compound, agent, substance or composition of this invention that is sufficient to produce a desired effect, which can be a therapeutic effect. The effective amount will vary with the age, general condition of the subject, the severity of the condition being treated, the particular compound, agent, substance or composition administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used if any, and like factors within the knowledge and expertise of those skilled in the art. As appropriate, an "effective amount" in any individual case can be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation. (Remington, The Science And Practice of Pharmacy (20th ed. 2000)).

[0150] A "pharmaceutically acceptable" component such as a salt, carrier, excipient or diluent of a composition according to the present invention is a component that (i) is compatible with the other ingredients of the composition in that it can be combined with the compositions of the present invention without rendering the composition unsuitable for its intended purpose, and (ii) is suitable for use with subjects as provided herein without undue adverse side effects (such as toxicity, irritation, and allergic response). Side effects are "undue" when their risk outweighs the benefit provided by the composition. Non-limiting examples of pharmaceutically acceptable components (e.g., pharmaceutically acceptable carriers) include any of the standard pharmaceutical carriers such as phosphate buffered saline solutions, water, emulsions such as oil/water emulsion, microemulsions and various types of wetting agents. In particular, it is intended that a pharmaceutically acceptable carrier be a sterile carrier that is formulated for administration to or delivery into a subject of this invention.

[0151] The compositions of the present invention can also include other medicinal agents, pharmaceutical agents, carriers, diluents, immunostimulatory cytokines, etc. and can be in a pharmaceutically acceptable carrier. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art.

[0152] An "immunomodulatory molecule" of this invention can be, but is not limited to an immunostimulatory cytokine that can be, but is not limited to, GM/CSF, interleukin-2, interleukin-12, interferon-gamma, interleukin-4, tumor necrosis factor-alpha, interleukin-1, hematopoietic factor flt3L, CD40L, B7.1 co-stimulatory molecules and B7.2 co-stimulatory molecules.

[0153] Additional examples of an immunomodulatory molecule of this invention include the adjuvants of this invention, including, for example, SYNTEX adjuvant formulation I (SAF-1) composed of 5 percent (wt/vol) squalene (DASF, Parsippany, N.J.), 2.5 percent Pluronic, L121 polymer (Aldrich Chemical, Milwaukee), and 0.2 percent polysorbate (Tween 80, Sigma) in phosphate-buffered saline. Suitable adjuvants also include an aluminum salt such as aluminum hydroxide gel (alum), aluminum phosphate, or algannmulin, but may also be a salt of calcium, iron or zinc, or may be an insoluble suspension of acylated tyrosine, or acylated sugars, cationically or anionically derivatized polysaccharides, or polyphosphazenes.

[0154] Other adjuvants are well known in the art and include QS-21, Freund's adjuvant (complete and incomplete), aluminum hydroxide, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetyl-normuramyl-L-alanyl-D-isoglutamine (CGP 11637, referred to as nor-MDP), N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-(1'-2'-dip- almitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine (CGP 19835A, referred to as MTP-PE) and RIBI, which contains three components extracted from bacteria, monophosphoryl lipid A, trealose dimycolate and cell wall skeleton (MPL+TDM+CWS) in 2% squalene/Tween 80 emulsion.

[0155] Additional adjuvants can include, for example, a combination of monophosphoryl lipid A, preferably 3-de-O-acylated monophosphoryl lipid A (3D-MPL) together with an aluminum salt. An enhanced adjuvant system involves the combination of a monophosphoryl lipid A and a saponin derivative, particularly the combination of QS21 and 3D-MPL as disclosed in PCT publication number WO 94/00153 (the entire contents of which are incorporated herein by reference), or a less reactogenic composition where the QS21 is quenched with cholesterol as disclosed in PCT publication number WO 96/33739 (the entire contents of which are incorporated herein by reference). A particularly potent adjuvant formulation involving QS21 3D-MPL & tocopherol in an oil in water emulsion is described in PCT publication number WO 95/17210 (the entire contents of which are incorporated herein by reference). In addition, the nucleic acid of this invention can include an adjuvant by comprising a nucleotide sequence encoding a Sema6D protein or active fragment thereof of this invention and a nucleotide sequence that provides an adjuvant function, such as CpG sequences. Such CpG sequences, or motifs, are well known in the art. Other TLR agonists, such as Pam3Cys, Poly(I:C), single stranded RNA, as well as CATERPILLER (NOD-LRR) agonists, such as proteoglycan-derived products, are also included herein.

[0156] The terms "treat," "treating" or "treatment" include any type of action that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease, condition or illness, including improvement in the disorder, disease, condition or illness of the subject (e.g., in one or more symptoms), delay in the progression of the disorder, disease, condition or illness, prevention or delay of the onset of the disorder, disease, condition or illness, and/or change in clinical parameters, disorder, disease, condition or illness status, etc., as would be well known in the art.

[0157] As used herein, the term "antibody" includes intact immunoglobulin molecules as well as fragments thereof that are capable of binding the epitopic determinant of an antigen (i.e., antigenic determinant). Antibodies that bind the polypeptides of this invention are prepared using intact polypeptides or fragments as the immunizing antigen. The polypeptide or fragment used to immunize an animal can be derived from enzymatic cleavage, recombinant expression, isolation from biological materials, synthesis, etc., and can be conjugated to a carrier protein, if desired. Commonly used carriers that are chemically coupled to peptides and proteins for the production of antibody include, but are not limited to, bovine serum albumin, thyroglobulin and keyhole limpet hemocyanin. The coupled peptide or protein is then used to immunize the animal (e.g., a mouse, rat, or rabbit). The polypeptide or peptide antigens can also be administered with an adjuvant, as described herein and as otherwise known in the art.

[0158] An antibody of this invention can be any type of immunoglobulin, including IgG, IgM, IgA, IgD, and/or IgE. The antibody can be monoclonal or polyclonal and can be of any species of origin, including, for example, mouse, rat, rabbit, horse, goat, sheep or human, or can be a chimeric or humanized antibody (e.g., Walker et al., Molec. Immunol. 26:403-11 (1989)). The antibodies can be recombinant monoclonal antibodies produced according to the methods disclosed in U.S. Pat. No. 4,474,893 or U.S. Pat. No. 4,816,567. The antibodies can also be chemically constructed according to methods disclosed in U.S. Pat. No. 4,676,980. The antibody can further be a single chain antibody (e.g., scFv) or bispecific antibody.

[0159] Antibody fragments included within the scope of the present invention include, for example, Fab, F(ab')2, and Fc fragments, and the corresponding fragments obtained from antibodies other than IgG. Such fragments can be produced by known techniques. For example, F(ab')2 fragments can be produced by pepsin digestion of the antibody molecule, and Fab fragments can be generated by reducing the disulfide bridges of the F(ab')2 fragments. Alternatively, Fab expression libraries can be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (Huse et al., (1989) Science 254:1275-1281). Antibodies can also be obtained by phage display techniques known in the art or by immunizing a heterologous host with a cell containing an epitope of interest.

[0160] The polypeptide, fragment or antigenic epitope that is used as an immunogen can be modified or administered in an adjuvant in order to increase antigenicity. Methods of increasing the antigenicity of a protein or peptide are well known in the art and include, but are not limited to, coupling the antigen with a heterologous protein (such as globulin or .beta.-galactosidase) or through the inclusion of an adjuvant during immunization.

[0161] For example, for the production of antibodies, various hosts including goats, rabbits, rats, mice, humans, and others, can be immunized by injection with the polypeptides and/or fragments of this invention, with or without a carrier protein. Additionally, various adjuvants may be used to increase the immunological response. Such adjuvants include, but are not limited to, Freund's complete and incomplete adjuvants, mineral gels such as aluminum hydroxide, and surface-active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol. Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable.

[0162] Monoclonal antibodies can be produced in a hybridoma cell line according to the technique of Kohler and Milstein (Nature 265:495-97 (1975)). Other techniques for the production of monoclonal antibodies include, but are not limited to, the human B-cell hybridoma technique, and the EBV-hybridoma technique (Kozbor et al. 1985. J. Immunol. Methods 81:31-42; Cote et al. 1983. Proc. Natl. Acad. Sci. 80:2026-2030; Cole et al. 1984. Mol. Cell. Biol. 62:109-120).

[0163] For example, to produce monoclonal antibodies, a solution containing the appropriate antigen can be injected into a mouse and, after a sufficient time, the mouse sacrificed and spleen cells obtained. The spleen cells are then immortalized by fusing them with myeloma cells or with lymphoma cells, typically in the presence of polyethylene glycol, to produce hybridoma cells. The hybridoma cells are then grown in a suitable medium and the supernatant screened for monoclonal antibodies having the desired specificity. Monoclonal Fab fragments can be produced in a bacterial cell such as E. coli by recombinant techniques known to those skilled in the art (e.g., Huse. Science 246:1275-81 (1989)). Any one of a number of methods well known in the art can be used to identify the hybridoma cell, which produces an antibody with the desired characteristics. These include screening the hybridomas by ELISA assay, Western blot analysis, or radioimmunoassay. Hybridomas secreting the desired antibodies are cloned and the class and subclass are identified using standard procedures known in the art.

[0164] For polyclonal antibodies, antibody-containing serum is isolated from the immunized animal and is screened for the presence of antibodies with the desired specificity using any of the well known procedures as described herein.

[0165] The present invention further provides antibodies of this invention in detectably labeled form. Antibodies can be detectably labeled through the use of radioisotopes, affinity labels (such as biotin, avidin, etc.), enzymatic labels (such as horseradish peroxidase, alkaline phosphatase, etc.) fluorescence labels (such as FITC or rhodamine, etc.), paramagnetic atoms, gold beads, etc. Such labeling procedures are well-known in the art. The labeled antibodies of the present invention can be used for in vitro, in vivo, and in situ assays to identify a polypeptide and/or fragment of this invention in a sample.

[0166] In some embodiments, the present invention further provides the above-described antibodies immobilized on a solid support (e.g., beads, plates, slides or wells formed from materials such as latex or polystyrene). Examples of such solid supports include plastics such as polycarbonate, complex carbohydrates such as agarose and sepharose, acrylic resins and such as polyacrylamide and latex beads. Techniques for coupling antibodies to such solid supports are well known in the art (Weir et al., Handbook of Experimental Immunology 4th Ed., Blackwell Scientific Publications, Oxford, England, Chapter 10 (1986)). Antibodies can likewise be conjugated to detectable groups such as radiolabels (e.g., .sup.35S, .sup.125I, .sup.131I), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), and fluorescence labels (e.g., fluorescein) in accordance with known techniques. Determination of the formation of an antibody/antigen complex in the methods of this invention can be by detection of, for example, precipitation, agglutination, flocculation, radioactivity, color development or change, fluorescence, luminescence, etc., as is well know in the art.

[0167] In addition, techniques developed for the production of chimeric antibodies or humanized antibodies by splicing mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity can be used (Morrison et al. 1984. Proc. Natl. Acad. Sci. 81:6851-6855; Neuberger et al. 1984. Nature 312:604-608; Takeda et al. 1985. Nature 314:452-454). Alternatively, techniques described for the production of single chain antibodies can be adapted, using methods known in the art, to produce single chain antibodies specific for the polypeptides and fragments of this invention. Antibodies with related specificity, but of distinct idiotypic composition, can be generated by chain shuffling from random combinatorial immunoglobulin libraries (Burton 1991. Proc. Natl. Acad. Sci. 88:11120-3).

[0168] Various immunoassays can be used for screening to identify antibodies having the desired specificity for the proteins and peptides of this invention. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificity are well known in the art. Such immunoassays typically involve the measurement of complex formation between an antigen and its specific antibody (e.g., antigen/antibody complex formation). For example, a two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on the proteins or peptides of this invention can be used, as well as a competitive binding assay.

[0169] The present invention is more particularly described in the following examples, which are intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art.

EXAMPLES

I. The Semaphorin 6D Receptor on T Cells is Required for Activation of CD4.sup.+ T Cells

[0170] Mice. All experiments were performed with 8-12 week old C57BL/6 mice from Jackson Labs. OT-II mice which express the OVA[323-339]-specific TCR transgene on the C57BL/6 background were generous gifts from M. Croft. All animal procedures were conducted in complete compliance with the NIH Guide for the Care and Use of Laboratory Animals, approved by the Institutional Animal Care and Use Committee of the University of North Carolina, Chapel Hill.

[0171] Cells. Murine bone marrow derived dendritic cells (BMDCs) were isolated from bone marrow and grown in vitro for maturation. Briefly cells were grown in GM-CSF and IL-4 for 10 days before maturing with 20 ng/ml TNF-.alpha. for 2 additional days.

[0172] Magnetic Bead isolation of TCR Tg OTII T cells. Splenic T cells were isolated from OTII mice based on expression of CD4. Magnetic bead purifications were performed according to the protocol provided by Miltenyi Biotec (Auburn, Calif.). Briefly, splenocytes isolated from B6 or OTII mice were incubated with anti-mouse CD4 antibody conjugated with PE (BD PharMingen, San Diego, Calif.). Spleen cell samples were then incubated with anti-PE antibody coated magnetic beads (Miltenyi Biotec, Auburn, Calif.) and cells positively selected by passage through LS columns attached to magnetic separators. Flow through and eluent fractions were collected following Miltenyi protocol guidelines.

[0173] SYBR Green Real-Time PCR. SYBR Green qPCR Rox mix (Abgene) was used for all quantitative PCR experiments. The following cycle conditions were used: Stage 1) 50.degree., for 2 minutes; Stage 2) 95.degree., for 15 minutes; Stage 3) 95.degree. for 15 seconds, 56-57.degree. for 15-30 seconds, 72.degree. for 15-30 seconds, repeat 40.times.; Stage 4) dissociation curve. The relative level of expression for each primer target was calculated via (.DELTA..DELTA.CT).times.1000. Target genes were calculated in reference to .beta.-actin for each sample. The .beta.-actin primers used were: (Forward) 5'-agggctatgctctccctcac-3' (SEQ ID NO:3) and (Reverse) 5'-ctctcagctgtggtggtgaa-3' (SEQ ID NO:4). The Sema6D primers used were: (Forward) 5'-cagaagcatgggagatggat-3' (SEQ ID NO:5) and (Reverse) 5'-gccacccatgtcgtttttac-3' (SEQ ID NO:6).

[0174] Cloning and production of mouse Semaphorin 6D-Ig fusion protein (Sema6D-Ig). Sema6D cDNA was obtained via reverse transcription reaction, according to manufacturer's instruction, utilizing Superscript III (Invitrogen) and an RNA sample isolated from the brain of C57BL/6J mice. Sema6D has multiple isoforms that differ slightly in the extracellular region between the Sema domain and the trans-membrane domain. Thus, to obtain a full length cDNA of Sema6D, the forward primer (5'-atggggttccttctgctttggtt) (SEQ ID NO:7) and reverse primer (3'-ctagtacgtgtacttgttcagtggtctg) (SEQ ID NO:8) were designed utilizing current mRNA sequence for Sema6D contained within the GenBank database. PCR utilizing heat-stable DNA polymerase LATaq (TAKARA) followed by 0.8% agarose gel electrophoresis, produced a band of approximately 3 kb. The 3 kb DNA band was isolated and cloned into the pCR2.1 TOPO vector (Invitrogen). Multiple sequencing reactions (UNC-CH genomics core facility) verified that the cloned DNA sequence was identical to the full-length sequence of Sema6D isoform 6 (Sema6D-6).

[0175] Isolation of a cDNA fragment encoding the extracellular region of mouse Sema6D-6 (amino acids 1-652) was obtained via PCR amplification utilizing the full length Sema6D-6 cloned into the pCR2.1 TOPO vector. The forward primer (5'-gcggatatcgccacccatggggttccttctgctttggttct) (SEQ ID NO:9) was designed to include a HindIII restriction endonuclease and the reverse primer (5'-gcgggatccagcggcaaacacgcaggtgatgagga) (SEQ ID NO: 10) was designed with a BamHI restriction endonuclease site. The PCR product was gel purified and digested by HindIII and BamHI restriction endonucleases (New England Biolabs). The digested fragment containing most of the extracellular region of Sema6D (Sema6DEC) was subcloned into a modified pcDNA3.1 vector (Invitrogen) containing a human IgG1 fragment (Hinge-CH2-CH3). For transient expression, the sequenced SEMA6DEC-Ig plasmid was transfected into the COS-7 cell line (ATCC CRL-1651) via a standard calcium phosphate transfection protocol. Serum containing DMEM medium was substituted with a serum-free DMEM medium at 48 hour post transfection. The supernatant containing SEMA6DEC-Ig protein was harvested at 48-72 hours after transfection and purified by protein A affinity chromatography. Expression and secretion of SEMA6DEC-Ig was verified by immunoprecipitation followed by western blot analysis. Five milliliters of the supernatant were removed from Sema6DEC-Ig-transfected COS-7 cells cultured in serum-free DMEM 48 hours post transfection, and incubated with protein A/G agarose beads (Promega). Subsequent western blotting using anti-human IgG-HRP indicated a clear band of approximately 100 kDa and no other major bands that might represent either degradation products or contaminating proteins.

[0176] Generation of stable expression cells was performed via co-transfection of SEMA6DEC-Ig plasmid and a mouse dihydrofolate reductase (DHFR) encoding expression vector pSV2-dhfr (ATCC 37146) into DHFR-Chinese hamster ovary cells (CHO/DG44, Invitrogen) at a 20:1 ratio (weight:weight) through electroporation technique (300V, 960 uF, Bio-rad). Stable Sema6D-Ig expressing CHO cell clones were selected in Excell 302 serum free CHO medium (JRH Biosciences) supplemented with L-glutamine (Invitrogen) and 100 nM methotrexate (MTX, Sigma). Sema6D-Ig produced by the CHO cells was harvested from large-scale cultures via protein A affinity chromatography followed by gel filtration chromatography purification (Biosilect 400, Bio-rad).

[0177] Semi-quantitative RT-PCR of Type III semaphorin transcripts. Total RNA was isolated from DO11.10 T cells with or without activation, 3B11 cells at day 0, day 3, day 5 and day 7 of maturation, and brain cells using TRIzol Reagent (Invitrogen). One microgram of RNA of each sample was reverse transcribed using MMLV reverse transcriptase (Invitrogen). Semaphorin 3A, 3B, 3C, 3D and 3E transcripts were assessed using Taq polymerase (Invitrogen) and semi-quantitative PCR (22 cycles). Standardization of cDNA amounts was analyzed via PCR for 18S RNA. Sequences of the primers for the class III semaphorins are as follows:

TABLE-US-00003 Semaphorin 3A, (forward) (SEQ ID NO: 11) 5'-CGGGACTTCGCTATCTTCAG-3' and (reverse) (SEQ ID NO: 12) 5'-AGCATGAGTGGCTTTTCCAG-3'; Semaphorin 3B, (forward) (SEQ ID NO: 13) 5'-GCTGTCTTCTCCACCTCCAG-3' and (reverse) (SEQ ID NO: 14) 5'-GGTTCCGACCAAACTGGATA-3'; Semaphorin 3C, (forward) (SEQ ID NO: 15) 5'-TCGGCAGTGTGTGTGTATCA-3' and (reverse) (SEQ ID NO: 16) 5'-CCTTCTGTGGATGGGGTAGA-3'; Semaphorin 3D, (forward) (SEQ ID NO: 17) 5'-ATGGCTGATATCCGAGCAGT-3' and (reverse) (SEQ ID NO: 18) 5'-TTCTCTTGAAGGTCGGTGCT-3'; and Semaphorin 3E, (forward) (SEQ ID NO: 19) 5'-GAGGCCATGCTGTATGTGTG-3' and (reverse) (SEQ ID NO: 20) 5'-CGTCATCGGGTAATCTTTGG-3'.

[0178] Flow Cytometry. Following splenic or BM isolation, cells were suspended in ammonium chloride-Tris buffer (ACT) for 3 minutes at 37.degree. C. to remove RBC. ACT treatment was performed with carboxyfluorescein diacetate succinimidyl ester (CFDAse, Molecular Probes, Eugene, Oreg.) labeled cells. Following ACT treatment, cells were washed and resuspended in 5% BCS in BSS and stained with the appropriate antibodies as described. For all studies, non-specific staining was reduced by addition of FcR blocking antibody and unlabeled Rat/Hamster Ig. Incubation with biotinylated antibodies was followed by incubation with Streptavidin-PE, PerCP or APC (BD PharMingen, San Diego, Calif.). Primary antibody incubations were for a minimum of 30 minutes at 4.degree. C. followed by washing in BCS/BSS. Secondary antibody incubations were for a maximum of 15 minutes at 4.degree. C. followed by washing in BCS/BSS. Stained cells were either analyzed immediately or fixed with 1% formaldehyde in 1.25.times.PBS. Staining was quantified with a Becton Dickinson FACSCalibur. A minimum of 50,000 events was collected and fluorescence signals detected via four-decade logarithmic amplification except for FSC and SSC which were detected via a linear scale. Spectral overlap compensation was made with single-color stained samples for each detection channel. For each experiment, data were analyzed using FlowJo software (Treestar, Calif.).

[0179] In vitro CD3/CD28 stimulation. For stimulation of T cells, 5 .mu.g/ml of anti-mouse CD3 and anti-mouse CD28 were added in PBS to cell culture plates for overnight coating at 4.degree. C. For a 6 well plate, 1 ml/well was used. Following the overnight incubation, the plates were washed 3.times. with PBS or complete medium (cRPMI: RPMI+serum). Primary T cells isolated from spleens were incubated at 1.times.10.sup.6 cells/ml in 2 mls per well of a 6 well coated plate.

[0180] Ovalbumin (OVA) (whole protein or peptide) loading of DCs. BMDCs, cultured for up to 10 days in cRPMI supplemented with GMCSF and IL4, were resuspended at a concentration of 1.times.10.sup.6 cells in 1 ml of cRPMI with 10 .mu.g/mL whole OVA protein or peptide. The cells were incubated for 12 hrs at 37.degree. C. with rotation. Following the incubation, the cells were washed 2.times. in cRPMI.

[0181] Adoptive transfer. Following isolation of splenocytes or BMDCs from mice, RBCs were lysed via incubation with ACT. The percentage of Tg OTII T cells within a population was determined by staining 2.times.10.sup.5 cells with anti-V.alpha.2 and anti-V.beta.5 in 5% BCS in BSS at 4.degree. C. and analyzed via a Becton Dickinson FACSCalibur cell sorter. For each primary transfer, 3.times.10.sup.6 T cells and BMDCs were injected via tail vein into B6 recipient mice. Typically, three mice were used per experimental group.

[0182] CFSE labeling of T cells. T cells labeled with carboxyfluorescein diacetate succinimidyl ester (CFDAse or CFSE; Molecular Probes, Eugene, Oreg.) were incubated at 37.degree. C. for 10 minutes in serum free RPMI. The final concentration of CFSE used was 15 .mu.M in RPMI with 10-20 million cells per ml. Following incubation with CFSE, the T cells were washed in cRPMI. Experimental conditions permitting, cells utilized for CFSE labeling were not treated with ASC red blood cell lysis buffer at the time of isolation.

[0183] Activation of T cells by co-culture with Ag-loaded BMDCs. For in vitro activation, OTII TCR Tg (OVA-specific) T cells were incubated with immature BMDCs at a ratio of 1:1 in RPMI. OTII T cells were isolated from the spleens of Tg mice and purified by negative selection with T enrichment columns (R&D systems). Isolated T cells were labeled with CFSE or unlabeled prior to culture. BMDCs were either unloaded or loaded with OVA antigen (Ag) prior to culture. Approximately 0.5.times.10.sup.6 T cells and BMDCs were cultured in 1 ml per well of a 24 well plate. At the culture initiation, IL4 & GM-CSF were added at a concentration of 5 .eta.g/mL.

[0184] Use of anti-Sema6D antibody or the Sema6D-Ig fusion protein to block the functional activation of T cells. Antibodies for blocking interactions between the T cells and BMDCs, such as anti-Sema6D Ab, were used at a final concentration of 10 .mu.g/ml. The Sema6D-Ig fusion protein was used at a final concentration of 5 .mu.g/ml. One day following initiation, cell cultures were supplemented with 1 ml of cRPMI. The cultured cells were analyzed by flow cytometry for indications of T cell activation via proliferation and expression of activation markers as described herein.

[0185] Activated CD4.sup.+ T cells express Semaphorin 6D in vitro. CD4.sup.+ T cells were isolated from splenocytes by magnetic bead separation and activated in vitro by anti-CD3 and anti-CD28 stimulation. Splenic CD4.sup.+ T cells were isolated by magnetic bead selection to a purity of greater than 90%. Purified T cells were cultured with plate bound anti-CD3 and -CD28 antibodies for stimulation. RNA was isolated from cultures at 12, 24 and 48 hr post initiation and analyzed by qPCR for Semaphorin 6D (Sema6D) expression. Following 12 hrs of stimulation, expression of Sema6D mRNA was increased as measured by qPCR, and this enhancement continued until at least 48 hrs post activation. Protein expression of Sema6D on activated CD4.sup.+ T cells was also examined by flow cytometry. Following 96 hrs of anti-CD3 and anti-CD28 stimulation, enhanced expression of CD25 and CD44 was detected on CD3.sup.+CD4.sup.+ T cells, indicative of their activation. Concurrently, upregulation of Sema6D was observed on CD3.sup.+CD4.sup.+ T cells following 96 hrs of stimulation. Isotype-matched control Ig showed no such increase. Thus, activation of CD4.sup.+ T cells via stimulation of CD3 and CD28 results in an upregulated expression of Sema6D at the cell surface. In contrast, measurements of Semaphorin 3A to 3F by the highly sensitive RT-PCR failed to detect any signals in resting or activated T cells. Semi-quantitative RT-PCR analysis revealed that OTII T cells did not express detectable levels of any type 3 semaphorins, including Sema 3A-E. Semaphorin 3 expression was detected in brain samples, used as positive controls.

[0186] DC mediated activation of Tg OTII T cells results in Sema6D expression in vivo. Although expression of Sema6D in vitro via anti-CD3 and --CD28 stimulation was observed, it remained uncertain whether this result reflected the physiological reality of in vivo T cell activation. To examine the in vivo situation, the TCR transgenic (Tg) mouse line, OTII, whose CD4 T cells express a TCR specific for the OVA antigen, was used. OTII Tg T cells were isolated from splenocytes and adoptively transferred to recipient mice with either OVA-loaded DCs (immune) or un-loaded DCs (naive). The recipient mouse splenocytes were harvested at days 2, 3 and 4 post adoptive transfer and the cells were analyzed by flow cytometry. The activation and expansion of the OTII T cells were visualized as an expansion of the population of T cells expressing the Tg TCR V.alpha.2 and V.beta.5 chains. Proliferation of the OTII T cells was observed in vivo by day 2 and peaked at day 4, representing an approximately 5-fold expansion in immune vs. naive mice. Concurrently, on day 4, the expression of CD25 was upregulated on OTII T cells from immune mice vs. naive mice. This was accompanied by an upregulation of Sema6D on activated OTII T cells in vivo vs. naive mice. Thus, in a physiologically relevant system of in vivo antigen presenting cell mediated T stimulation, enhanced expression of Sema6D on activated CD4.sup.+ T cells was observed, confirming the induction of Sema6D during T cell activation.

[0187] Blocking Sema6D antibody inhibits DC mediated OTII T cell proliferation and activation. To examine the functional consequence of Sema6D expression on T cells, an in vitro DC-mediated T cell activation assay was used. Tg OTII T cells were cultured with OVA loaded BMDCs (OVA-BMDC) or unloaded BMDCs (BMDC). Following isolation but prior to co-culture, the OTII T cells were labeled with CFSE to enable monitoring of activation-induced proliferation. At days 2, 6 and 7 post culture initiation, cultured cells were collected and analyzed by flow cytometry. Activation is associated with proliferation, which results in a serial dilution of CFSE staining intensity with each cell division. Thus a pattern of serially diluted CFSE staining is indicative of T cell activation. OTII T cells cultured control exhibited little change, while OTII T cells incubated with OVA-BMDC cells displayed activation-induced proliferation as measured by a dilution of CFSE intensity. Initially, a small amount of proliferation was observed on day 2 post-culture of V.beta.5.sup.+ (OTII) T cells with OVA-BMDC but not control BMDC (0.94% V.beta.5.sup.+CFSE.sup.low vs. 0.064%). By day 7 of co-culture, the OTII T cells incubated with OVA-BMDC proliferated greatly compared with those cultured with control BMDC, representing a greater than 11 fold induction. The proliferating cells observed on day 7 were TCR.sup.+CD4.sup.+CD8.sup.- T cells, indicative of the OTII Tg T cell phenotype.

[0188] Significantly, when OTII T cells were cultured with OVA-BMDC in the presence of an antibody to block Sema6D (Sema6D Ab), the proliferation of the T cells was abrogated. While proliferation on day 6 and 7 was markedly reduced, the initial level of proliferation observed on day 2 was comparable to cultures with a control antibody (Ctrl Ab). Thus, while early survival may be unaffected, optimal proliferation and homeostasis of the V.beta.5.sup.+ OTII T cells were inhibited by Sema6D blockade at both days 6 and 7.

[0189] The expression of Sema6D on in vitro activated OTII T cells was also examined and expression on both unactivated and activated T cells by day 7 was observed. BMDCs that were loaded (OVA-BMDC) or unloaded (BMDC) with whole OVA protein were cultured with purified OTII T cells in vitro. Prior to culture initiation, OTII T cells were labeled with CFSE. Antigen positive cultures were also treated with either a Sema6D blocking antibody or a control antibody. As expected, addition of blocking antibody significantly inhibited the detection of Sema6D expression compared with control antibody or unactivated cultures.

[0190] Finally, the ability of blocking Sema6D Ab to inhibit the appearance of an activated T cell phenotype was examined. Expression levels of CD25, CD62L, CD69, CD154 and CD44 were analyzed. For all the phenotypic markers analyzed, blocking Sema6D antibody inhibited the accumulation or appearance of activated OTII Tg T cells while isotype-control antibody did not. The low number of cells displaying an activated phenotype in the Sema6D Ab treated group may reflect an initial activation and proliferation that occurs in the presence of Sema6D Ab. Moreover, there does not appear to be reduced viability of CFSE.sup.bright T cells lacking activation makers, suggesting that Sema6D Ab affects only stimulated T cells. These data indicate that Sema6D regulates DC mediated T cell proliferation, activation and survival.

[0191] Sema6D-Ig inhibits BMDC mediated T cell activation. To further characterize the function of Sema6D, a hybrid of a cDNA fragment encoding the extracellular region of mouse Sema6D-6 (amino acids 1-652) and a human IgG1 fragment (hinge-CH2-CH3) was produced, resulting in a Sema6D-Ig fusion protein. This fusion protein was used along with the anti-Sema6D antibody in an experimental procedure as described herein. BMDCs that were loaded (OVA-BMDC) or unloaded (BMDC) with whole OVA protein were cultured with purified OTII T cells in vitro. Prior to culture initiation, OTII T cells were labeled with CFSE. Antigen positive cultures were also treated with a control antibody, a MHC class II blocking antibody, a Sema6D blocking antibody or the Sema6D-Ig fusion protein. At day 5 post culture initiation, the proliferation of CD4.sup.+ T cells was analyzed. Utilizing Sema6D-Ig as a blocking reagent administered to in vitro cultures, inhibition of BMDC mediated T cell proliferation was observed, as compared to a control antibody treated group (5.15% CFSE.sup.lowCD4.sup.+ vs. 29%). The level of inhibition with the Sema6D-Ig fusion protein was comparable to inhibition via the anti-Sema6D Ab. As a control, treatment with a blocking antibody for MHC II resulted in complete inhibition of T cell activation.

[0192] These studies demonstrate that activated T cells express high levels of Semaphorin 6D both in vitro and in vivo and that inhibition of Sema6D, via treatment with a blocking Ab or Sema6D-Ig, significantly inhibits dendritic cell mediated T cell activation. These data demonstrate that Sema6D represents an important novel receptor for the regulation of T cell immunity.

[0193] These studies further indicate that Sema6D inhibitors may reduce the survival of activated T cells only and do not appear to function as general inhibitors of T cell survival. In Sema6D Ab treated cultures (OVA-BMDC+Sema6D), the viability of non-dividing CFSE.sup.bright and TCR.sup.+ or CD4.sup.+ cells did not appear to be affected when compared with T cells from naive (BMDC) cultures (72.5 vs. 72.4%; and 66.1 vs. 67.2% respectively). Thus, in the case of autoimmunity, blocking Sema6D would allow for the specific targeting of activated autoimmune T cells while allowing unactivated, non-autoimmune T cells to persist. A similar method could be applied to transplant patients to induce a tolerizing effect on rejecting T cells. Alternatively, stimulating activated T cells via agonist ligand binding of Sema6D, could lead to enhanced vaccine efficacy or even enhanced tumor rejection via stimulation of anti-tumor T cells.

II. Blocking Sema6D with the Sema6D-Ig Fusion Protein Caused a Delayed Inhibition of T Cell Activation

[0194] This was tested by assaying the phosphorylation of three T cell activating molecules, CrkL, LAT and CD3.zeta.. CD3.zeta. phosphorylation is an early event in T cell activation that occurs proximal to the T cell receptor. Its activation as indicated by phosphorylation is not altered by Sema6D-Ig inhibition. In the studies conducted, Sema6D was shown to regulate endogenous T cell signaling during late-stage activation. OTII T cells were co-cultured with DCs loaded with OVA antigen (OVA-DC) or unloaded DCs (DC). Antigen positive cultures were treated with Sema6D-Ig (S6D-Ig) or human IgG1 (hIgG1). OTII T cells co-cultured with DCs were analyzed by phosphor-specific flow cytometry for endogenous signaling pathways. FACS analysis of phosphorylated CrkL in TCR.sup.+ OTII T cells was carried out at days 3 and 6 of co-culture with DCs. FACS analysis of phosphorylated LAT in TCR.sup.+ OTII T cells was also carried out at days 3 and 6. FACS analysis of phosphorylated CD3.zeta. in TCR.sup.+ OTII T cells was also carried out at days 3 and 6 of co-culture.

[0195] Phosphorylation of CrkL is an indication of c-Abl activation, and it was inhibited by Sema6D-Ig inhibition but only at a late time point (day 6 but not day 3). LAT phosphorylation which lies downstream of c-Abl phosphorylation was inhibited by Sema6D-Ig at a late time point (day 6 but not day 3). These results indicate that Sema6D signaling is most relevant late during T cell activation. Further it lies upstream of c-Abl, CrkL and LAT phosphorylation but does not affect CD3.zeta. phosphorylation. Thus blocking Sema6D-Ig is a mechanism to block late T cell activation, which provides a different intervening point from most immune clinical biologics used in the market.

III. Expression of Sema6D on B Cells

[0196] This is of particular interest as recently anti-B cell antibodies have been effective in both reducing autoimmunity in people, and reducing B lymphoma growth. Sema6D was found to be expressed by B cells to a similar extent as T cells, in both mouse and human (FIGS. 1a,b). Furthermore, expression was shown in four different types of leukemia (FIG. 1c). Blocking Sema6D was shown to reduce T cell proliferation and B cell proliferation. This indicates that blocking Sema6D can reduce lymphocyte survival, which is important in the control of autoimmunity, but also in the control of transformed B and T lymphomas/leukemia.

[0197] Expression of Sema6D protein in B cells is enhanced during an immune response. To explore if the expression of Sema6D is enhanced during B cell activation (a state similar to auto-activated B cells implicated in autoimmune diseases such as systemic lupus and arthritis, and transformed B cells found in leukemia and lymphomas), B cells activated in vivo were tested with antigens and antigen presenting cells. DCs matured for 8 days in vitro were loaded with whole OVA protein and then transferred by i.v. injection with OTII TCR transgenic (OVA specific) T cells to recipient B6 mice. At day 4 post-transfer, recipient mouse splenocytes were isolated and analyzed by flow cytometry for the expression of Sema6D. Splenocytes were incubated with anti-CD45, -B220 and -Sema6D antibodies. B220.sup.+ CD45.sup.+ splenocytes were gated and analyzed for expression of Sema6D. The percentage of B220.sup.+ Sema6D.sup.+ cells was displayed for splenocytes from naive and immune animals. These studies showed that in vivo activated B cells expressed significantly higher levels of Sema6D. In these experiments, B cells were marked with B220, and they showed elevated Sema6D after antigen stimulation. This suggests that Sema6D-Ig molecules might selectively target activated B cells and transformed B cells, but not naive resting B cells.

[0198] Although the present invention has been described with reference to specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention except as and to the extent that they are included in the accompanying claims.

[0199] Throughout this application, various patents, patent publications and non-patent publications are referenced. The disclosures of these patents and publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0200] The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

REFERENCES

[0201] 1. Keir, M. E., and A. H. Sharpe. 2005. The B71CD28 costimulatory family in autoimmunity. Immunol Rev 204:128. [0202] 2. Greenwald, R. J., G. J. Freeman, and A. H. Sharpe. 2005. The B7 family revisited. Annu Rev Immunol 23:515. [0203] 3. Girvin, A. M., M. C. Dal Canto, L. Rhee, B. Salomon, A. Sharpe, J. A. Bluestone, and S. D. Miller. 2000. A critical role for B7/CD28 costimulation in experimental autoimmune encephalomyelitis: a comparative study using costimulatory molecule-deficient mice and monoclonal antibody blockade. J Immunol 164:136. [0204] 4. Salomon, B., and J. A. Bluestone. 2001. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19:225. [0205] 5. Feldmann, M., and L. Steinman. 2005. Design of effective immunotherapy for human autoimmunity. Nature 435:612. [0206] 6. Quezada, S. A., L. Z. Jarvinen, E. F. Lind, and R. J. Noelle. 2004. CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 22:307. [0207] 7. Watts, T. H. 2005. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol 23:23. [0208] 8. Wong, A. W., W. J. Brickey, D. J. Taxman, H. W. van Deventer, W. Reed, J. X. Gao, P. Zheng, Y. Liu, P. Li, J. S. Blum, K. P. McKinnon, and J. P. Ting. 2003. CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nat Immunol 4:891. [0209] 9. Tamagnone, L., S. Artigiani, H. Chen, Z. He, G. I. Ming, H. Song, A. Chedotal, M. L. Winberg, C. S. Goodman, M. Poo, M. Tessier-Lavigne, and P. M. Comoglio. 1999. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99:71. [0210] 10. Castellani, V., and G. Rougon. 2002. Control of semaphorin signaling. Curr Opin Neurobiol 12:532. [0211] 11. Kikutani, H., and A. Kumanogoh. 2003. Semaphorins in interactions between T cells and antigen-presenting cells. Nat Rev Immunol 3:159. [0212] 12. Kumanogoh, A., and H. Kikutani. 2003. Immune semaphorins: a new area of semaphorin research. J Cell Sci 116:3463. [0213] 13. Liu, B. P., and S. M. Strittmatter. 2001. Semaphorin-mediated axonal guidance via Rho-related G proteins. Curr Opin Cell Biol 13:619. [0214] 14. Tamagnone, L., and P. M. Comoglio. 2004. To move or not to move? Semaphorin signalling in cell migration. EMBO Rep 5:356. [0215] 15. Toyofuku, T., H. Zhang, A. Kumanogoh, N. Takegahara, M. Yabuki, K. Harada, M. Hori, and H. Kikutani. 2004. Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nat Cell Biol 6:1204. [0216] 16. Toyofuku, T., H. Zhang, A. Kumanogoh, N. Takegahara, F. Suto, J. Kamei, K. Aoki, M. Yabuki, M. Hori, H. Fujisawa, and H. Kikutani. 2004. Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 18:435. [0217] 17. Turner, L. J., S. Nicholls, and A. Hall. 2004. The activity of the plexin-A1 receptor is regulated by Rac. J Biol Chem 279:33199. [0218] 18. Zanata, S. M., I. Hovatta, B. Rohm, and A. W. Puschel. 2002. Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse. J Neurosci 22:471. [0219] 19. Zipfel, P. A., W. Zhang, M. Quiroz, and A. M. Pendergast. 2004. Requirement for Abl kinases in T cell receptor signaling. Curr Biol 14:1222.

TABLE-US-00004 [0219] TABLE 1 Nucleotide and amino acid sequences of the Sema6D protein of the invention and a fusion protein of the invention. SEQ ID Accession No. Organism Definition NO: NM_020858 Homo sapiens Homo sapiens sema domain, transmembrane 21 domain (TM), and cytoplasmic domain, (semaphorin) 6D (SEMA6D), transcript variant 1, mRNA. NP_065909 Homo sapiens semaphorin 6D isoform 1 precursor 22 NM_153616 Homo sapiens Homo sapiens sema domain, transmembrane 23 domain (TM), and cytoplasmic domain, (semaphorin) 6D (SEMA6D), transcript variant 2, mRNA NP_705869 Homo sapiens semaphorin 6D isoform 2 precursor 24 NM_153617 Homo sapiens Homo sapiens sema domain, transmembrane 25 domain (TM), and cytoplasmic domain, (semaphorin) 6D (SEMA6D), transcript variant 3, mRNA NP_705870 Homo sapiens semaphorin 6D isoform 3 precursor 26 NM_153618 Homo sapiens Homo sapiens sema domain, transmembrane 27 domain (TM), and cytoplasmic domain, (semaphorin) 6D (SEMA6D), transcript variant 4, mRNA NP_705871 Homo sapiens semaphorin 6D isoform 4 precursor 28 NM_153619 Homo sapiens Homo sapiens sema domain, transmembrane 29 domain (TM), and cytoplasmic domain, (semaphorin) 6D (SEMA6D), transcript variant 5, mRNA NP_705872 Homo sapiens semaphorin 6D isoform 5 precursor 30 NM_024966 Homo sapiens Homo sapiens sema domain, transmembrane 31 domain (TM), and cytoplasmic domain, (semaphorin) 6D (SEMA6D), transcript variant 6, mRNA NP_079242 Homo sapiens semaphorin 6D isoform 6 precursor 32 NM_172537 Mus musculus Mus musculus sema domain, transmembrane 33 domain (TM), and cytoplasmic domain, (semaphorin) 6D (Sema6d), transcript variant 1, mRNA n/a Mus musculus CDS of NM_172537 34 NP_766125 Mus musculus sema domain, transmembrane domain (TM), 35 and cytoplasmic domain, (semaphorin) 6D isoform 1 n/a Mus musculus CDS of NM_199238 36 NP_954708 Mus musculus sema domain, transmembrane domain (TM), 37 and cytoplasmic domain, (semaphorin) 6D isoform 2 n/a Mus musculus CDS of NM_199241 38 NP_954711 Mus musculus sema domain, transmembrane domain (TM), 39 and cytoplasmic domain, (semaphorin) 6D isoform 4 n/a Mus musculus CDS of NM_199239 47 NP_954709 Mus musculus sema domain, transmembrane domain (TM), 48 and cytoplasmic domain, (semaphorin) 6D isoform 5 n/a Mus musculus CDS of NM_199240 49 NP_954710 Mus musculus sema domain, transmembrane domain (TM), 50 and cytoplasmic domain, (semaphorin) 6D isoform 6 n/a Mus musculus CDS of Sema6D-6 51 BC098887 Danio rerio Danio rerio sema domain, transmembrane 52 domain (TM), and cytoplasmic domain, (semaphorin) 6D, mRNA AAH98887 Danio rerio Sema domain, transmembrane domain (TM), 53 and cytoplasmic domain, (semaphorin) 6D XM_230583 Rattus PREDICTED: Rattus norvegicus sema 54 norvegius domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D (predicted) (Sema6d_predicted), mRNA XP_230583 Rattus PREDICTED: similar to sema domain, 55 norvegius transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D isoform 4 XM_596649 Bos taurus PREDICTED: Bos taurus similar to 56 semaphorin 6D, transcript variant 5 (LOC518458), mRNA XP_596649 Bos taurus PREDICTED: similar to semaphorin 6D 57 isoform 5 n/a Artificial CDS of Murine sema6D-Ig fusion protein 58

TABLE-US-00005 TABLE 2 PCR and Sequencing primers Primer sequence SEQ ID NO: ATGGGGTTCCTTCTGCTTTGGTT (offset: 1; 7 23 nt) CTAGTACGTGTACTTGTTCAGTGGTCTG (offset: 8 2997; 28 nt) AAAGCAGAAGGAACCCCATGGTT (Rev. -838) 40 ACCAGGTAGCTAAGTGGGACTTCTG (For. 761-) 41 TGACACCCTGGCTTTCATCAAGT (For. 1161-) 42 AAAGTCTTGCATTGCATCACGTGAC (For. 1566-) 43 CCAATCAGATGGTCCACATGAA (For. 1964-) 44 ATGAAGAGCCACTCTGAGAAGGC (For. 2362-) 45 TAACCGGGAGGCATCTCTATAC (For. 2769-) 46

Sequence CWU 1

1

5812668DNAArtificialMurine Sema6D-Ig fusion nucleotide sequence 1gccaccc atg ggg ttc ctt ctg ctt tgg ttc tgc gtg ctg ttc ctt ctg 49 Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu 1 5 10gtc tcc agg tta cgg gcg gtc agc ttc cca gaa gac gat gag ccc ctc 97Val Ser Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu15 20 25 30aac acg gtt gac tat cac tat tca agg caa tat ccg gtt ttt aga gga 145Asn Thr Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly 35 40 45cgc cct tca ggc aac gaa tcg cag cac agg ctg gac ttt cag ctg atg 193Arg Pro Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met 50 55 60ttg aaa att cga gac aca ctt tat att gct ggc agg gat caa gtc tat 241Leu Lys Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr 65 70 75aca gtg aac tta aat gaa atc ccc caa aca gag gtg ata cca agc aag 289Thr Val Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys 80 85 90aag ctg acg tgg agg tcc aga cag cag gat cga gaa aat tgt gct atg 337Lys Leu Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met95 100 105 110aaa ggc aag cat aaa gat gaa tgc cac aac ttc atc aaa gtc ttt gtc 385Lys Gly Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val 115 120 125cca aga aat gat gag atg gtt ttt gtc tgt ggt acc aat gct ttc aac 433Pro Arg Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn 130 135 140ccg atg tgc aga tac tat agg ttg aga acg tta gag tat gat ggg gaa 481Pro Met Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu 145 150 155gaa att agt ggc ctg gca cga tgc ccg ttt gat gcc cga caa acc aat 529Glu Ile Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn 160 165 170gtc gcc ctc ttt gct gat gga aaa ctc tat tct gcc aca gtg gct gat 577Val Ala Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp175 180 185 190ttc ctg gcc agt gat gct gtc att tac aga agc atg gga gat gga tct 625Phe Leu Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser 195 200 205gcc ctt cgc aca ata aaa tac gat tcc aag tgg atc aaa gaa cca cac 673Ala Leu Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His 210 215 220ttc ctt cat gcc ata gaa tat gga aac tat gtc tat ttc ttc ttc aga 721Phe Leu His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg 225 230 235gaa atc gcc gtg gaa cat aat aac tta ggc aag gct gtg tat tcc cgc 769Glu Ile Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg 240 245 250gtg gct cgc att tgt aaa aac gac atg ggt ggc tca cag cgg gtc ctg 817Val Ala Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu255 260 265 270gag aaa cac tgg act tcc ttc ctt aag gct cgg ctg aac tgc tcc gtt 865Glu Lys His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val 275 280 285cct gga gat tcc ttt ttc tac ttc gac gtc ctg cag tct ata aca gac 913Pro Gly Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp 290 295 300ata atc caa atc aat ggc atc ccc act gtg gtt ggg gtc ttc acc aca 961Ile Ile Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr 305 310 315cag ctc aac agc att cct ggt tct gca gtc tgt gcc ttt agc atg gac 1009Gln Leu Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp 320 325 330gac att gag aaa gtg ttc aaa ggg cgg ttc aaa gag cag aaa acc cca 1057Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro335 340 345 350gac tct gtt tgg aca gca gtt ccc gaa gac aaa gta cca aaa cca agg 1105Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg 355 360 365cct ggc tgt tgt gcc aaa cac ggc ctc gca gaa gct tac aag acc tcc 1153Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser 370 375 380atc gac ttt cca gat gac acc ctg gct ttc atc aag tcc cac ccg ctg 1201Ile Asp Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu 385 390 395atg gac tct gcc gtc cca ccc att gcc gat gag ccc tgg ttc aca aag 1249Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys 400 405 410aca cgg gtc agg tac agg ttg aca gcc atc gaa gtg gac cgt tca gca 1297Thr Arg Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala415 420 425 430ggg cca tac caa aac tac aca gtc atc ttt gtt ggc tct gaa gct ggc 1345Gly Pro Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly 435 440 445gtg gta ctt aaa gtt ttg gca aag acc agt cct ttc tct ctg aat gac 1393Val Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp 450 455 460agt gta tta ctc gaa gag att gaa gct tat aac cca gcc aag tgc agc 1441Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser 465 470 475gcc gag agt gag gag gac aga aag gtg gtc tca tta cag ctg gac aag 1489Ala Glu Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys 480 485 490gat cac cat gct tta tac gtg gcc ttc tct agc tgc gtg gtc cgc atc 1537Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile495 500 505 510ccc ctc agc cgc tgt gag cgc tac gga tcg tgt aaa aag tct tgc att 1585Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile 515 520 525gca tca cgt gac ccg tac tgt ggt tgg tta agc cag gga gtt tgt gag 1633Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu 530 535 540aga gtg acc cta ggg atg ctc cct gga gga tat gag cag gac acg gag 1681Arg Val Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu 545 550 555tac ggc aac aca gcc cac cta ggg gac tgc cac gac atg gag gta tcc 1729Tyr Gly Asn Thr Ala His Leu Gly Asp Cys His Asp Met Glu Val Ser 560 565 570tca tct tct gtt acc act gtg gca agt agc cca gaa att aca tct aaa 1777Ser Ser Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser Lys575 580 585 590gtg att gat acc tgg aga cct aaa ctg acg agc tcc cgg aaa ttt gta 1825Val Ile Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe Val 595 600 605gtt caa gat gac cca aat act tct gat ttt act gat act ata tca ggt 1873Val Gln Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser Gly 610 615 620atc cca aag ggt gta cgg tgg gaa gtc cag tct gga gaa tcc aat cag 1921Ile Pro Lys Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn Gln 625 630 635atg gtc cac atg aat gtc ctc atc acc tgc gtg ttt gcc gct gga tcc 1969Met Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Gly Ser 640 645 650gag ccc aaa tct tgt gac aaa act cac aca tgc cca ccg tgc cca gca 2017Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala655 660 665 670cct gaa ctc ctg ggg gga ccg tca gtc ttc ctc ttc ccc cca aaa ccc 2065Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 675 680 685aag gac acc ctc atg atc tcc cgg acc cct gag gtc aca tgc gtg gtg 2113Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 690 695 700gtg gac gtg agc cac gaa gac cct gag gtc aag ttc aac tgg tac gtg 2161Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 705 710 715gac ggc gtg gag gtg cat aat gcc aag aca aag ccg cgg gag gag cag 2209Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 720 725 730tac aac agc acg tac cgt gtg gtc agc gtc ctc acc gtc ctg cac cag 2257Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln735 740 745 750gac tgg ctg aat ggc aag gag tac aag tgc aag gtc tcc aac aaa gcc 2305Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 755 760 765ctc cca gcc ccc atc gag aaa acc atc tcc aaa gcc aaa ggg cag ccc 2353Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 770 775 780cga gaa cca cag gtg tac acc ctg ccc cca tcc cgg gat gag ctg acc 2401Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 785 790 795aag aac cag gtc agc ctg acc tgc ctg gtc aaa ggc ttc tat ccc agc 2449Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 800 805 810gac atc gcc gtg gag tgg gag agc aat ggg cag ccg gag aac aac tac 2497Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr815 820 825 830aag acc acg cct ccc gtg ctg gac tcc gac ggc tcc ttc ttc ctc tac 2545Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 835 840 845agc aag ctc acc gtg gac aag agc agg tgg cag cag ggg aac gtc ttc 2593Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 850 855 860tca tgc tcc gtg atg cat gag gct ctg cac aac cac tac acg cag aag 2641Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 865 870 875agc ctc tcc ctg tct ccg ggt aaa tga 2668Ser Leu Ser Leu Ser Pro Gly Lys 880 8852886PRTArtificialSynthetic Construct 2Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Asp Met Glu Val Ser Ser Ser 565 570 575Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser Lys Val Ile 580 585 590Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe Val Val Gln 595 600 605Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser Gly Ile Pro 610 615 620Lys Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn Gln Met Val625 630 635 640His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Gly Ser Glu Pro 645 650 655Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 660 665 670Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 675 680 685Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 690 695 700Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly705 710 715 720Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 725 730 735Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 740 745 750Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 755 760 765Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 770 775 780Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn785 790 795 800Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 805 810 815Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 820 825 830Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 835 840 845Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 850 855 860Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu865 870 875 880Ser Leu Ser Pro Gly Lys 885320DNAArtificialPCR primer 3agggctatgc tctccctcac 20420DNAArtificialPCR primer 4ctctcagctg tggtggtgaa 20520DNAArtificialPCR primer 5cagaagcatg ggagatggat 20620DNAArtificialPCR primer 6gccacccatg tcgtttttac 20723DNAArtificialPCR primer 7atggggttcc ttctgctttg gtt 23828DNAArtificialPCR primer 8ctagtacgtg tacttgttca gtggtctg 28941DNAArtificialPCR primer 9gcggatatcg ccacccatgg ggttccttct gctttggttc t 411035DNAArtificialPCR primer 10gcgggatcca gcggcaaaca cgcaggtgat gagga 351120DNAArtificialPCR primer 11cgggacttcg ctatcttcag 201220DNAArtificialPCR primer 12agcatgagtg gcttttccag

201320DNAArtificialPCR primer 13gctgtcttct ccacctccag 201420DNAArtificialPCR primer 14ggttccgacc aaactggata 201520DNAArtificialPCR primer 15tcggcagtgt gtgtgtatca 201620DNAArtificialPCR primer 16ccttctgtgg atggggtaga 201720DNAArtificialPCR primer 17atggctgata tccgagcagt 201820DNAArtificialPCR primer 18ttctcttgaa ggtcggtgct 201920DNAArtificialPCR primer 19gaggccatgc tgtatgtgtg 202020DNAArtificialPCR primer 20cgtcatcggg taatctttgg 20215923DNAHomo sapiensCDS(440)..(3472) 21gcggccgctt cccaccgtcc ctctcccctt actggcagag cgcgctgcgg gcggactccc 60gggcccggag cagcccaccg gccaccccac cgcccacccg gctcccggtg tctcctcccg 120gccgctctac ccagcaactt tccgtgcttt gttccccgac tggaaatgct ttacggaagc 180gtcttggaca gggtctccgc caggcgacaa gagctcggtg ctgagatgtg ttacgttctc 240atctccccat caattatgga tggaaacaaa taaggaagag tcaattttgc tgagcccctt 300ctccggcaac gagaggcgtt ctgcagccgg gagggagccg ccgctcgcgc cggcagccgc 360tggcaggggc atggtgagga ggaaggtagc tcagtggcat ttctgagcag gggccaccct 420gacttcacct tggcccacc atg agg gtc ttc ctg ctt tgt gcc tac ata ctg 472 Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu 1 5 10ctg ctg atg gtt tcc cag ttg agg gca gtc agc ttt cct gaa gat gat 520Leu Leu Met Val Ser Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp 15 20 25gaa ccc ctt aat act gtc gac tat cac tat tca agg caa tat ccg gtt 568Glu Pro Leu Asn Thr Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val 30 35 40ttt aga gga cgc cct tca ggc aat gaa tcg cag cac agg ctg gac ttt 616Phe Arg Gly Arg Pro Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe 45 50 55cag ctg atg ttg aaa att cga gac aca ctt tat att gct ggc agg gat 664Gln Leu Met Leu Lys Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp60 65 70 75caa gtt tat aca gta aac tta aat gaa atg ccc aaa aca gaa gta ata 712Gln Val Tyr Thr Val Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile 80 85 90ccc aac aag aaa ctg aca tgg cga tca aga caa cag gat cga gaa aac 760Pro Asn Lys Lys Leu Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn 95 100 105tgt gct atg aaa ggc aag cat aaa gat gaa tgc cac aac ttt atc aaa 808Cys Ala Met Lys Gly Lys His Lys Asp Glu Cys His Asn Phe Ile Lys 110 115 120gta ttt gtt cca aga aac gat gag atg gtt ttt gtt tgt ggt acc aat 856Val Phe Val Pro Arg Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn 125 130 135gca ttc aat ccc atg tgt aga tac tac agg ttg agt acc tta gaa tat 904Ala Phe Asn Pro Met Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr140 145 150 155gat ggg gaa gaa att agt ggc ctg gca aga tgc cca ttt gat gcc aga 952Asp Gly Glu Glu Ile Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg 160 165 170caa acc aat gtt gcc ctc ttt gct gat ggg aag ctg tat tct gcc aca 1000Gln Thr Asn Val Ala Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr 175 180 185gtg gct gac ttc ttg gcc agc gat gcc gtt att tat cga agc atg ggt 1048Val Ala Asp Phe Leu Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly 190 195 200gat gga tct gcc ctt cgc aca ata aaa tat gat tcc aaa tgg ata aaa 1096Asp Gly Ser Ala Leu Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys 205 210 215gag cca cac ttt ctt cat gcc ata gaa tat gga aac tat gtc tat ttc 1144Glu Pro His Phe Leu His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe220 225 230 235ttc ttt cga gaa atc gct gtc gaa cat aat aat tta ggc aag gct gtg 1192Phe Phe Arg Glu Ile Ala Val Glu His Asn Asn Leu Gly Lys Ala Val 240 245 250tat tcc cgc gtg gcc cgc ata tgt aaa aac gac atg ggt ggt tcc cag 1240Tyr Ser Arg Val Ala Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln 255 260 265cgg gtc ctg gag aaa cac tgg act tca ttt cta aag gct cgg ctg aac 1288Arg Val Leu Glu Lys His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn 270 275 280tgt tct gtc cct gga gat tcg ttt ttc tac ttt gat gtt ctg cag tct 1336Cys Ser Val Pro Gly Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser 285 290 295att aca gac ata ata caa atc aat ggc atc ccc act gtg gtc ggg gtg 1384Ile Thr Asp Ile Ile Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val300 305 310 315ttt acc acg cag ctc aat agc atc cct ggt tct gct gtc tgt gca ttt 1432Phe Thr Thr Gln Leu Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe 320 325 330agc atg gat gac att gaa aaa gta ttc aaa gga cgg ttt aag gaa cag 1480Ser Met Asp Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln 335 340 345aaa act cca gat tct gtt tgg aca gca gtt ccc gaa gac aaa gtg cca 1528Lys Thr Pro Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro 350 355 360aag cca agg cct ggc tgt tgt gca aaa cac ggc ctt gcc gaa gct tat 1576Lys Pro Arg Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr 365 370 375aaa acc tcc atc gat ttc ccg gat gaa act ctg tca ttc atc aaa tct 1624Lys Thr Ser Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser380 385 390 395cat ccc ctg atg gac tct gcc gtt cca ccc att gcc gat gag ccc tgg 1672His Pro Leu Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp 400 405 410ttc aca aag act cgg gtc agg tac aga ctg acg gcc atc tca gtg gac 1720Phe Thr Lys Thr Arg Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp 415 420 425cat tca gcc gga ccc tac cag aac tac aca gtc atc ttt gtt ggc tct 1768His Ser Ala Gly Pro Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser 430 435 440gaa gct ggc atg gta ctt aaa gtt ctg gca aag acc agt cct ttc tct 1816Glu Ala Gly Met Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser 445 450 455ttg aac gac agc gta tta ctg gaa gag att gaa gcc tac aac cat gca 1864Leu Asn Asp Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala460 465 470 475aag tgc agt gct gag aat gag gaa gac aaa aag gtc atc tca tta cag 1912Lys Cys Ser Ala Glu Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln 480 485 490ttg gat aaa gat cac cac gct tta tat gtg gcg ttc tct agc tgc att 1960Leu Asp Lys Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile 495 500 505atc cgc atc ccc ctc agt cgc tgt gag cgt tat gga tca tgt aaa aag 2008Ile Arg Ile Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys 510 515 520tct tgt att gca tct cgt gac ccg tat tgt ggc tgg tta agc cag gga 2056Ser Cys Ile Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly 525 530 535tcc tgt ggt aga gtg acc cca ggg atg ctg ctg tta acc gaa gac ttc 2104Ser Cys Gly Arg Val Thr Pro Gly Met Leu Leu Leu Thr Glu Asp Phe540 545 550 555ttt gct ttc cat aac cac agt gct gaa gga tat gaa caa gac aca gaa 2152Phe Ala Phe His Asn His Ser Ala Glu Gly Tyr Glu Gln Asp Thr Glu 560 565 570ttc ggc aac aca gct cat cta ggg gac tgc cat ggt gta cga tgg gaa 2200Phe Gly Asn Thr Ala His Leu Gly Asp Cys His Gly Val Arg Trp Glu 575 580 585gtc cag tct gga gag tcc aac cag atg gtc cac atg aat gtc ctc atc 2248Val Gln Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu Ile 590 595 600acc tgt gtc ttt gct gct ttt gtt ttg ggg gca ttc att gca ggt gtg 2296Thr Cys Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val 605 610 615gca gta tac tgc tat cga gac atg ttt gtt cgg aaa aac aga aag atc 2344Ala Val Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile620 625 630 635cat aaa gat gca gag tcc gcc cag tca tgc aca gac tcc agt gga agt 2392His Lys Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser 640 645 650ttt gcc aaa ctg aat ggt ctc ttt gac agc cct gtc aag gaa tac caa 2440Phe Ala Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln 655 660 665cag aat att gat tct cct aaa ctg tat agt aac ctg cta acc agt cgg 2488Gln Asn Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg 670 675 680aaa gag cta cca ccc aat gga gat act aaa tcc atg gta atg gac cat 2536Lys Glu Leu Pro Pro Asn Gly Asp Thr Lys Ser Met Val Met Asp His 685 690 695cga ggg caa cct cca gag ttg gct gct ctt cct act cct gag tct aca 2584Arg Gly Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr700 705 710 715ccc gtg ctt cac cag aag acc ctg cag gcc atg aag agc cac tca gaa 2632Pro Val Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu 720 725 730aag gcc cat ggc cat gga gct tca agg aaa gaa acc cct cag ttt ttt 2680Lys Ala His Gly His Gly Ala Ser Arg Lys Glu Thr Pro Gln Phe Phe 735 740 745ccg tct agt ccg cca cct cat tcc cca tta agt cat ggg cat atc ccc 2728Pro Ser Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro 750 755 760agt gcc att gtt ctt cca aat gct acc cat gac tac aac acg tct ttc 2776Ser Ala Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe 765 770 775tca aac tcc aat gct cac aaa gct gaa aag aag ctt caa aac att gat 2824Ser Asn Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Asn Ile Asp780 785 790 795cac cct ctc aca aag tca tcc agt aag aga gat cac cgg cgt tct gtt 2872His Pro Leu Thr Lys Ser Ser Ser Lys Arg Asp His Arg Arg Ser Val 800 805 810gat tcc aga aat acc ctc aat gat ctc ctg aag cat ctg aat gac cca 2920Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro 815 820 825aat agt aac ccc aaa gcc atc atg gga gac atc cag atg gca cac cag 2968Asn Ser Asn Pro Lys Ala Ile Met Gly Asp Ile Gln Met Ala His Gln 830 835 840aac tta atg ctg gat ccc atg gga tcg atg tct gag gtc cca cct aaa 3016Asn Leu Met Leu Asp Pro Met Gly Ser Met Ser Glu Val Pro Pro Lys 845 850 855gtc cct aac cgg gag gca tcg cta tac tcc cct cct tca act ctc ccc 3064Val Pro Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro860 865 870 875aga aat agc cca acc aag cga gtg gat gtc ccc acc act cct gga gtc 3112Arg Asn Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val 880 885 890cca atg act tct ctg gaa aga caa aga ggt tat cac aaa aat tcc tcc 3160Pro Met Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser 895 900 905cag agg cac tct ata tct gct atg cct aaa aac tta aac tca cca aat 3208Gln Arg His Ser Ile Ser Ala Met Pro Lys Asn Leu Asn Ser Pro Asn 910 915 920ggt gtt ttg tta tcc aga cag cct agt atg aac cgt gga gga tat atg 3256Gly Val Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met 925 930 935ccc acc ccc act ggg gcg aag gtg gac tat att cag gga aca cca gtg 3304Pro Thr Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val940 945 950 955agt gtt cat ctg cag cct tcc ctc tcc aga cag agc agc tac acc agt 3352Ser Val His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser 960 965 970aat ggc act ctt cct agg acg gga cta aag agg acg ccg tcc tta aaa 3400Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys 975 980 985cct gac gtg cca cca aag cct tcc ttt gtt cct caa acc cca tct gtc 3448Pro Asp Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Pro Ser Val 990 995 1000aga cca ctg aac aaa tac aca tac taggcctcaa gtgtgctatt 3492Arg Pro Leu Asn Lys Tyr Thr Tyr 1005 1010cccatgtggc tttatcctgt ccgtgttgtt gagaggatga tgttgtaagg gtaccttaaa 3552acaagagact cgcttgtatt ttaagagaac caagtggcca aagaaactct ttctaacttt 3612ggcaacatca gaacttgcca catgtagcta ctgcagcaag gcttctgtgt acttgcctga 3672aaacaaagga aggtgctggt cattccattt cttttgtttg aagctaaaga gatgtgtagc 3732tcacaggggc taccttacca gtataaagag ctgataacag tactcagaag aatctgtgaa 3792caaatacttg aaaatgggtt caatgtagac tgccattatg tgtggtcttc ccattaaatg 3852tgaacatttt aatatgtatg cattcacctt gcctcttgca caaatgtcaa aaaaaagatg 3912gtaatatctc aaagaaatga acttgtagat taccaagcag tttgctaaaa attcaatctt 3972tgacccaagc tgtagcattt ttttttcatg tgtggcatct ttttcatgcc accaacaaac 4032ttgttgtgtg tgtgcgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtt ctgtacccac 4092taggatttgt ttaggtgccc attgcatctt tttgtgctat ggagttgttt acattaagca 4152tgaccgaacg agagacaata ctatttccca caggagtcca ttgggttcag ctttgaaaga 4212ggaatagaat cgaggctcct ttgaccatca aaatgatgaa ctttacttat gtggtaccca 4272atgccagaat gtaagagttg caagtgattt tgtgctgcta ttcattaaaa cttgtattcc 4332agtcttgcca gcttaaggag atcaagatat taagaggtat ccttgattta ttttccagta 4392ttcagtagta aaattttcct gtccactgtg aatcaaagcc tgagtcactc tatttaacct 4452tggacacact aataaggttt tattttgatt gtgttcgttt cccccccccc aatagtaaaa 4512tttctcctcc tttaactcct cctacccccc aaggtaagaa acaaaaaaca aacaaacaaa 4572caaaaataga agacaaaaga aagacatatg aaaggaattg taattggctt aacagaaaca 4632gtctgtaaaa acctaacagt ggtgcaatca tgttgtctgt gttgtgttat gtgagaattt 4692tctcctaagt catgcaggta atgacaatat actgtaaata ccacatgtga gtttacctga 4752atctgtgcat tttgtgcctt attcatgaga atgatagaag tactaaaatc tgtcaagtgt 4812tttcagtata gcacattatt tactgagtgc cagttgtaaa tgtttttcaa ccagcaccta 4872aaaagactct tttcaaaaaa tcacagaaac aacctaggac aattatttgt tacataatcc 4932gacctcatag cagcattaca ttctttgccg tgataaacat tccactcctg ctttcctaag 4992gatgaaacag tgataatgtg aactcaaatg aggtttcctg ggtaatgtga cacctgcaga 5052aactatagag cgtcatttat acgtagtttg gcagaaacca cttacggctg atgatgcgca 5112accctgctga ctgtttcagt taatatgctg cacaccacac acttgtttag tgaaccaaat 5172ctagaaagta ccaaggcaga ggtatgctcc tgctgtaatc aggcaaatga gttcaactgg 5232atttcttttg acaatactgt tggtacctat tacttggggg aggacatgtt gcagaagacc 5292agatcatttt tatacagaat gtgaaatact gatacagtta ttcttttttt taaagaacat 5352tgttttataa agaacgtgat ttccagtgat ctctggaagc gctaaagcta aaatttctgt 5412tcttgaaaca cttcagcttt gcaactaaaa tattacagat taataataaa ttaaaccaac 5472caatgataaa cactactcag tccaccaaca acaaacgtgt ttgaattcac cttaccaata 5532ttaatcccag cgtgtgtaaa acagaacagt aactctatgt gaccccagat aacattttgt 5592aacattgtgc ttccttgtag tttgtaatgt gagttcaatc agtatttatg ttgaaatttc 5652taacattaaa tctagtctct atcctgttaa tttaattttt aaatgcttta tccatttgtg 5712caaaggtaaa cgcagattgt atctttttta atggtacggc ataaaaagta accctcaagt 5772gaagtgtctc tatactgttt tatagagtac tttaacatga atagatacct tgtaaacttg 5832tattgtggat gtgtaaataa tatgtacttt gggtttttaa caccgcatgt aaagtcaaaa 5892taaaatatac aaatcattat aaaaaaaaaa a 5923221011PRTHomo sapiens 22Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu Leu Leu Met Val Ser1 5 10 15Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225

230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp His Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Met Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala Lys Cys Ser Ala Glu465 470 475 480Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile Ile Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Ser Cys Gly Arg Val 530 535 540Thr Pro Gly Met Leu Leu Leu Thr Glu Asp Phe Phe Ala Phe His Asn545 550 555 560His Ser Ala Glu Gly Tyr Glu Gln Asp Thr Glu Phe Gly Asn Thr Ala 565 570 575His Leu Gly Asp Cys His Gly Val Arg Trp Glu Val Gln Ser Gly Glu 580 585 590Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala 595 600 605Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr 610 615 620Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu625 630 635 640Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn 645 650 655Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser 660 665 670Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro 675 680 685Asn Gly Asp Thr Lys Ser Met Val Met Asp His Arg Gly Gln Pro Pro 690 695 700Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln705 710 715 720Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala His Gly His 725 730 735Gly Ala Ser Arg Lys Glu Thr Pro Gln Phe Phe Pro Ser Ser Pro Pro 740 745 750Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala Ile Val Leu 755 760 765Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala 770 775 780His Lys Ala Glu Lys Lys Leu Gln Asn Ile Asp His Pro Leu Thr Lys785 790 795 800Ser Ser Ser Lys Arg Asp His Arg Arg Ser Val Asp Ser Arg Asn Thr 805 810 815Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys 820 825 830Ala Ile Met Gly Asp Ile Gln Met Ala His Gln Asn Leu Met Leu Asp 835 840 845Pro Met Gly Ser Met Ser Glu Val Pro Pro Lys Val Pro Asn Arg Glu 850 855 860Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr865 870 875 880Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu 885 890 895Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile 900 905 910Ser Ala Met Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser 915 920 925Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly 930 935 940Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val His Leu Gln945 950 955 960Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro 965 970 975Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro Pro 980 985 990Lys Pro Ser Phe Val Pro Gln Thr Pro Ser Val Arg Pro Leu Asn Lys 995 1000 1005Tyr Thr Tyr 1010235884DNAHomo sapiensCDS(440)..(3433) 23gcggccgctt cccaccgtcc ctctcccctt actggcagag cgcgctgcgg gcggactccc 60gggcccggag cagcccaccg gccaccccac cgcccacccg gctcccggtg tctcctcccg 120gccgctctac ccagcaactt tccgtgcttt gttccccgac tggaaatgct ttacggaagc 180gtcttggaca gggtctccgc caggcgacaa gagctcggtg ctgagatgtg ttacgttctc 240atctccccat caattatgga tggaaacaaa taaggaagag tcaattttgc tgagcccctt 300ctccggcaac gagaggcgtt ctgcagccgg gagggagccg ccgctcgcgc cggcagccgc 360tggcaggggc atggtgagga ggaaggtagc tcagtggcat ttctgagcag gggccaccct 420gacttcacct tggcccacc atg agg gtc ttc ctg ctt tgt gcc tac ata ctg 472 Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu 1 5 10ctg ctg atg gtt tcc cag ttg agg gca gtc agc ttt cct gaa gat gat 520Leu Leu Met Val Ser Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp 15 20 25gaa ccc ctt aat act gtc gac tat cac tat tca agg caa tat ccg gtt 568Glu Pro Leu Asn Thr Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val 30 35 40ttt aga gga cgc cct tca ggc aat gaa tcg cag cac agg ctg gac ttt 616Phe Arg Gly Arg Pro Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe 45 50 55cag ctg atg ttg aaa att cga gac aca ctt tat att gct ggc agg gat 664Gln Leu Met Leu Lys Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp60 65 70 75caa gtt tat aca gta aac tta aat gaa atg ccc aaa aca gaa gta ata 712Gln Val Tyr Thr Val Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile 80 85 90ccc aac aag aaa ctg aca tgg cga tca aga caa cag gat cga gaa aac 760Pro Asn Lys Lys Leu Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn 95 100 105tgt gct atg aaa ggc aag cat aaa gat gaa tgc cac aac ttt atc aaa 808Cys Ala Met Lys Gly Lys His Lys Asp Glu Cys His Asn Phe Ile Lys 110 115 120gta ttt gtt cca aga aac gat gag atg gtt ttt gtt tgt ggt acc aat 856Val Phe Val Pro Arg Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn 125 130 135gca ttc aat ccc atg tgt aga tac tac agg ttg agt acc tta gaa tat 904Ala Phe Asn Pro Met Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr140 145 150 155gat ggg gaa gaa att agt ggc ctg gca aga tgc cca ttt gat gcc aga 952Asp Gly Glu Glu Ile Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg 160 165 170caa acc aat gtt gcc ctc ttt gct gat ggg aag ctg tat tct gcc aca 1000Gln Thr Asn Val Ala Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr 175 180 185gtg gct gac ttc ttg gcc agc gat gcc gtt att tat cga agc atg ggt 1048Val Ala Asp Phe Leu Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly 190 195 200gat gga tct gcc ctt cgc aca ata aaa tat gat tcc aaa tgg ata aaa 1096Asp Gly Ser Ala Leu Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys 205 210 215gag cca cac ttt ctt cat gcc ata gaa tat gga aac tat gtc tat ttc 1144Glu Pro His Phe Leu His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe220 225 230 235ttc ttt cga gaa atc gct gtc gaa cat aat aat tta ggc aag gct gtg 1192Phe Phe Arg Glu Ile Ala Val Glu His Asn Asn Leu Gly Lys Ala Val 240 245 250tat tcc cgc gtg gcc cgc ata tgt aaa aac gac atg ggt ggt tcc cag 1240Tyr Ser Arg Val Ala Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln 255 260 265cgg gtc ctg gag aaa cac tgg act tca ttt cta aag gct cgg ctg aac 1288Arg Val Leu Glu Lys His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn 270 275 280tgt tct gtc cct gga gat tcg ttt ttc tac ttt gat gtt ctg cag tct 1336Cys Ser Val Pro Gly Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser 285 290 295att aca gac ata ata caa atc aat ggc atc ccc act gtg gtc ggg gtg 1384Ile Thr Asp Ile Ile Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val300 305 310 315ttt acc acg cag ctc aat agc atc cct ggt tct gct gtc tgt gca ttt 1432Phe Thr Thr Gln Leu Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe 320 325 330agc atg gat gac att gaa aaa gta ttc aaa gga cgg ttt aag gaa cag 1480Ser Met Asp Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln 335 340 345aaa act cca gat tct gtt tgg aca gca gtt ccc gaa gac aaa gtg cca 1528Lys Thr Pro Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro 350 355 360aag cca agg cct ggc tgt tgt gca aaa cac ggc ctt gcc gaa gct tat 1576Lys Pro Arg Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr 365 370 375aaa acc tcc atc gat ttc ccg gat gaa act ctg tca ttc atc aaa tct 1624Lys Thr Ser Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser380 385 390 395cat ccc ctg atg gac tct gcc gtt cca ccc att gcc gat gag ccc tgg 1672His Pro Leu Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp 400 405 410ttc aca aag act cgg gtc agg tac aga ctg acg gcc atc tca gtg gac 1720Phe Thr Lys Thr Arg Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp 415 420 425cat tca gcc gga ccc tac cag aac tac aca gtc atc ttt gtt ggc tct 1768His Ser Ala Gly Pro Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser 430 435 440gaa gct ggc atg gta ctt aaa gtt ctg gca aag acc agt cct ttc tct 1816Glu Ala Gly Met Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser 445 450 455ttg aac gac agc gta tta ctg gaa gag att gaa gcc tac aac cat gca 1864Leu Asn Asp Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala460 465 470 475aag tgc agt gct gag aat gag gaa gac aaa aag gtc atc tca tta cag 1912Lys Cys Ser Ala Glu Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln 480 485 490ttg gat aaa gat cac cac gct tta tat gtg gcg ttc tct agc tgc att 1960Leu Asp Lys Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile 495 500 505atc cgc atc ccc ctc agt cgc tgt gag cgt tat gga tca tgt aaa aag 2008Ile Arg Ile Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys 510 515 520tct tgt att gca tct cgt gac ccg tat tgt ggc tgg tta agc cag gga 2056Ser Cys Ile Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly 525 530 535tcc tgt ggt aga gtg acc cca ggg atg ctt gct gaa gga tat gaa caa 2104Ser Cys Gly Arg Val Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln540 545 550 555gac aca gaa ttc ggc aac aca gct cat cta ggg gac tgc cat ggt gta 2152Asp Thr Glu Phe Gly Asn Thr Ala His Leu Gly Asp Cys His Gly Val 560 565 570cga tgg gaa gtc cag tct gga gag tcc aac cag atg gtc cac atg aat 2200Arg Trp Glu Val Gln Ser Gly Glu Ser Asn Gln Met Val His Met Asn 575 580 585gtc ctc atc acc tgt gtc ttt gct gct ttt gtt ttg ggg gca ttc att 2248Val Leu Ile Thr Cys Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile 590 595 600gca ggt gtg gca gta tac tgc tat cga gac atg ttt gtt cgg aaa aac 2296Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn 605 610 615aga aag atc cat aaa gat gca gag tcc gcc cag tca tgc aca gac tcc 2344Arg Lys Ile His Lys Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser620 625 630 635agt gga agt ttt gcc aaa ctg aat ggt ctc ttt gac agc cct gtc aag 2392Ser Gly Ser Phe Ala Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys 640 645 650gaa tac caa cag aat att gat tct cct aaa ctg tat agt aac ctg cta 2440Glu Tyr Gln Gln Asn Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu 655 660 665acc agt cgg aaa gag cta cca ccc aat gga gat act aaa tcc atg gta 2488Thr Ser Arg Lys Glu Leu Pro Pro Asn Gly Asp Thr Lys Ser Met Val 670 675 680atg gac cat cga ggg caa cct cca gag ttg gct gct ctt cct act cct 2536Met Asp His Arg Gly Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro 685 690 695gag tct aca ccc gtg ctt cac cag aag acc ctg cag gcc atg aag agc 2584Glu Ser Thr Pro Val Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser700 705 710 715cac tca gaa aag gcc cat ggc cat gga gct tca agg aaa gaa acc cct 2632His Ser Glu Lys Ala His Gly His Gly Ala Ser Arg Lys Glu Thr Pro 720 725 730cag ttt ttt ccg tct agt ccg cca cct cat tcc cca tta agt cat ggg 2680Gln Phe Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu Ser His Gly 735 740 745cat atc ccc agt gcc att gtt ctt cca aat gct acc cat gac tac aac 2728His Ile Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn 750 755 760acg tct ttc tca aac tcc aat gct cac aaa gct gaa aag aag ctt caa 2776Thr Ser Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln 765 770 775aac att gat cac cct ctc aca aag tca tcc agt aag aga gat cac cgg 2824Asn Ile Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg Asp His Arg780 785 790 795cgt tct gtt gat tcc aga aat acc ctc aat gat ctc ctg aag cat ctg 2872Arg Ser Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu 800 805 810aat gac cca aat agt aac ccc aaa gcc atc atg gga gac atc cag atg 2920Asn Asp Pro Asn Ser Asn Pro Lys Ala Ile Met Gly Asp Ile Gln Met 815 820 825gca cac cag aac tta atg ctg gat ccc atg gga tcg atg tct gag gtc 2968Ala His Gln Asn Leu Met Leu Asp Pro Met Gly Ser Met Ser Glu Val 830 835 840cca cct aaa gtc cct aac cgg gag gca tcg cta tac tcc cct cct tca 3016Pro Pro Lys Val Pro Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser 845 850 855act ctc ccc aga aat agc cca acc aag cga gtg gat gtc ccc acc act 3064Thr Leu Pro Arg Asn Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr860 865 870 875cct gga gtc cca atg act tct ctg gaa aga caa aga ggt tat cac aaa 3112Pro Gly Val Pro Met Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys 880 885 890aat tcc tcc cag agg cac tct ata tct gct atg cct aaa aac tta aac 3160Asn Ser Ser Gln Arg His Ser Ile Ser Ala Met Pro Lys Asn Leu Asn 895 900 905tca cca aat ggt gtt ttg tta tcc aga cag cct agt atg aac cgt gga 3208Ser Pro Asn Gly Val Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly 910 915 920gga tat atg ccc acc ccc act ggg gcg aag gtg gac tat att cag gga 3256Gly Tyr Met Pro Thr Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly 925 930 935aca cca gtg agt gtt cat ctg cag cct tcc ctc tcc aga cag agc agc 3304Thr Pro Val Ser Val His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser940 945 950 955tac acc agt aat ggc act ctt cct agg acg gga cta aag agg acg ccg 3352Tyr Thr Ser Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro 960 965 970tcc tta aaa cct gac gtg cca cca aag cct tcc ttt gtt cct caa acc 3400Ser Leu Lys Pro Asp Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr 975 980 985cca tct gtc aga cca ctg aac aaa tac aca tac taggcctcaa gtgtgctatt 3453Pro Ser Val Arg Pro Leu Asn Lys Tyr Thr Tyr 990 995cccatgtggc tttatcctgt ccgtgttgtt gagaggatga tgttgtaagg gtaccttaaa

3513acaagagact cgcttgtatt ttaagagaac caagtggcca aagaaactct ttctaacttt 3573ggcaacatca gaacttgcca catgtagcta ctgcagcaag gcttctgtgt acttgcctga 3633aaacaaagga aggtgctggt cattccattt cttttgtttg aagctaaaga gatgtgtagc 3693tcacaggggc taccttacca gtataaagag ctgataacag tactcagaag aatctgtgaa 3753caaatacttg aaaatgggtt caatgtagac tgccattatg tgtggtcttc ccattaaatg 3813tgaacatttt aatatgtatg cattcacctt gcctcttgca caaatgtcaa aaaaaagatg 3873gtaatatctc aaagaaatga acttgtagat taccaagcag tttgctaaaa attcaatctt 3933tgacccaagc tgtagcattt ttttttcatg tgtggcatct ttttcatgcc accaacaaac 3993ttgttgtgtg tgtgcgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtt ctgtacccac 4053taggatttgt ttaggtgccc attgcatctt tttgtgctat ggagttgttt acattaagca 4113tgaccgaacg agagacaata ctatttccca caggagtcca ttgggttcag ctttgaaaga 4173ggaatagaat cgaggctcct ttgaccatca aaatgatgaa ctttacttat gtggtaccca 4233atgccagaat gtaagagttg caagtgattt tgtgctgcta ttcattaaaa cttgtattcc 4293agtcttgcca gcttaaggag atcaagatat taagaggtat ccttgattta ttttccagta 4353ttcagtagta aaattttcct gtccactgtg aatcaaagcc tgagtcactc tatttaacct 4413tggacacact aataaggttt tattttgatt gtgttcgttt cccccccccc aatagtaaaa 4473tttctcctcc tttaactcct cctacccccc aaggtaagaa acaaaaaaca aacaaacaaa 4533caaaaataga agacaaaaga aagacatatg aaaggaattg taattggctt aacagaaaca 4593gtctgtaaaa acctaacagt ggtgcaatca tgttgtctgt gttgtgttat gtgagaattt 4653tctcctaagt catgcaggta atgacaatat actgtaaata ccacatgtga gtttacctga 4713atctgtgcat tttgtgcctt attcatgaga atgatagaag tactaaaatc tgtcaagtgt 4773tttcagtata gcacattatt tactgagtgc cagttgtaaa tgtttttcaa ccagcaccta 4833aaaagactct tttcaaaaaa tcacagaaac aacctaggac aattatttgt tacataatcc 4893gacctcatag cagcattaca ttctttgccg tgataaacat tccactcctg ctttcctaag 4953gatgaaacag tgataatgtg aactcaaatg aggtttcctg ggtaatgtga cacctgcaga 5013aactatagag cgtcatttat acgtagtttg gcagaaacca cttacggctg atgatgcgca 5073accctgctga ctgtttcagt taatatgctg cacaccacac acttgtttag tgaaccaaat 5133ctagaaagta ccaaggcaga ggtatgctcc tgctgtaatc aggcaaatga gttcaactgg 5193atttcttttg acaatactgt tggtacctat tacttggggg aggacatgtt gcagaagacc 5253agatcatttt tatacagaat gtgaaatact gatacagtta ttcttttttt taaagaacat 5313tgttttataa agaacgtgat ttccagtgat ctctggaagc gctaaagcta aaatttctgt 5373tcttgaaaca cttcagcttt gcaactaaaa tattacagat taataataaa ttaaaccaac 5433caatgataaa cactactcag tccaccaaca acaaacgtgt ttgaattcac cttaccaata 5493ttaatcccag cgtgtgtaaa acagaacagt aactctatgt gaccccagat aacattttgt 5553aacattgtgc ttccttgtag tttgtaatgt gagttcaatc agtatttatg ttgaaatttc 5613taacattaaa tctagtctct atcctgttaa tttaattttt aaatgcttta tccatttgtg 5673caaaggtaaa cgcagattgt atctttttta atggtacggc ataaaaagta accctcaagt 5733gaagtgtctc tatactgttt tatagagtac tttaacatga atagatacct tgtaaacttg 5793tattgtggat gtgtaaataa tatgtacttt gggtttttaa caccgcatgt aaagtcaaaa 5853taaaatatac aaatcattat aaaaaaaaaa a 588424998PRTHomo sapiens 24Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu Leu Leu Met Val Ser1 5 10 15Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp His Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Met Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala Lys Cys Ser Ala Glu465 470 475 480Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile Ile Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Ser Cys Gly Arg Val 530 535 540Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln Asp Thr Glu Phe Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Gly Val Arg Trp Glu Val Gln 565 570 575Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys 580 585 590Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val 595 600 605Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys 610 615 620Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala625 630 635 640Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn 645 650 655Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu 660 665 670Leu Pro Pro Asn Gly Asp Thr Lys Ser Met Val Met Asp His Arg Gly 675 680 685Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val 690 695 700Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala705 710 715 720His Gly His Gly Ala Ser Arg Lys Glu Thr Pro Gln Phe Phe Pro Ser 725 730 735Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala 740 745 750Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn 755 760 765Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Asn Ile Asp His Pro 770 775 780Leu Thr Lys Ser Ser Ser Lys Arg Asp His Arg Arg Ser Val Asp Ser785 790 795 800Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser 805 810 815Asn Pro Lys Ala Ile Met Gly Asp Ile Gln Met Ala His Gln Asn Leu 820 825 830Met Leu Asp Pro Met Gly Ser Met Ser Glu Val Pro Pro Lys Val Pro 835 840 845Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn 850 855 860Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met865 870 875 880Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg 885 890 895His Ser Ile Ser Ala Met Pro Lys Asn Leu Asn Ser Pro Asn Gly Val 900 905 910Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr 915 920 925Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val 930 935 940His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly945 950 955 960Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp 965 970 975Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Pro Ser Val Arg Pro 980 985 990Leu Asn Lys Tyr Thr Tyr 995255941DNAHomo sapiensCDS(440)..(3490) 25gcggccgctt cccaccgtcc ctctcccctt actggcagag cgcgctgcgg gcggactccc 60gggcccggag cagcccaccg gccaccccac cgcccacccg gctcccggtg tctcctcccg 120gccgctctac ccagcaactt tccgtgcttt gttccccgac tggaaatgct ttacggaagc 180gtcttggaca gggtctccgc caggcgacaa gagctcggtg ctgagatgtg ttacgttctc 240atctccccat caattatgga tggaaacaaa taaggaagag tcaattttgc tgagcccctt 300ctccggcaac gagaggcgtt ctgcagccgg gagggagccg ccgctcgcgc cggcagccgc 360tggcaggggc atggtgagga ggaaggtagc tcagtggcat ttctgagcag gggccaccct 420gacttcacct tggcccacc atg agg gtc ttc ctg ctt tgt gcc tac ata ctg 472 Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu 1 5 10ctg ctg atg gtt tcc cag ttg agg gca gtc agc ttt cct gaa gat gat 520Leu Leu Met Val Ser Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp 15 20 25gaa ccc ctt aat act gtc gac tat cac tat tca agg caa tat ccg gtt 568Glu Pro Leu Asn Thr Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val 30 35 40ttt aga gga cgc cct tca ggc aat gaa tcg cag cac agg ctg gac ttt 616Phe Arg Gly Arg Pro Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe 45 50 55cag ctg atg ttg aaa att cga gac aca ctt tat att gct ggc agg gat 664Gln Leu Met Leu Lys Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp60 65 70 75caa gtt tat aca gta aac tta aat gaa atg ccc aaa aca gaa gta ata 712Gln Val Tyr Thr Val Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile 80 85 90ccc aac aag aaa ctg aca tgg cga tca aga caa cag gat cga gaa aac 760Pro Asn Lys Lys Leu Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn 95 100 105tgt gct atg aaa ggc aag cat aaa gat gaa tgc cac aac ttt atc aaa 808Cys Ala Met Lys Gly Lys His Lys Asp Glu Cys His Asn Phe Ile Lys 110 115 120gta ttt gtt cca aga aac gat gag atg gtt ttt gtt tgt ggt acc aat 856Val Phe Val Pro Arg Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn 125 130 135gca ttc aat ccc atg tgt aga tac tac agg ttg agt acc tta gaa tat 904Ala Phe Asn Pro Met Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr140 145 150 155gat ggg gaa gaa att agt ggc ctg gca aga tgc cca ttt gat gcc aga 952Asp Gly Glu Glu Ile Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg 160 165 170caa acc aat gtt gcc ctc ttt gct gat ggg aag ctg tat tct gcc aca 1000Gln Thr Asn Val Ala Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr 175 180 185gtg gct gac ttc ttg gcc agc gat gcc gtt att tat cga agc atg ggt 1048Val Ala Asp Phe Leu Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly 190 195 200gat gga tct gcc ctt cgc aca ata aaa tat gat tcc aaa tgg ata aaa 1096Asp Gly Ser Ala Leu Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys 205 210 215gag cca cac ttt ctt cat gcc ata gaa tat gga aac tat gtc tat ttc 1144Glu Pro His Phe Leu His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe220 225 230 235ttc ttt cga gaa atc gct gtc gaa cat aat aat tta ggc aag gct gtg 1192Phe Phe Arg Glu Ile Ala Val Glu His Asn Asn Leu Gly Lys Ala Val 240 245 250tat tcc cgc gtg gcc cgc ata tgt aaa aac gac atg ggt ggt tcc cag 1240Tyr Ser Arg Val Ala Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln 255 260 265cgg gtc ctg gag aaa cac tgg act tca ttt cta aag gct cgg ctg aac 1288Arg Val Leu Glu Lys His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn 270 275 280tgt tct gtc cct gga gat tcg ttt ttc tac ttt gat gtt ctg cag tct 1336Cys Ser Val Pro Gly Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser 285 290 295att aca gac ata ata caa atc aat ggc atc ccc act gtg gtc ggg gtg 1384Ile Thr Asp Ile Ile Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val300 305 310 315ttt acc acg cag ctc aat agc atc cct ggt tct gct gtc tgt gca ttt 1432Phe Thr Thr Gln Leu Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe 320 325 330agc atg gat gac att gaa aaa gta ttc aaa gga cgg ttt aag gaa cag 1480Ser Met Asp Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln 335 340 345aaa act cca gat tct gtt tgg aca gca gtt ccc gaa gac aaa gtg cca 1528Lys Thr Pro Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro 350 355 360aag cca agg cct ggc tgt tgt gca aaa cac ggc ctt gcc gaa gct tat 1576Lys Pro Arg Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr 365 370 375aaa acc tcc atc gat ttc ccg gat gaa act ctg tca ttc atc aaa tct 1624Lys Thr Ser Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser380 385 390 395cat ccc ctg atg gac tct gcc gtt cca ccc att gcc gat gag ccc tgg 1672His Pro Leu Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp 400 405 410ttc aca aag act cgg gtc agg tac aga ctg acg gcc atc tca gtg gac 1720Phe Thr Lys Thr Arg Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp 415 420 425cat tca gcc gga ccc tac cag aac tac aca gtc atc ttt gtt ggc tct 1768His Ser Ala Gly Pro Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser 430 435 440gaa gct ggc atg gta ctt aaa gtt ctg gca aag acc agt cct ttc tct 1816Glu Ala Gly Met Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser 445 450 455ttg aac gac agc gta tta ctg gaa gag att gaa gcc tac aac cat gca 1864Leu Asn Asp Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala460 465 470 475aag tgc agt gct gag aat gag gaa gac aaa aag gtc atc tca tta cag 1912Lys Cys Ser Ala Glu Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln 480 485 490ttg gat aaa gat cac cac gct tta tat gtg gcg ttc tct agc tgc att 1960Leu Asp Lys Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile 495 500 505atc cgc atc ccc ctc agt cgc tgt gag cgt tat gga tca tgt aaa aag 2008Ile Arg Ile Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys 510 515 520tct tgt att gca tct cgt gac ccg tat tgt ggc tgg tta agc cag gga 2056Ser Cys Ile Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly 525 530 535tcc tgt ggt aga gtg acc cca ggg atg ctt gct gaa gga tat gaa caa 2104Ser Cys Gly Arg Val Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln540 545 550 555gac aca gaa ttc ggc aac aca gct cat cta ggg gac tgc cat gaa att 2152Asp Thr Glu Phe Gly Asn Thr Ala His Leu Gly Asp Cys His Glu Ile 560 565 570ttg cct act tca act aca cca gat tac aaa ata ttt ggc ggt cca aca 2200Leu Pro Thr Ser Thr Thr Pro Asp Tyr Lys Ile Phe Gly Gly Pro Thr 575 580 585tct ggt gta cga tgg gaa gtc cag tct gga gag tcc aac cag atg gtc 2248Ser Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn Gln Met Val 590 595 600cac atg aat gtc ctc atc acc tgt gtc ttt gct gct ttt gtt ttg ggg 2296His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Phe Val Leu Gly 605 610 615gca ttc att gca ggt

gtg gca gta tac tgc tat cga gac atg ttt gtt 2344Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp Met Phe Val620 625 630 635cgg aaa aac aga aag atc cat aaa gat gca gag tcc gcc cag tca tgc 2392Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser Ala Gln Ser Cys 640 645 650aca gac tcc agt gga agt ttt gcc aaa ctg aat ggt ctc ttt gac agc 2440Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn Gly Leu Phe Asp Ser 655 660 665cct gtc aag gaa tac caa cag aat att gat tct cct aaa ctg tat agt 2488Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser Pro Lys Leu Tyr Ser 670 675 680aac ctg cta acc agt cgg aaa gag cta cca ccc aat gga gat act aaa 2536Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro Asn Gly Asp Thr Lys 685 690 695tcc atg gta atg gac cat cga ggg caa cct cca gag ttg gct gct ctt 2584Ser Met Val Met Asp His Arg Gly Gln Pro Pro Glu Leu Ala Ala Leu700 705 710 715cct act cct gag tct aca ccc gtg ctt cac cag aag acc ctg cag gcc 2632Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln Lys Thr Leu Gln Ala 720 725 730atg aag agc cac tca gaa aag gcc cat ggc cat gga gct tca agg aaa 2680Met Lys Ser His Ser Glu Lys Ala His Gly His Gly Ala Ser Arg Lys 735 740 745gaa acc cct cag ttt ttt ccg tct agt ccg cca cct cat tcc cca tta 2728Glu Thr Pro Gln Phe Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu 750 755 760agt cat ggg cat atc ccc agt gcc att gtt ctt cca aat gct acc cat 2776Ser His Gly His Ile Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His 765 770 775gac tac aac acg tct ttc tca aac tcc aat gct cac aaa gct gaa aag 2824Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys780 785 790 795aag ctt caa aac att gat cac cct ctc aca aag tca tcc agt aag aga 2872Lys Leu Gln Asn Ile Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg 800 805 810gat cac cgg cgt tct gtt gat tcc aga aat acc ctc aat gat ctc ctg 2920Asp His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu 815 820 825aag cat ctg aat gac cca aat agt aac ccc aaa gcc atc atg gga gac 2968Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys Ala Ile Met Gly Asp 830 835 840atc cag atg gca cac cag aac tta atg ctg gat ccc atg gga tcg atg 3016Ile Gln Met Ala His Gln Asn Leu Met Leu Asp Pro Met Gly Ser Met 845 850 855tct gag gtc cca cct aaa gtc cct aac cgg gag gca tcg cta tac tcc 3064Ser Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser Leu Tyr Ser860 865 870 875cct cct tca act ctc ccc aga aat agc cca acc aag cga gtg gat gtc 3112Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys Arg Val Asp Val 880 885 890ccc acc act cct gga gtc cca atg act tct ctg gaa aga caa aga ggt 3160Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu Glu Arg Gln Arg Gly 895 900 905tat cac aaa aat tcc tcc cag agg cac tct ata tct gct atg cct aaa 3208Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile Ser Ala Met Pro Lys 910 915 920aac tta aac tca cca aat ggt gtt ttg tta tcc aga cag cct agt atg 3256Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser Arg Gln Pro Ser Met 925 930 935aac cgt gga gga tat atg ccc acc ccc act ggg gcg aag gtg gac tat 3304Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly Ala Lys Val Asp Tyr940 945 950 955att cag gga aca cca gtg agt gtt cat ctg cag cct tcc ctc tcc aga 3352Ile Gln Gly Thr Pro Val Ser Val His Leu Gln Pro Ser Leu Ser Arg 960 965 970cag agc agc tac acc agt aat ggc act ctt cct agg acg gga cta aag 3400Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys 975 980 985agg acg ccg tcc tta aaa cct gac gtg cca cca aag cct tcc ttt gtt 3448Arg Thr Pro Ser Leu Lys Pro Asp Val Pro Pro Lys Pro Ser Phe Val 990 995 1000cct caa acc cca tct gtc aga cca ctg aac aaa tac aca tac 3490Pro Gln Thr Pro Ser Val Arg Pro Leu Asn Lys Tyr Thr Tyr 1005 1010 1015taggcctcaa gtgtgctatt cccatgtggc tttatcctgt ccgtgttgtt gagaggatga 3550tgttgtaagg gtaccttaaa acaagagact cgcttgtatt ttaagagaac caagtggcca 3610aagaaactct ttctaacttt ggcaacatca gaacttgcca catgtagcta ctgcagcaag 3670gcttctgtgt acttgcctga aaacaaagga aggtgctggt cattccattt cttttgtttg 3730aagctaaaga gatgtgtagc tcacaggggc taccttacca gtataaagag ctgataacag 3790tactcagaag aatctgtgaa caaatacttg aaaatgggtt caatgtagac tgccattatg 3850tgtggtcttc ccattaaatg tgaacatttt aatatgtatg cattcacctt gcctcttgca 3910caaatgtcaa aaaaaagatg gtaatatctc aaagaaatga acttgtagat taccaagcag 3970tttgctaaaa attcaatctt tgacccaagc tgtagcattt ttttttcatg tgtggcatct 4030ttttcatgcc accaacaaac ttgttgtgtg tgtgcgtgtg tgtgtgtgtg tgtgtgtgtg 4090tgtgtgtgtt ctgtacccac taggatttgt ttaggtgccc attgcatctt tttgtgctat 4150ggagttgttt acattaagca tgaccgaacg agagacaata ctatttccca caggagtcca 4210ttgggttcag ctttgaaaga ggaatagaat cgaggctcct ttgaccatca aaatgatgaa 4270ctttacttat gtggtaccca atgccagaat gtaagagttg caagtgattt tgtgctgcta 4330ttcattaaaa cttgtattcc agtcttgcca gcttaaggag atcaagatat taagaggtat 4390ccttgattta ttttccagta ttcagtagta aaattttcct gtccactgtg aatcaaagcc 4450tgagtcactc tatttaacct tggacacact aataaggttt tattttgatt gtgttcgttt 4510cccccccccc aatagtaaaa tttctcctcc tttaactcct cctacccccc aaggtaagaa 4570acaaaaaaca aacaaacaaa caaaaataga agacaaaaga aagacatatg aaaggaattg 4630taattggctt aacagaaaca gtctgtaaaa acctaacagt ggtgcaatca tgttgtctgt 4690gttgtgttat gtgagaattt tctcctaagt catgcaggta atgacaatat actgtaaata 4750ccacatgtga gtttacctga atctgtgcat tttgtgcctt attcatgaga atgatagaag 4810tactaaaatc tgtcaagtgt tttcagtata gcacattatt tactgagtgc cagttgtaaa 4870tgtttttcaa ccagcaccta aaaagactct tttcaaaaaa tcacagaaac aacctaggac 4930aattatttgt tacataatcc gacctcatag cagcattaca ttctttgccg tgataaacat 4990tccactcctg ctttcctaag gatgaaacag tgataatgtg aactcaaatg aggtttcctg 5050ggtaatgtga cacctgcaga aactatagag cgtcatttat acgtagtttg gcagaaacca 5110cttacggctg atgatgcgca accctgctga ctgtttcagt taatatgctg cacaccacac 5170acttgtttag tgaaccaaat ctagaaagta ccaaggcaga ggtatgctcc tgctgtaatc 5230aggcaaatga gttcaactgg atttcttttg acaatactgt tggtacctat tacttggggg 5290aggacatgtt gcagaagacc agatcatttt tatacagaat gtgaaatact gatacagtta 5350ttcttttttt taaagaacat tgttttataa agaacgtgat ttccagtgat ctctggaagc 5410gctaaagcta aaatttctgt tcttgaaaca cttcagcttt gcaactaaaa tattacagat 5470taataataaa ttaaaccaac caatgataaa cactactcag tccaccaaca acaaacgtgt 5530ttgaattcac cttaccaata ttaatcccag cgtgtgtaaa acagaacagt aactctatgt 5590gaccccagat aacattttgt aacattgtgc ttccttgtag tttgtaatgt gagttcaatc 5650agtatttatg ttgaaatttc taacattaaa tctagtctct atcctgttaa tttaattttt 5710aaatgcttta tccatttgtg caaaggtaaa cgcagattgt atctttttta atggtacggc 5770ataaaaagta accctcaagt gaagtgtctc tatactgttt tatagagtac tttaacatga 5830atagatacct tgtaaacttg tattgtggat gtgtaaataa tatgtacttt gggtttttaa 5890caccgcatgt aaagtcaaaa taaaatatac aaatcattat aaaaaaaaaa a 5941261017PRTHomo sapiens 26Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu Leu Leu Met Val Ser1 5 10 15Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp His Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Met Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala Lys Cys Ser Ala Glu465 470 475 480Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile Ile Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Ser Cys Gly Arg Val 530 535 540Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln Asp Thr Glu Phe Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Glu Ile Leu Pro Thr Ser Thr 565 570 575Thr Pro Asp Tyr Lys Ile Phe Gly Gly Pro Thr Ser Gly Val Arg Trp 580 585 590Glu Val Gln Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu 595 600 605Ile Thr Cys Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly 610 615 620Val Ala Val Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys625 630 635 640Ile His Lys Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly 645 650 655Ser Phe Ala Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr 660 665 670Gln Gln Asn Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser 675 680 685Arg Lys Glu Leu Pro Pro Asn Gly Asp Thr Lys Ser Met Val Met Asp 690 695 700His Arg Gly Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser705 710 715 720Thr Pro Val Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser 725 730 735Glu Lys Ala His Gly His Gly Ala Ser Arg Lys Glu Thr Pro Gln Phe 740 745 750Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile 755 760 765Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser 770 775 780Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Asn Ile785 790 795 800Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg Asp His Arg Arg Ser 805 810 815Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp 820 825 830Pro Asn Ser Asn Pro Lys Ala Ile Met Gly Asp Ile Gln Met Ala His 835 840 845Gln Asn Leu Met Leu Asp Pro Met Gly Ser Met Ser Glu Val Pro Pro 850 855 860Lys Val Pro Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu865 870 875 880Pro Arg Asn Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly 885 890 895Val Pro Met Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser 900 905 910Ser Gln Arg His Ser Ile Ser Ala Met Pro Lys Asn Leu Asn Ser Pro 915 920 925Asn Gly Val Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr 930 935 940Met Pro Thr Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro945 950 955 960Val Ser Val His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr 965 970 975Ser Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu 980 985 990Lys Pro Asp Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Pro Ser 995 1000 1005Val Arg Pro Leu Asn Lys Tyr Thr Tyr 1010 1015276109DNAHomo sapiensCDS(440)..(3658) 27gcggccgctt cccaccgtcc ctctcccctt actggcagag cgcgctgcgg gcggactccc 60gggcccggag cagcccaccg gccaccccac cgcccacccg gctcccggtg tctcctcccg 120gccgctctac ccagcaactt tccgtgcttt gttccccgac tggaaatgct ttacggaagc 180gtcttggaca gggtctccgc caggcgacaa gagctcggtg ctgagatgtg ttacgttctc 240atctccccat caattatgga tggaaacaaa taaggaagag tcaattttgc tgagcccctt 300ctccggcaac gagaggcgtt ctgcagccgg gagggagccg ccgctcgcgc cggcagccgc 360tggcaggggc atggtgagga ggaaggtagc tcagtggcat ttctgagcag gggccaccct 420gacttcacct tggcccacc atg agg gtc ttc ctg ctt tgt gcc tac ata ctg 472 Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu 1 5 10ctg ctg atg gtt tcc cag ttg agg gca gtc agc ttt cct gaa gat gat 520Leu Leu Met Val Ser Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp 15 20 25gaa ccc ctt aat act gtc gac tat cac tat tca agg caa tat ccg gtt 568Glu Pro Leu Asn Thr Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val 30 35 40ttt aga gga cgc cct tca ggc aat gaa tcg cag cac agg ctg gac ttt 616Phe Arg Gly Arg Pro Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe 45 50 55cag ctg atg ttg aaa att cga gac aca ctt tat att gct ggc agg gat 664Gln Leu Met Leu Lys Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp60 65 70 75caa gtt tat aca gta aac tta aat gaa atg ccc aaa aca gaa gta ata 712Gln Val Tyr Thr Val Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile 80 85 90ccc aac aag aaa ctg aca tgg cga tca aga caa cag gat cga gaa aac 760Pro Asn Lys Lys Leu Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn 95 100 105tgt gct atg aaa ggc aag cat aaa gat gaa tgc cac aac ttt atc aaa 808Cys Ala Met Lys Gly Lys His Lys Asp Glu Cys His Asn Phe Ile Lys 110 115 120gta ttt gtt cca aga aac gat gag atg gtt ttt gtt tgt ggt acc aat 856Val Phe Val Pro Arg Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn 125 130 135gca ttc aat ccc atg tgt aga tac tac agg ttg agt acc tta gaa tat 904Ala Phe Asn Pro Met Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr140 145 150 155gat ggg gaa gaa att agt ggc ctg gca aga tgc cca ttt gat gcc aga 952Asp Gly Glu Glu Ile Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg 160 165 170caa acc aat gtt gcc ctc ttt gct gat ggg aag ctg tat tct gcc aca 1000Gln Thr Asn Val Ala Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr 175 180 185gtg gct gac ttc ttg gcc agc gat gcc gtt att tat cga agc atg ggt 1048Val Ala Asp Phe Leu Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly 190 195

200gat gga tct gcc ctt cgc aca ata aaa tat gat tcc aaa tgg ata aaa 1096Asp Gly Ser Ala Leu Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys 205 210 215gag cca cac ttt ctt cat gcc ata gaa tat gga aac tat gtc tat ttc 1144Glu Pro His Phe Leu His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe220 225 230 235ttc ttt cga gaa atc gct gtc gaa cat aat aat tta ggc aag gct gtg 1192Phe Phe Arg Glu Ile Ala Val Glu His Asn Asn Leu Gly Lys Ala Val 240 245 250tat tcc cgc gtg gcc cgc ata tgt aaa aac gac atg ggt ggt tcc cag 1240Tyr Ser Arg Val Ala Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln 255 260 265cgg gtc ctg gag aaa cac tgg act tca ttt cta aag gct cgg ctg aac 1288Arg Val Leu Glu Lys His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn 270 275 280tgt tct gtc cct gga gat tcg ttt ttc tac ttt gat gtt ctg cag tct 1336Cys Ser Val Pro Gly Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser 285 290 295att aca gac ata ata caa atc aat ggc atc ccc act gtg gtc ggg gtg 1384Ile Thr Asp Ile Ile Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val300 305 310 315ttt acc acg cag ctc aat agc atc cct ggt tct gct gtc tgt gca ttt 1432Phe Thr Thr Gln Leu Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe 320 325 330agc atg gat gac att gaa aaa gta ttc aaa gga cgg ttt aag gaa cag 1480Ser Met Asp Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln 335 340 345aaa act cca gat tct gtt tgg aca gca gtt ccc gaa gac aaa gtg cca 1528Lys Thr Pro Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro 350 355 360aag cca agg cct ggc tgt tgt gca aaa cac ggc ctt gcc gaa gct tat 1576Lys Pro Arg Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr 365 370 375aaa acc tcc atc gat ttc ccg gat gaa act ctg tca ttc atc aaa tct 1624Lys Thr Ser Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser380 385 390 395cat ccc ctg atg gac tct gcc gtt cca ccc att gcc gat gag ccc tgg 1672His Pro Leu Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp 400 405 410ttc aca aag act cgg gtc agg tac aga ctg acg gcc atc tca gtg gac 1720Phe Thr Lys Thr Arg Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp 415 420 425cat tca gcc gga ccc tac cag aac tac aca gtc atc ttt gtt ggc tct 1768His Ser Ala Gly Pro Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser 430 435 440gaa gct ggc atg gta ctt aaa gtt ctg gca aag acc agt cct ttc tct 1816Glu Ala Gly Met Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser 445 450 455ttg aac gac agc gta tta ctg gaa gag att gaa gcc tac aac cat gca 1864Leu Asn Asp Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala460 465 470 475aag tgc agt gct gag aat gag gaa gac aaa aag gtc atc tca tta cag 1912Lys Cys Ser Ala Glu Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln 480 485 490ttg gat aaa gat cac cac gct tta tat gtg gcg ttc tct agc tgc att 1960Leu Asp Lys Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile 495 500 505atc cgc atc ccc ctc agt cgc tgt gag cgt tat gga tca tgt aaa aag 2008Ile Arg Ile Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys 510 515 520tct tgt att gca tct cgt gac ccg tat tgt ggc tgg tta agc cag gga 2056Ser Cys Ile Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly 525 530 535tcc tgt ggt aga gtg acc cca ggg atg ctt gct gaa gga tat gaa caa 2104Ser Cys Gly Arg Val Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln540 545 550 555gac aca gaa ttc ggc aac aca gct cat cta ggg gac tgc cat gaa att 2152Asp Thr Glu Phe Gly Asn Thr Ala His Leu Gly Asp Cys His Glu Ile 560 565 570ttg cct act tca act aca cca gat tac aaa ata ttt ggc ggt cca aca 2200Leu Pro Thr Ser Thr Thr Pro Asp Tyr Lys Ile Phe Gly Gly Pro Thr 575 580 585tct gac atg gag gta tct tca tct tct gtt acc aca atg gca agt atc 2248Ser Asp Met Glu Val Ser Ser Ser Ser Val Thr Thr Met Ala Ser Ile 590 595 600cca gaa atc aca cct aaa gtg att gat acc tgg aga cct aaa ctg aca 2296Pro Glu Ile Thr Pro Lys Val Ile Asp Thr Trp Arg Pro Lys Leu Thr 605 610 615agc tct cgg aaa ttt gta gtt caa gat gat cca aac act tct gat ttt 2344Ser Ser Arg Lys Phe Val Val Gln Asp Asp Pro Asn Thr Ser Asp Phe620 625 630 635act gat cct tta tcg ggt atc cca aag ggt gta cga tgg gaa gtc cag 2392Thr Asp Pro Leu Ser Gly Ile Pro Lys Gly Val Arg Trp Glu Val Gln 640 645 650tct gga gag tcc aac cag atg gtc cac atg aat gtc ctc atc acc tgt 2440Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys 655 660 665gtc ttt gct gct ttt gtt ttg ggg gca ttc att gca ggt gtg gca gta 2488Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val 670 675 680tac tgc tat cga gac atg ttt gtt cgg aaa aac aga aag atc cat aaa 2536Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys 685 690 695gat gca gag tcc gcc cag tca tgc aca gac tcc agt gga agt ttt gcc 2584Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala700 705 710 715aaa ctg aat ggt ctc ttt gac agc cct gtc aag gaa tac caa cag aat 2632Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn 720 725 730att gat tct cct aaa ctg tat agt aac ctg cta acc agt cgg aaa gag 2680Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu 735 740 745cta cca ccc aat gga gat act aaa tcc atg gta atg gac cat cga ggg 2728Leu Pro Pro Asn Gly Asp Thr Lys Ser Met Val Met Asp His Arg Gly 750 755 760caa cct cca gag ttg gct gct ctt cct act cct gag tct aca ccc gtg 2776Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val 765 770 775ctt cac cag aag acc ctg cag gcc atg aag agc cac tca gaa aag gcc 2824Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala780 785 790 795cat ggc cat gga gct tca agg aaa gaa acc cct cag ttt ttt ccg tct 2872His Gly His Gly Ala Ser Arg Lys Glu Thr Pro Gln Phe Phe Pro Ser 800 805 810agt ccg cca cct cat tcc cca tta agt cat ggg cat atc ccc agt gcc 2920Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala 815 820 825att gtt ctt cca aat gct acc cat gac tac aac acg tct ttc tca aac 2968Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn 830 835 840tcc aat gct cac aaa gct gaa aag aag ctt caa aac att gat cac cct 3016Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Asn Ile Asp His Pro 845 850 855ctc aca aag tca tcc agt aag aga gat cac cgg cgt tct gtt gat tcc 3064Leu Thr Lys Ser Ser Ser Lys Arg Asp His Arg Arg Ser Val Asp Ser860 865 870 875aga aat acc ctc aat gat ctc ctg aag cat ctg aat gac cca aat agt 3112Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser 880 885 890aac ccc aaa gcc atc atg gga gac atc cag atg gca cac cag aac tta 3160Asn Pro Lys Ala Ile Met Gly Asp Ile Gln Met Ala His Gln Asn Leu 895 900 905atg ctg gat ccc atg gga tcg atg tct gag gtc cca cct aaa gtc cct 3208Met Leu Asp Pro Met Gly Ser Met Ser Glu Val Pro Pro Lys Val Pro 910 915 920aac cgg gag gca tcg cta tac tcc cct cct tca act ctc ccc aga aat 3256Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn 925 930 935agc cca acc aag cga gtg gat gtc ccc acc act cct gga gtc cca atg 3304Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met940 945 950 955act tct ctg gaa aga caa aga ggt tat cac aaa aat tcc tcc cag agg 3352Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg 960 965 970cac tct ata tct gct atg cct aaa aac tta aac tca cca aat ggt gtt 3400His Ser Ile Ser Ala Met Pro Lys Asn Leu Asn Ser Pro Asn Gly Val 975 980 985ttg tta tcc aga cag cct agt atg aac cgt gga gga tat atg ccc acc 3448Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr 990 995 1000ccc act ggg gcg aag gtg gac tat att cag gga aca cca gtg agt 3493Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser 1005 1010 1015gtt cat ctg cag cct tcc ctc tcc aga cag agc agc tac acc agt 3538Val His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser 1020 1025 1030aat ggc act ctt cct agg acg gga cta aag agg acg ccg tcc tta 3583Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu 1035 1040 1045aaa cct gac gtg cca cca aag cct tcc ttt gtt cct caa acc cca 3628Lys Pro Asp Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Pro 1050 1055 1060tct gtc aga cca ctg aac aaa tac aca tac taggcctcaa gtgtgctatt 3678Ser Val Arg Pro Leu Asn Lys Tyr Thr Tyr 1065 1070cccatgtggc tttatcctgt ccgtgttgtt gagaggatga tgttgtaagg gtaccttaaa 3738acaagagact cgcttgtatt ttaagagaac caagtggcca aagaaactct ttctaacttt 3798ggcaacatca gaacttgcca catgtagcta ctgcagcaag gcttctgtgt acttgcctga 3858aaacaaagga aggtgctggt cattccattt cttttgtttg aagctaaaga gatgtgtagc 3918tcacaggggc taccttacca gtataaagag ctgataacag tactcagaag aatctgtgaa 3978caaatacttg aaaatgggtt caatgtagac tgccattatg tgtggtcttc ccattaaatg 4038tgaacatttt aatatgtatg cattcacctt gcctcttgca caaatgtcaa aaaaaagatg 4098gtaatatctc aaagaaatga acttgtagat taccaagcag tttgctaaaa attcaatctt 4158tgacccaagc tgtagcattt ttttttcatg tgtggcatct ttttcatgcc accaacaaac 4218ttgttgtgtg tgtgcgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtt ctgtacccac 4278taggatttgt ttaggtgccc attgcatctt tttgtgctat ggagttgttt acattaagca 4338tgaccgaacg agagacaata ctatttccca caggagtcca ttgggttcag ctttgaaaga 4398ggaatagaat cgaggctcct ttgaccatca aaatgatgaa ctttacttat gtggtaccca 4458atgccagaat gtaagagttg caagtgattt tgtgctgcta ttcattaaaa cttgtattcc 4518agtcttgcca gcttaaggag atcaagatat taagaggtat ccttgattta ttttccagta 4578ttcagtagta aaattttcct gtccactgtg aatcaaagcc tgagtcactc tatttaacct 4638tggacacact aataaggttt tattttgatt gtgttcgttt cccccccccc aatagtaaaa 4698tttctcctcc tttaactcct cctacccccc aaggtaagaa acaaaaaaca aacaaacaaa 4758caaaaataga agacaaaaga aagacatatg aaaggaattg taattggctt aacagaaaca 4818gtctgtaaaa acctaacagt ggtgcaatca tgttgtctgt gttgtgttat gtgagaattt 4878tctcctaagt catgcaggta atgacaatat actgtaaata ccacatgtga gtttacctga 4938atctgtgcat tttgtgcctt attcatgaga atgatagaag tactaaaatc tgtcaagtgt 4998tttcagtata gcacattatt tactgagtgc cagttgtaaa tgtttttcaa ccagcaccta 5058aaaagactct tttcaaaaaa tcacagaaac aacctaggac aattatttgt tacataatcc 5118gacctcatag cagcattaca ttctttgccg tgataaacat tccactcctg ctttcctaag 5178gatgaaacag tgataatgtg aactcaaatg aggtttcctg ggtaatgtga cacctgcaga 5238aactatagag cgtcatttat acgtagtttg gcagaaacca cttacggctg atgatgcgca 5298accctgctga ctgtttcagt taatatgctg cacaccacac acttgtttag tgaaccaaat 5358ctagaaagta ccaaggcaga ggtatgctcc tgctgtaatc aggcaaatga gttcaactgg 5418atttcttttg acaatactgt tggtacctat tacttggggg aggacatgtt gcagaagacc 5478agatcatttt tatacagaat gtgaaatact gatacagtta ttcttttttt taaagaacat 5538tgttttataa agaacgtgat ttccagtgat ctctggaagc gctaaagcta aaatttctgt 5598tcttgaaaca cttcagcttt gcaactaaaa tattacagat taataataaa ttaaaccaac 5658caatgataaa cactactcag tccaccaaca acaaacgtgt ttgaattcac cttaccaata 5718ttaatcccag cgtgtgtaaa acagaacagt aactctatgt gaccccagat aacattttgt 5778aacattgtgc ttccttgtag tttgtaatgt gagttcaatc agtatttatg ttgaaatttc 5838taacattaaa tctagtctct atcctgttaa tttaattttt aaatgcttta tccatttgtg 5898caaaggtaaa cgcagattgt atctttttta atggtacggc ataaaaagta accctcaagt 5958gaagtgtctc tatactgttt tatagagtac tttaacatga atagatacct tgtaaacttg 6018tattgtggat gtgtaaataa tatgtacttt gggtttttaa caccgcatgt aaagtcaaaa 6078taaaatatac aaatcattat aaaaaaaaaa a 6109281073PRTHomo sapiens 28Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu Leu Leu Met Val Ser1 5 10 15Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp His Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Met Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala Lys Cys Ser Ala Glu465 470 475 480Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile Ile Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Ser Cys Gly Arg Val 530 535 540Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln Asp Thr Glu Phe Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Glu Ile Leu Pro Thr Ser Thr 565 570 575Thr Pro Asp Tyr Lys Ile Phe Gly Gly Pro Thr Ser Asp Met Glu Val 580 585 590Ser Ser Ser Ser Val Thr Thr Met Ala Ser Ile Pro Glu Ile Thr Pro 595 600 605Lys Val Ile Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe 610 615 620Val Val Gln Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Pro Leu Ser625 630 635 640Gly Ile Pro Lys Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn 645 650 655Gln Met Val His Met Asn Val Leu Ile Thr Cys Val

Phe Ala Ala Phe 660 665 670Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp 675 680 685Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser Ala 690 695 700Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn Gly Leu705 710 715 720Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser Pro Lys 725 730 735Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro Asn Gly 740 745 750Asp Thr Lys Ser Met Val Met Asp His Arg Gly Gln Pro Pro Glu Leu 755 760 765Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln Lys Thr 770 775 780Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala His Gly His Gly Ala785 790 795 800Ser Arg Lys Glu Thr Pro Gln Phe Phe Pro Ser Ser Pro Pro Pro His 805 810 815Ser Pro Leu Ser His Gly His Ile Pro Ser Ala Ile Val Leu Pro Asn 820 825 830Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala His Lys 835 840 845Ala Glu Lys Lys Leu Gln Asn Ile Asp His Pro Leu Thr Lys Ser Ser 850 855 860Ser Lys Arg Asp His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn865 870 875 880Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys Ala Ile 885 890 895Met Gly Asp Ile Gln Met Ala His Gln Asn Leu Met Leu Asp Pro Met 900 905 910Gly Ser Met Ser Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser 915 920 925Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys Arg 930 935 940Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu Glu Arg945 950 955 960Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile Ser Ala 965 970 975Met Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser Arg Gln 980 985 990Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly Ala Lys 995 1000 1005Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val His Leu Gln Pro 1010 1015 1020Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro 1025 1030 1035Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro 1040 1045 1050Pro Lys Pro Ser Phe Val Pro Gln Thr Pro Ser Val Arg Pro Leu 1055 1060 1065Asn Lys Tyr Thr Tyr 1070295919DNAHomo sapiensCDS(440)..(2230) 29gcggccgctt cccaccgtcc ctctcccctt actggcagag cgcgctgcgg gcggactccc 60gggcccggag cagcccaccg gccaccccac cgcccacccg gctcccggtg tctcctcccg 120gccgctctac ccagcaactt tccgtgcttt gttccccgac tggaaatgct ttacggaagc 180gtcttggaca gggtctccgc caggcgacaa gagctcggtg ctgagatgtg ttacgttctc 240atctccccat caattatgga tggaaacaaa taaggaagag tcaattttgc tgagcccctt 300ctccggcaac gagaggcgtt ctgcagccgg gagggagccg ccgctcgcgc cggcagccgc 360tggcaggggc atggtgagga ggaaggtagc tcagtggcat ttctgagcag gggccaccct 420gacttcacct tggcccacc atg agg gtc ttc ctg ctt tgt gcc tac ata ctg 472 Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu 1 5 10ctg ctg atg gtt tcc cag ttg agg gca gtc agc ttt cct gaa gat gat 520Leu Leu Met Val Ser Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp 15 20 25gaa ccc ctt aat act gtc gac tat cac tat tca agg caa tat ccg gtt 568Glu Pro Leu Asn Thr Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val 30 35 40ttt aga gga cgc cct tca ggc aat gaa tcg cag cac agg ctg gac ttt 616Phe Arg Gly Arg Pro Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe 45 50 55cag ctg atg ttg aaa att cga gac aca ctt tat att gct ggc agg gat 664Gln Leu Met Leu Lys Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp60 65 70 75caa gtt tat aca gta aac tta aat gaa atg ccc aaa aca gaa gta ata 712Gln Val Tyr Thr Val Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile 80 85 90ccc aac aag aaa ctg aca tgg cga tca aga caa cag gat cga gaa aac 760Pro Asn Lys Lys Leu Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn 95 100 105tgt gct atg aaa ggc aag cat aaa gat gaa tgc cac aac ttt atc aaa 808Cys Ala Met Lys Gly Lys His Lys Asp Glu Cys His Asn Phe Ile Lys 110 115 120gta ttt gtt cca aga aac gat gag atg gtt ttt gtt tgt ggt acc aat 856Val Phe Val Pro Arg Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn 125 130 135gca ttc aat ccc atg tgt aga tac tac agg ttg agt acc tta gaa tat 904Ala Phe Asn Pro Met Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr140 145 150 155gat ggg gaa gaa att agt ggc ctg gca aga tgc cca ttt gat gcc aga 952Asp Gly Glu Glu Ile Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg 160 165 170caa acc aat gtt gcc ctc ttt gct gat ggg aag ctg tat tct gcc aca 1000Gln Thr Asn Val Ala Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr 175 180 185gtg gct gac ttc ttg gcc agc gat gcc gtt att tat cga agc atg ggt 1048Val Ala Asp Phe Leu Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly 190 195 200gat gga tct gcc ctt cgc aca ata aaa tat gat tcc aaa tgg ata aaa 1096Asp Gly Ser Ala Leu Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys 205 210 215gag cca cac ttt ctt cat gcc ata gaa tat gga aac tat gtc tat ttc 1144Glu Pro His Phe Leu His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe220 225 230 235ttc ttt cga gaa atc gct gtc gaa cat aat aat tta ggc aag gct gtg 1192Phe Phe Arg Glu Ile Ala Val Glu His Asn Asn Leu Gly Lys Ala Val 240 245 250tat tcc cgc gtg gcc cgc ata tgt aaa aac gac atg ggt ggt tcc cag 1240Tyr Ser Arg Val Ala Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln 255 260 265cgg gtc ctg gag aaa cac tgg act tca ttt cta aag gct cgg ctg aac 1288Arg Val Leu Glu Lys His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn 270 275 280tgt tct gtc cct gga gat tcg ttt ttc tac ttt gat gtt ctg cag tct 1336Cys Ser Val Pro Gly Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser 285 290 295att aca gac ata ata caa atc aat ggc atc ccc act gtg gtc ggg gtg 1384Ile Thr Asp Ile Ile Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val300 305 310 315ttt acc acg cag ctc aat agc atc cct ggt tct gct gtc tgt gca ttt 1432Phe Thr Thr Gln Leu Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe 320 325 330agc atg gat gac att gaa aaa gta ttc aaa gga cgg ttt aag gaa cag 1480Ser Met Asp Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln 335 340 345aaa act cca gat tct gtt tgg aca gca gtt ccc gaa gac aaa gtg cca 1528Lys Thr Pro Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro 350 355 360aag cca agg cct ggc tgt tgt gca aaa cac ggc ctt gcc gaa gct tat 1576Lys Pro Arg Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr 365 370 375aaa acc tcc atc gat ttc ccg gat gaa act ctg tca ttc atc aaa tct 1624Lys Thr Ser Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser380 385 390 395cat ccc ctg atg gac tct gcc gtt cca ccc att gcc gat gag ccc tgg 1672His Pro Leu Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp 400 405 410ttc aca aag act cgg gtc agg tac aga ctg acg gcc atc tca gtg gac 1720Phe Thr Lys Thr Arg Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp 415 420 425cat tca gcc gga ccc tac cag aac tac aca gtc atc ttt gtt ggc tct 1768His Ser Ala Gly Pro Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser 430 435 440gaa gct ggc atg gta ctt aaa gtt ctg gca aag acc agt cct ttc tct 1816Glu Ala Gly Met Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser 445 450 455ttg aac gac agc gta tta ctg gaa gag att gaa gcc tac aac cat gca 1864Leu Asn Asp Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala460 465 470 475aag tgc agt gct gag aat gag gaa gac aaa aag gtc atc tca tta cag 1912Lys Cys Ser Ala Glu Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln 480 485 490ttg gat aaa gat cac cac gct tta tat gtg gcg ttc tct agc tgc att 1960Leu Asp Lys Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile 495 500 505atc cgc atc ccc ctc agt cgc tgt gag cgt tat gga tca tgt aaa aag 2008Ile Arg Ile Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys 510 515 520tct tgt att gca tct cgt gac ccg tat tgt ggc tgg tta agc cag gga 2056Ser Cys Ile Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly 525 530 535tcc tgt ggt aga gtg acc cca ggg atg ctt gct gaa gga tat gaa caa 2104Ser Cys Gly Arg Val Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln540 545 550 555gac aca gaa ttc ggc aac aca gct cat cta ggg gac tgc cat gac atg 2152Asp Thr Glu Phe Gly Asn Thr Ala His Leu Gly Asp Cys His Asp Met 560 565 570gag gta tct tca tct tct gtt acc aca atg gtg tac gat ggg aag tcc 2200Glu Val Ser Ser Ser Ser Val Thr Thr Met Val Tyr Asp Gly Lys Ser 575 580 585agt ctg gag agt cca acc aga tgg tcc aca tgaatgtcct catcacctgt 2250Ser Leu Glu Ser Pro Thr Arg Trp Ser Thr 590 595gtctttgctg cttttgtttt gggggcattc attgcaggtg tggcagtata ctgctatcga 2310gacatgtttg ttcggaaaaa cagaaagatc cataaagatg cagagtccgc ccagtcatgc 2370acagactcca gtggaagttt tgccaaactg aatggtctct ttgacagccc tgtcaaggaa 2430taccaacaga atattgattc tcctaaactg tatagtaacc tgctaaccag tcggaaagag 2490ctaccaccca atggagatac taaatccatg gtaatggacc atcgagggca acctccagag 2550ttggctgctc ttcctactcc tgagtctaca cccgtgcttc accagaagac cctgcaggcc 2610atgaagagcc actcagaaaa ggcccatggc catggagctt caaggaaaga aacccctcag 2670ttttttccgt ctagtccgcc acctcattcc ccattaagtc atgggcatat ccccagtgcc 2730attgttcttc caaatgctac ccatgactac aacacgtctt tctcaaactc caatgctcac 2790aaagctgaaa agaagcttca aaacattgat caccctctca caaagtcatc cagtaagaga 2850gatcaccggc gttctgttga ttccagaaat accctcaatg atctcctgaa gcatctgaat 2910gacccaaata gtaaccccaa agccatcatg ggagacatcc agatggcaca ccagaactta 2970atgctggatc ccatgggatc gatgtctgag gtcccaccta aagtccctaa ccgggaggca 3030tcgctatact cccctccttc aactctcccc agaaatagcc caaccaagcg agtggatgtc 3090cccaccactc ctggagtccc aatgacttct ctggaaagac aaagaggtta tcacaaaaat 3150tcctcccaga ggcactctat atctgctatg cctaaaaact taaactcacc aaatggtgtt 3210ttgttatcca gacagcctag tatgaaccgt ggaggatata tgcccacccc cactggggcg 3270aaggtggact atattcaggg aacaccagtg agtgttcatc tgcagccttc cctctccaga 3330cagagcagct acaccagtaa tggcactctt cctaggacgg gactaaagag gacgccgtcc 3390ttaaaacctg acgtgccacc aaagccttcc tttgttcctc aaaccccatc tgtcagacca 3450ctgaacaaat acacatacta ggcctcaagt gtgctattcc catgtggctt tatcctgtcc 3510gtgttgttga gaggatgatg ttgtaagggt accttaaaac aagagactcg cttgtatttt 3570aagagaacca agtggccaaa gaaactcttt ctaactttgg caacatcaga acttgccaca 3630tgtagctact gcagcaaggc ttctgtgtac ttgcctgaaa acaaaggaag gtgctggtca 3690ttccatttct tttgtttgaa gctaaagaga tgtgtagctc acaggggcta ccttaccagt 3750ataaagagct gataacagta ctcagaagaa tctgtgaaca aatacttgaa aatgggttca 3810atgtagactg ccattatgtg tggtcttccc attaaatgtg aacattttaa tatgtatgca 3870ttcaccttgc ctcttgcaca aatgtcaaaa aaaagatggt aatatctcaa agaaatgaac 3930ttgtagatta ccaagcagtt tgctaaaaat tcaatctttg acccaagctg tagcattttt 3990ttttcatgtg tggcatcttt ttcatgccac caacaaactt gttgtgtgtg tgcgtgtgtg 4050tgtgtgtgtg tgtgtgtgtg tgtgtgttct gtacccacta ggatttgttt aggtgcccat 4110tgcatctttt tgtgctatgg agttgtttac attaagcatg accgaacgag agacaatact 4170atttcccaca ggagtccatt gggttcagct ttgaaagagg aatagaatcg aggctccttt 4230gaccatcaaa atgatgaact ttacttatgt ggtacccaat gccagaatgt aagagttgca 4290agtgattttg tgctgctatt cattaaaact tgtattccag tcttgccagc ttaaggagat 4350caagatatta agaggtatcc ttgatttatt ttccagtatt cagtagtaaa attttcctgt 4410ccactgtgaa tcaaagcctg agtcactcta tttaaccttg gacacactaa taaggtttta 4470ttttgattgt gttcgtttcc ccccccccaa tagtaaaatt tctcctcctt taactcctcc 4530taccccccaa ggtaagaaac aaaaaacaaa caaacaaaca aaaatagaag acaaaagaaa 4590gacatatgaa aggaattgta attggcttaa cagaaacagt ctgtaaaaac ctaacagtgg 4650tgcaatcatg ttgtctgtgt tgtgttatgt gagaattttc tcctaagtca tgcaggtaat 4710gacaatatac tgtaaatacc acatgtgagt ttacctgaat ctgtgcattt tgtgccttat 4770tcatgagaat gatagaagta ctaaaatctg tcaagtgttt tcagtatagc acattattta 4830ctgagtgcca gttgtaaatg tttttcaacc agcacctaaa aagactcttt tcaaaaaatc 4890acagaaacaa cctaggacaa ttatttgtta cataatccga cctcatagca gcattacatt 4950ctttgccgtg ataaacattc cactcctgct ttcctaagga tgaaacagtg ataatgtgaa 5010ctcaaatgag gtttcctggg taatgtgaca cctgcagaaa ctatagagcg tcatttatac 5070gtagtttggc agaaaccact tacggctgat gatgcgcaac cctgctgact gtttcagtta 5130atatgctgca caccacacac ttgtttagtg aaccaaatct agaaagtacc aaggcagagg 5190tatgctcctg ctgtaatcag gcaaatgagt tcaactggat ttcttttgac aatactgttg 5250gtacctatta cttgggggag gacatgttgc agaagaccag atcattttta tacagaatgt 5310gaaatactga tacagttatt ctttttttta aagaacattg ttttataaag aacgtgattt 5370ccagtgatct ctggaagcgc taaagctaaa atttctgttc ttgaaacact tcagctttgc 5430aactaaaata ttacagatta ataataaatt aaaccaacca atgataaaca ctactcagtc 5490caccaacaac aaacgtgttt gaattcacct taccaatatt aatcccagcg tgtgtaaaac 5550agaacagtaa ctctatgtga ccccagataa cattttgtaa cattgtgctt ccttgtagtt 5610tgtaatgtga gttcaatcag tatttatgtt gaaatttcta acattaaatc tagtctctat 5670cctgttaatt taatttttaa atgctttatc catttgtgca aaggtaaacg cagattgtat 5730cttttttaat ggtacggcat aaaaagtaac cctcaagtga agtgtctcta tactgtttta 5790tagagtactt taacatgaat agataccttg taaacttgta ttgtggatgt gtaaataata 5850tgtactttgg gtttttaaca ccgcatgtaa agtcaaaata aaatatacaa atcattataa 5910aaaaaaaaa 591930597PRTHomo sapiens 30Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu Leu Leu Met Val Ser1 5 10 15Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro

Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp His Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Met Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala Lys Cys Ser Ala Glu465 470 475 480Asn Glu Glu Asp Lys Lys Val Ile Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Ile Ile Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Ser Cys Gly Arg Val 530 535 540Thr Pro Gly Met Leu Ala Glu Gly Tyr Glu Gln Asp Thr Glu Phe Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Asp Met Glu Val Ser Ser Ser 565 570 575Ser Val Thr Thr Met Val Tyr Asp Gly Lys Ser Ser Leu Glu Ser Pro 580 585 590Thr Arg Trp Ser Thr 595312290DNAHomo sapiensCDS(440)..(1867) 31gcggccgctt cccaccgtcc ctctcccctt actggcagag cgcgctgcgg gcggactccc 60gggcccggag cagcccaccg gccaccccac cgcccacccg gctcccggtg tctcctcccg 120gccgctctac ccagcaactt tccgtgcttt gttccccgac tggaaatgct ttacggaagc 180gtcttggaca gggtctccgc caggcgacaa gagctcggtg ctgagatgtg ttacgttctc 240atctccccat caattatgga tggaaacaaa taaggaagag tcaattttgc tgagcccctt 300ctccggcaac gagaggcgtt ctgcagccgg gagggagccg ccgctcgcgc cggcagccgc 360tggcaggggc atggtgagga ggaaggtagc tcagtggcat ttctgagcag gggccaccct 420gacttcacct tggcccacc atg agg gtc ttc ctg ctt tgt gcc tac ata ctg 472 Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu 1 5 10ctg ctg atg gtt tcc cag ttg agg gca gtc agc ttt cct gaa gat gat 520Leu Leu Met Val Ser Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp 15 20 25gaa ccc ctt aat act gtc gac tat cac tat tca agg caa tat ccg gtt 568Glu Pro Leu Asn Thr Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val 30 35 40ttt aga gga cgc cct tca ggc aat gaa tcg cag cac agg ctg gac ttt 616Phe Arg Gly Arg Pro Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe 45 50 55cag ctg atg ttg aaa att cga gac aca ctt tat att gct ggc agg gat 664Gln Leu Met Leu Lys Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp60 65 70 75caa gtt tat aca gta aac tta aat gaa atg ccc aaa aca gaa gta ata 712Gln Val Tyr Thr Val Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile 80 85 90ccc aac aag aaa ctg aca tgg cga tca aga caa cag gat cga gaa aac 760Pro Asn Lys Lys Leu Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn 95 100 105tgt gct atg aaa ggc aag cat aaa gat gaa tgc cac aac ttt atc aaa 808Cys Ala Met Lys Gly Lys His Lys Asp Glu Cys His Asn Phe Ile Lys 110 115 120gta ttt gtt cca aga aac gat gag atg gtt ttt gtt tgt ggt acc aat 856Val Phe Val Pro Arg Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn 125 130 135gca ttc aat ccc atg tgt aga tac tac agg ttg agt acc tta gaa tat 904Ala Phe Asn Pro Met Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr140 145 150 155gat ggg gaa gaa att agt ggc ctg gca aga tgc cca ttt gat gcc aga 952Asp Gly Glu Glu Ile Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg 160 165 170caa acc aat gtt gcc ctc ttt gct gat ggg aag ctg tat tct gcc aca 1000Gln Thr Asn Val Ala Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr 175 180 185gtg gct gac ttc ttg gcc agc gat gcc gtt att tat cga agc atg ggt 1048Val Ala Asp Phe Leu Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly 190 195 200gat gga tct gcc ctt cgc aca ata aaa tat gat tcc aaa tgg ata aaa 1096Asp Gly Ser Ala Leu Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys 205 210 215gag cca cac ttt ctt cat gcc ata gaa tat gga aac tat gtc tat ttc 1144Glu Pro His Phe Leu His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe220 225 230 235ttc ttt cga gaa atc gct gtc gaa cat aat aat tta ggc aag gct gtg 1192Phe Phe Arg Glu Ile Ala Val Glu His Asn Asn Leu Gly Lys Ala Val 240 245 250tat tcc cgc gtg gcc cgc ata tgt aaa aac gac atg ggt ggt tcc cag 1240Tyr Ser Arg Val Ala Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln 255 260 265cgg gtc ctg gag aaa cac tgg act tca ttt cta aag gct cgg ctg aac 1288Arg Val Leu Glu Lys His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn 270 275 280tgt tct gtc cct gga gat tcg ttt ttc tac ttt gat gtt ctg cag tct 1336Cys Ser Val Pro Gly Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser 285 290 295att aca gac ata ata caa atc aat ggc atc ccc act gtg gtc ggg gtg 1384Ile Thr Asp Ile Ile Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val300 305 310 315ttt acc acg cag ctc aat agc atc cct ggt tct gct gtc tgt gca ttt 1432Phe Thr Thr Gln Leu Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe 320 325 330agc atg gat gac att gaa aaa gta ttc aaa gga cgg ttt aag gaa cag 1480Ser Met Asp Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln 335 340 345aaa act cca gat tct gtt tgg aca gca gtt ccc gaa gac aaa gtg cca 1528Lys Thr Pro Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro 350 355 360aag cca agg cct ggc tgt tgt gca aaa cac ggc ctt gcc gaa gct tat 1576Lys Pro Arg Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr 365 370 375aaa acc tcc atc gat ttc ccg gat gaa act ctg tca ttc atc aaa tct 1624Lys Thr Ser Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser380 385 390 395cat ccc ctg atg gac tct gcc gtt cca ccc att gcc gat gag ccc tgg 1672His Pro Leu Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp 400 405 410ttc aca aag act cgg gtc agg tac aga ctg acg gcc atc tca gtg gac 1720Phe Thr Lys Thr Arg Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp 415 420 425cat tca gcc gga ccc tac cag aac tac aca gtc atc ttt gtt ggc tct 1768His Ser Ala Gly Pro Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser 430 435 440gaa gct ggc atg gta ctt aaa gtt ctg gca aag acc agt cct ttc tct 1816Glu Ala Gly Met Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser 445 450 455ttg aac gac agc gta tta ctg gaa gag att gaa gcc tac aac cat gca 1864Leu Asn Asp Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala460 465 470 475aag taggtatatg ttacgagaac gcccttcagc actgctcaaa aattttcggc 1917Lysatgtatttca tctagtcatg tccttttggt cctctaaatt agcagtggtt tggcataata 1977gtgttttgtg ttttttttct cattgaaata aatcttgggt ttgttttttt cccgagcctg 2037ctagggcgag gggggtgaat ggttgatgag tttaaaaata atgcagccct tgtttttcac 2097ctgtagaata tgagaacatt ttaacagcac ctctcttatc ttgcagatat attccaagat 2157gctacatgca gcagacagct gtgagcttgc atacacacac acacaaatat acatgcacat 2217acatacacag aatgcagtac tagttaagta tttccttcct atctttaata agtaagagaa 2277tatttagacc att 229032476PRTHomo sapiens 32Met Arg Val Phe Leu Leu Cys Ala Tyr Ile Leu Leu Leu Met Val Ser1 5 10 15Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Met Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Ser Val Asp His Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Met Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala Lys465 470 475336330DNAMus musculus 33ctccgctgac gctctgggtg cgtgatgggg gtgggacccc gagccgggag cccgcagcgc 60agctgtgtgc ggacgcgtgt gtttgcgtgg gcgtagcgtc gtagctcccg ggagttcatt 120gctctcccaa gccacacggt ctccagcggt gcccgaggcg ccaggggagg tctggctgac 180cagtcccagc tggccggtgg gcggcctggg ggcggggcgg ggcagctcgg ccctcctcct 240aggcgcaccc ctcctctgag gcgcacccct aagggaagaa aagacaccct gggctgcgag 300gaaaagtttc ttcttggcag ggccggctcg gcgccgctcc gcaagccgtc agggtgagcc 360cgccttcctc gctgcggggc ttggagcctc cagcccgccc gcagcgcagc ccgggccgcc 420gggccagctt cggccgggag aacgcaggga cagcctggga gtgcggagcc actgactgtc 480cacgcgggga ccgtgagcac ccactcgcgg gtctcccagc cactctcccc cgcaactttg 540cgtgctttgt tctctggctg aaaaaatgct ccacagaagc gccatagacc gggtctcctc 600caggcggcaa gggctcggcc gggagacgtg ttacgctctc agctccccat caattatgga 660tggaaacaaa taaggaaaag tcaattttgt atgagccgcg tctttcgcag ccagaggcgt 720cttgtagcct ggagcagagg caggcaaacc gagcccaaca accaggtagc taagtgggac 780ttctgaggag ggggagctca gatttcttct tggccaacca tggggttcct tctgctttgg 840ttctgcgtgc tgttccttct ggtctccagg ttacgggcgg tcagcttccc agaagacgat 900gagcccctca acacggttga ctatcactat tcaaggcaat atccggtttt tagaggacgc 960ccttcaggca acgaatcgca gcacaggctg gactttcagc tgatgttgaa aattcgagac 1020acactttata ttgctggcag ggatcaagtc tatacagtga acttaaatga aatcccccaa 1080acagaggtga taccaagcaa gaagctgacg tggaggtcca gacagcagga tcgagaaaat 1140tgtgctatga aaggcaagca taaagatgaa tgccacaact tcatcaaagt ctttgtccca 1200agaaatgatg agatggtttt tgtctgtggt accaatgctt tcaacccgat gtgcagatac 1260tataggttga gaacgttaga gtatgatggg gaagaaatta gtggcctggc acgatgcccg 1320tttgatgccc gacaaaccaa tgtcgccctc tttgctgatg gaaaactcta ttctgccaca 1380gtggctgatt tcctggccag tgatgctgtc atttacagaa gcatgggaga tggatctgcc 1440cttcgcacaa taaaatacga ttccaagtgg atcaaagaac cacacttcct tcatgccata 1500gaatatggaa actatgtcta tttcttcttc agagaaatcg ccgtggaaca taataactta 1560ggcaaggctg tgtattcccg cgtggctcgc atttgtaaaa acgacatggg tggctcacag 1620cgggtcctgg agaaacactg gacttccttc cttaaggctc ggctgaactg ctccgttcct 1680ggagattcct ttttctactt cgacgtcctg cagtctataa cagacataat ccaaatcaat 1740ggcatcccca ctgtggttgg ggtcttcacc acacagctca acagcattcc tggttctgca 1800gtctgtgcct ttagcatgga cgacattgag aaagtgttca aagggcggtt caaagagcag 1860aaaaccccag actctgtttg gacagcagtt cccgaagaca aagtaccaaa accaaggcct 1920ggctgttgtg ccaaacacgg cctcgcagaa gcttacaaga cctccatcga ctttccagat 1980gacaccctgg ctttcatcaa gtcccacccg ctgatggact ctgccgtccc acccattgcc 2040gatgagccct ggttcacaaa gacacgggtc aggtacaggt tgacagccat cgaagtggac 2100cgttcagcag ggccatacca aaactacaca gtcatctttg ttggctctga agctggcgtg 2160gtacttaaag ttttggcaaa gaccagtcct ttctctctga atgacagtgt attactcgaa 2220gagattgaag cttataaccc agccaagtgc agcgccgaga gtgaggagga cagaaaggtg 2280gtctcattac agctggacaa ggatcaccat gctttatacg tggccttctc tagctgcgtg 2340gtccgcatcc ccctcagccg ctgtgagcgc tacggatcgt gtaaaaagtc ttgcattgca 2400tcacgtgacc cgtactgtgg ttggttaagc cagggagttt gtgagagagt gaccctaggg 2460atgctgctgt taaccgaaga cttctttgct ttccataacc acagccctgg aggatatgag 2520caggacacgg agtacggcaa cacagcccac ctaggggact gccacggtgt acggtgggaa 2580gtccagtctg gagaatccaa tcagatggtc cacatgaatg tcctcatcac ctgcgtgttt 2640gccgcttttg tcttgggcgc gttcatcgca ggagtggccg tgtactgcta ccgtgacatg 2700ttcgttcgga agaacagaaa gatccataaa gacgcagaat ccgcccagtc gtgcacagac 2760tccagcggaa gcttcgccaa gctgaacggc ctctttgaca gccccgtcaa ggaataccag 2820cagaacattg attctcccaa actctacagc aacctgctga ccagtcggaa ggaactgcca 2880ccaaacacgg atacaaagtc catggccgtg gaccacagag gccagcctcc cgagctggct 2940gctctcccca cgccggaatc cacacctgtc ctccaccaga agaccctgca ggccatgaag 3000agccactctg agaaggccca cagccacggt gcttcaagga aagaacaccc ccagtttttt 3060ccttctagtc ctccacccca ttccccattg agtcacgggc atatccccag tgccatcgtt 3120cttccaaacg ccactcacga ctacaataca tccttctcca actcgaatgc ccacaaagcc 3180gaaaagaagc ttcagagcat ggatcaccct cttacgaagt catccagtaa gcgggagcac 3240cggcggtctg tggattccag gaatactctc aatgatctcc tgaagcatct aaatgaccca 3300aacagtaacc ccaaagccat cctgggagag atccatatgg ctcatcaaac cctcatgctg 3360gacccggtgg gaccaatggc tgaggtccca cccaaggtcc ctaaccggga ggcatctcta 3420tactcccctc cctccacact ccccagaaat agtccaacca agagagtaga tgtccccacc 3480actcctgggg tgccaatgac ttctctggaa agacaaaggg gttatcacaa aaattcctcc 3540cagaggcact ctatatctgc cgtgcctaaa aacttaaact caccaaatgg tgttttgtta 3600tctagacagc cgagtatgaa ccgtggaggc tatatgccca ccccaacagg ggcgaaggtg 3660gactatattc aggggacacc ggtgagtgtt catctgcagc cctccctctc cagacagagc 3720agctatacca gtaatggcac cctccccagg acgggactaa agaggacacc atccttaaaa 3780cctgatgtgc caccaaagcc ttcctttgtt ccgcaaacca catctgtcag accactgaac 3840aagtacacgt actaggcctc aagtatgcta ttcccgtgtg gctttatcct gtccctgctg 3900ttgcgaggaa gctgtgaggg taccttcaga tgagatacct gcttgtattt taagagaaac 3960aagtagccaa agaaactctg tcactttggt aacaccagaa cttgccacat gtagctacta 4020cagcaaggct tctgtgtact tgccggaaac gaagggaggt cctgctcact ccatttcttt 4080cgtttgaagc agaagggatg tgtagccagg gaaggctccc ttcaccagtg taaagagctg 4140atacagtact cagaagactg aacaaatact tgaaaatggg ttcaatgtag actgccattc 4200tgtgtggtct tcccattaaa tgtgaacatt ttaatatgta tgcattcacc ttgcctcttg 4260cacaaatgtc aaaatggaaa gatgggaatg tctcaaaaca aaatgagctt ggagattacc 4320aagcagtttg ctgaaaattc aatctttgac ccaaactgta gcaattttta ttttctgagt 4380gtggcactgt tttgttttat ttttttgttt tgttttgttt ttcaatgcca ccaacaaact 4440atgttaagag aggggcgagt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtga 4500gagagagaga gagagagaga gagagagaga gagagatcta cccattagaa ttgatttagg 4560tgcccattgc atcttttgta ctatggagtt gtttacagta agcatgactg aacaagcact 4620aacatcctcc tacaccggtc catcgtgttc ggctctgatc aggaatagac aaggcttctt 4680tgactgtcaa gtgattaaca tatggtaccc ggtgtcagaa catttaagcg ttctaaataa 4740ttttgtgctg ctatccatca gaacgtctat tccagccttg ccagcttaag aacttagaga 4800aattaagagg tatctttgat gtatctacca gtattcaata gtaacattta cctgtccact 4860gtgaatcaaa gcctggggca cgctactcaa ccttagacac acttacaggc ttttattttg 4920attgtgttat tttattttcc atacagtaaa aaatgtcctc tcttaactcc tctcaccccc 4980aactcccaag gcaaaagaga aaccaaaagt aggacaaaag aaagagacag acagacagac 5040agacagaaca ggaattacag ttggcttagc agggaggatc tgtagagctc tcgatgatcc 5100ttcctccatg tgtgtcctgt gaggattttg ctcatgagtc atgcaggcag tgacagtgaa 5160ctgtaaatac cacatgtgag tttacctgga tctgtgcatt ttgtgcctta ttcactcgag 5220tggtagaagt tccgcggtat gttgagtgtt tccactacag agcatcattt cccatgtgcc 5280acttgtaaat gttttgcagc cagcacctga ggacttctta tacagtcata aagccaccta

5340gagcgatttg ttgttgagca acgccgcccc ttccctccag gatcagaagc agcacccacc 5400cttgccatga taaacattcc atcccctgct gttctgataa tgtgaagtca gatgagggtt 5460cccaggttat gtggcacctg cggaaaccat gtctagagtc gtttctatgt agcttggcag 5520agcccactga tggctgcagg tgtgtagcct actgacagct ttggttaacc cactgcacat 5580cacccagtca tttacccaac ttactctaga aatgtccaca gctaaggaag gctcctgagc 5640cagtcaggcg gagttcaagt gatatcttgg gacagtgacc atggtctgca ttacttgggg 5700gaggatgggg tacaagacac cagatcattt ttatacagga tgtagagtac tgatgcggtt 5760gatcttttcc ttcaagaaca ttcttttcta tagaaaaatg attccctgtg atcttctgga 5820agctccaaag ctgaaaccct tcagctttgc aactaaaaat attacagttt aataatcaat 5880taaaccaacc aacaataagc actacacatc tgccaccaac aatgttgttt gcatttacct 5940taccaatatt aatcccagcg tggtaactct gtgtgacccc gataacattt tgtaacattg 6000tgctgcctta gagtttgtac tgtgagttct atcagtattt atgttgaaat ttctaacatg 6060gattctagtc tctattctgt taatttaatt ttaaatgctt tatccatttg tgcaaaggta 6120aacacagatt gtatcttttt taatggtacg gcataaaaaa ataaccctaa agtgaagtgg 6180ctctatactg ttttatagag tactttaacg tgtatagata tcttgtaaac ttgtattgtg 6240gatgtgtaaa taatatgtac tttgggtttt taacaccgca tgtaaagtca aaataaaata 6300tccaagtcat taaaaaaaaa aaaaaaaaaa 6330343036DNAMus musculusCDS(1)..(3033) 34atg ggg ttc ctt ctg ctt tgg ttc tgc gtg ctg ttc ctt ctg gtc tcc 48Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15agg tta cgg gcg gtc agc ttc cca gaa gac gat gag ccc ctc aac acg 96Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30gtt gac tat cac tat tca agg caa tat ccg gtt ttt aga gga cgc cct 144Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45tca ggc aac gaa tcg cag cac agg ctg gac ttt cag ctg atg ttg aaa 192Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60att cga gac aca ctt tat att gct ggc agg gat caa gtc tat aca gtg 240Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80aac tta aat gaa atc ccc caa aca gag gtg ata cca agc aag aag ctg 288Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95acg tgg agg tcc aga cag cag gat cga gaa aat tgt gct atg aaa ggc 336Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110aag cat aaa gat gaa tgc cac aac ttc atc aaa gtc ttt gtc cca aga 384Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125aat gat gag atg gtt ttt gtc tgt ggt acc aat gct ttc aac ccg atg 432Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140tgc aga tac tat agg ttg aga acg tta gag tat gat ggg gaa gaa att 480Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160agt ggc ctg gca cga tgc ccg ttt gat gcc cga caa acc aat gtc gcc 528Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175ctc ttt gct gat gga aaa ctc tat tct gcc aca gtg gct gat ttc ctg 576Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190gcc agt gat gct gtc att tac aga agc atg gga gat gga tct gcc ctt 624Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205cgc aca ata aaa tac gat tcc aag tgg atc aaa gaa cca cac ttc ctt 672Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220cat gcc ata gaa tat gga aac tat gtc tat ttc ttc ttc aga gaa atc 720His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240gcc gtg gaa cat aat aac tta ggc aag gct gtg tat tcc cgc gtg gct 768Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255cgc att tgt aaa aac gac atg ggt ggc tca cag cgg gtc ctg gag aaa 816Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270cac tgg act tcc ttc ctt aag gct cgg ctg aac tgc tcc gtt cct gga 864His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285gat tcc ttt ttc tac ttc gac gtc ctg cag tct ata aca gac ata atc 912Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300caa atc aat ggc atc ccc act gtg gtt ggg gtc ttc acc aca cag ctc 960Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320aac agc att cct ggt tct gca gtc tgt gcc ttt agc atg gac gac att 1008Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335gag aaa gtg ttc aaa ggg cgg ttc aaa gag cag aaa acc cca gac tct 1056Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350gtt tgg aca gca gtt ccc gaa gac aaa gta cca aaa cca agg cct ggc 1104Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365tgt tgt gcc aaa cac ggc ctc gca gaa gct tac aag acc tcc atc gac 1152Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380ttt cca gat gac acc ctg gct ttc atc aag tcc cac ccg ctg atg gac 1200Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400tct gcc gtc cca ccc att gcc gat gag ccc tgg ttc aca aag aca cgg 1248Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415gtc agg tac agg ttg aca gcc atc gaa gtg gac cgt tca gca ggg cca 1296Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430tac caa aac tac aca gtc atc ttt gtt ggc tct gaa gct ggc gtg gta 1344Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445ctt aaa gtt ttg gca aag acc agt cct ttc tct ctg aat gac agt gta 1392Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460tta ctc gaa gag att gaa gct tat aac cca gcc aag tgc agc gcc gag 1440Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480agt gag gag gac aga aag gtg gtc tca tta cag ctg gac aag gat cac 1488Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495cat gct tta tac gtg gcc ttc tct agc tgc gtg gtc cgc atc ccc ctc 1536His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510agc cgc tgt gag cgc tac gga tcg tgt aaa aag tct tgc att gca tca 1584Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525cgt gac ccg tac tgt ggt tgg tta agc cag gga gtt tgt gag aga gtg 1632Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540acc cta ggg atg ctg ctg tta acc gaa gac ttc ttt gct ttc cat aac 1680Thr Leu Gly Met Leu Leu Leu Thr Glu Asp Phe Phe Ala Phe His Asn545 550 555 560cac agc cct gga gga tat gag cag gac acg gag tac ggc aac aca gcc 1728His Ser Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly Asn Thr Ala 565 570 575cac cta ggg gac tgc cac ggt gta cgg tgg gaa gtc cag tct gga gaa 1776His Leu Gly Asp Cys His Gly Val Arg Trp Glu Val Gln Ser Gly Glu 580 585 590tcc aat cag atg gtc cac atg aat gtc ctc atc acc tgc gtg ttt gcc 1824Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala 595 600 605gct ttt gtc ttg ggc gcg ttc atc gca gga gtg gcc gtg tac tgc tac 1872Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr 610 615 620cgt gac atg ttc gtt cgg aag aac aga aag atc cat aaa gac gca gaa 1920Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu625 630 635 640tcc gcc cag tcg tgc aca gac tcc agc gga agc ttc gcc aag ctg aac 1968Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn 645 650 655ggc ctc ttt gac agc ccc gtc aag gaa tac cag cag aac att gat tct 2016Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser 660 665 670ccc aaa ctc tac agc aac ctg ctg acc agt cgg aag gaa ctg cca cca 2064Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro 675 680 685aac acg gat aca aag tcc atg gcc gtg gac cac aga ggc cag cct ccc 2112Asn Thr Asp Thr Lys Ser Met Ala Val Asp His Arg Gly Gln Pro Pro 690 695 700gag ctg gct gct ctc ccc acg ccg gaa tcc aca cct gtc ctc cac cag 2160Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln705 710 715 720aag acc ctg cag gcc atg aag agc cac tct gag aag gcc cac agc cac 2208Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala His Ser His 725 730 735ggt gct tca agg aaa gaa cac ccc cag ttt ttt cct tct agt cct cca 2256Gly Ala Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser Ser Pro Pro 740 745 750ccc cat tcc cca ttg agt cac ggg cat atc ccc agt gcc atc gtt ctt 2304Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala Ile Val Leu 755 760 765cca aac gcc act cac gac tac aat aca tcc ttc tcc aac tcg aat gcc 2352Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala 770 775 780cac aaa gcc gaa aag aag ctt cag agc atg gat cac cct ctt acg aag 2400His Lys Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro Leu Thr Lys785 790 795 800tca tcc agt aag cgg gag cac cgg cgg tct gtg gat tcc agg aat act 2448Ser Ser Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser Arg Asn Thr 805 810 815ctc aat gat ctc ctg aag cat cta aat gac cca aac agt aac ccc aaa 2496Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys 820 825 830gcc atc ctg gga gag atc cat atg gct cat caa acc ctc atg ctg gac 2544Ala Ile Leu Gly Glu Ile His Met Ala His Gln Thr Leu Met Leu Asp 835 840 845ccg gtg gga cca atg gct gag gtc cca ccc aag gtc cct aac cgg gag 2592Pro Val Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro Asn Arg Glu 850 855 860gca tct cta tac tcc cct ccc tcc aca ctc ccc aga aat agt cca acc 2640Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr865 870 875 880aag aga gta gat gtc ccc acc act cct ggg gtg cca atg act tct ctg 2688Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu 885 890 895gaa aga caa agg ggt tat cac aaa aat tcc tcc cag agg cac tct ata 2736Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile 900 905 910tct gcc gtg cct aaa aac tta aac tca cca aat ggt gtt ttg tta tct 2784Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser 915 920 925aga cag ccg agt atg aac cgt gga ggc tat atg ccc acc cca aca ggg 2832Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly 930 935 940gcg aag gtg gac tat att cag ggg aca ccg gtg agt gtt cat ctg cag 2880Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val His Leu Gln945 950 955 960ccc tcc ctc tcc aga cag agc agc tat acc agt aat ggc acc ctc ccc 2928Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro 965 970 975agg acg gga cta aag agg aca cca tcc tta aaa cct gat gtg cca cca 2976Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro Pro 980 985 990aag cct tcc ttt gtt ccg caa acc aca tct gtc aga cca ctg aac aag 3024Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg Pro Leu Asn Lys 995 1000 1005tac acg tac tag 3036Tyr Thr Tyr 1010351011PRTMus musculus 35Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540Thr Leu Gly Met Leu Leu Leu Thr Glu Asp Phe Phe Ala Phe His Asn545 550 555 560His Ser Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly Asn Thr Ala 565 570 575His Leu Gly Asp Cys His Gly Val Arg Trp Glu Val Gln Ser Gly Glu 580 585 590Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala 595 600 605Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr 610 615 620Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu625 630 635 640Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn 645 650 655Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser 660

665 670Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro 675 680 685Asn Thr Asp Thr Lys Ser Met Ala Val Asp His Arg Gly Gln Pro Pro 690 695 700Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln705 710 715 720Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala His Ser His 725 730 735Gly Ala Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser Ser Pro Pro 740 745 750Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala Ile Val Leu 755 760 765Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala 770 775 780His Lys Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro Leu Thr Lys785 790 795 800Ser Ser Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser Arg Asn Thr 805 810 815Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys 820 825 830Ala Ile Leu Gly Glu Ile His Met Ala His Gln Thr Leu Met Leu Asp 835 840 845Pro Val Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro Asn Arg Glu 850 855 860Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr865 870 875 880Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu 885 890 895Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile 900 905 910Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser 915 920 925Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly 930 935 940Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val His Leu Gln945 950 955 960Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro 965 970 975Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro Pro 980 985 990Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg Pro Leu Asn Lys 995 1000 1005Tyr Thr Tyr 1010362997DNAMus musculusCDS(1)..(2994) 36atg ggg ttc ctt ctg ctt tgg ttc tgc gtg ctg ttc ctt ctg gtc tcc 48Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15agg tta cgg gcg gtc agc ttc cca gaa gac gat gag ccc ctc aac acg 96Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30gtt gac tat cac tat tca agg caa tat ccg gtt ttt aga gga cgc cct 144Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45tca ggc aac gaa tcg cag cac agg ctg gac ttt cag ctg atg ttg aaa 192Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60att cga gac aca ctt tat att gct ggc agg gat caa gtc tat aca gtg 240Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80aac tta aat gaa atc ccc caa aca gag gtg ata cca agc aag aag ctg 288Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95acg tgg agg tcc aga cag cag gat cga gaa aat tgt gct atg aaa ggc 336Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110aag cat aaa gat gaa tgc cac aac ttc atc aaa gtc ttt gtc cca aga 384Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125aat gat gag atg gtt ttt gtc tgt ggt acc aat gct ttc aac ccg atg 432Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140tgc aga tac tat agg ttg aga acg tta gag tat gat ggg gaa gaa att 480Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160agt ggc ctg gca cga tgc ccg ttt gat gcc cga caa acc aat gtc gcc 528Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175ctc ttt gct gat gga aaa ctc tat tct gcc aca gtg gct gat ttc ctg 576Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190gcc agt gat gct gtc att tac aga agc atg gga gat gga tct gcc ctt 624Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205cgc aca ata aaa tac gat tcc aag tgg atc aaa gaa cca cac ttc ctt 672Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220cat gcc ata gaa tat gga aac tat gtc tat ttc ttc ttc aga gaa atc 720His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240gcc gtg gaa cat aat aac tta ggc aag gct gtg tat tcc cgc gtg gct 768Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255cgc att tgt aaa aac gac atg ggt ggc tca cag cgg gtc ctg gag aaa 816Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270cac tgg act tcc ttc ctt aag gct cgg ctg aac tgc tcc gtt cct gga 864His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285gat tcc ttt ttc tac ttc gac gtc ctg cag tct ata aca gac ata atc 912Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300caa atc aat ggc atc ccc act gtg gtt ggg gtc ttc acc aca cag ctc 960Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320aac agc att cct ggt tct gca gtc tgt gcc ttt agc atg gac gac att 1008Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335gag aaa gtg ttc aaa ggg cgg ttc aaa gag cag aaa acc cca gac tct 1056Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350gtt tgg aca gca gtt ccc gaa gac aaa gta cca aaa cca agg cct ggc 1104Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365tgt tgt gcc aaa cac ggc ctc gca gaa gct tac aag acc tcc atc gac 1152Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380ttt cca gat gac acc ctg gct ttc atc aag tcc cac ccg ctg atg gac 1200Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400tct gcc gtc cca ccc att gcc gat gag ccc tgg ttc aca aag aca cgg 1248Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415gtc agg tac agg ttg aca gcc atc gaa gtg gac cgt tca gca ggg cca 1296Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430tac caa aac tac aca gtc atc ttt gtt ggc tct gaa gct ggc gtg gta 1344Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445ctt aaa gtt ttg gca aag acc agt cct ttc tct ctg aat gac agt gta 1392Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460tta ctc gaa gag att gaa gct tat aac cca gcc aag tgc agc gcc gag 1440Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480agt gag gag gac aga aag gtg gtc tca tta cag ctg gac aag gat cac 1488Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495cat gct tta tac gtg gcc ttc tct agc tgc gtg gtc cgc atc ccc ctc 1536His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510agc cgc tgt gag cgc tac gga tcg tgt aaa aag tct tgc att gca tca 1584Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525cgt gac ccg tac tgt ggt tgg tta agc cag gga gtt tgt gag aga gtg 1632Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540acc cta ggg atg ctc cct gga gga tat gag cag gac acg gag tac ggc 1680Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly545 550 555 560aac aca gcc cac cta ggg gac tgc cac ggt gta cgg tgg gaa gtc cag 1728Asn Thr Ala His Leu Gly Asp Cys His Gly Val Arg Trp Glu Val Gln 565 570 575tct gga gaa tcc aat cag atg gtc cac atg aat gtc ctc atc acc tgc 1776Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys 580 585 590gtg ttt gcc gct ttt gtc ttg ggc gcg ttc atc gca gga gtg gcc gtg 1824Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val 595 600 605tac tgc tac cgt gac atg ttc gtt cgg aag aac aga aag atc cat aaa 1872Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys 610 615 620gac gca gaa tcc gcc cag tcg tgc aca gac tcc agc gga agc ttc gcc 1920Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala625 630 635 640aag ctg aac ggc ctc ttt gac agc ccc gtc aag gaa tac cag cag aac 1968Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn 645 650 655att gat tct ccc aaa ctc tac agc aac ctg ctg acc agt cgg aag gaa 2016Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu 660 665 670ctg cca cca aac acg gat aca aag tcc atg gcc gtg gac cac aga ggc 2064Leu Pro Pro Asn Thr Asp Thr Lys Ser Met Ala Val Asp His Arg Gly 675 680 685cag cct ccc gag ctg gct gct ctc ccc acg ccg gaa tcc aca cct gtc 2112Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val 690 695 700ctc cac cag aag acc ctg cag gcc atg aag agc cac tct gag aag gcc 2160Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala705 710 715 720cac agc cac ggt gct tca agg aaa gaa cac ccc cag ttt ttt cct tct 2208His Ser His Gly Ala Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser 725 730 735agt cct cca ccc cat tcc cca ttg agt cac ggg cat atc ccc agt gcc 2256Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala 740 745 750atc gtt ctt cca aac gcc act cac gac tac aat aca tcc ttc tcc aac 2304Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn 755 760 765tcg aat gcc cac aaa gcc gaa aag aag ctt cag agc atg gat cac cct 2352Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro 770 775 780ctt acg aag tca tcc agt aag cgg gag cac cgg cgg tct gtg gat tcc 2400Leu Thr Lys Ser Ser Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser785 790 795 800agg aat act ctc aat gat ctc ctg aag cat cta aat gac cca aac agt 2448Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser 805 810 815aac ccc aaa gcc atc ctg gga gag atc cat atg gct cat caa acc ctc 2496Asn Pro Lys Ala Ile Leu Gly Glu Ile His Met Ala His Gln Thr Leu 820 825 830atg ctg gac ccg gtg gga cca atg gct gag gtc cca ccc aag gtc cct 2544Met Leu Asp Pro Val Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro 835 840 845aac cgg gag gca tct cta tac tcc cct ccc tcc aca ctc ccc aga aat 2592Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn 850 855 860agt cca acc aag aga gta gat gtc ccc acc act cct ggg gtg cca atg 2640Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met865 870 875 880act tct ctg gaa aga caa agg ggt tat cac aaa aat tcc tcc cag agg 2688Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg 885 890 895cac tct ata tct gcc gtg cct aaa aac tta aac tca cca aat ggt gtt 2736His Ser Ile Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val 900 905 910ttg tta tct aga cag ccg agt atg aac cgt gga ggc tat atg ccc acc 2784Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr 915 920 925cca aca ggg gcg aag gtg gac tat att cag ggg aca ccg gtg agt gtt 2832Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val 930 935 940cat ctg cag ccc tcc ctc tcc aga cag agc agc tat acc agt aat ggc 2880His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly945 950 955 960acc ctc ccc agg acg gga cta aag agg aca cca tcc tta aaa cct gat 2928Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp 965 970 975gtg cca cca aag cct tcc ttt gtt ccg caa acc aca tct gtc aga cca 2976Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg Pro 980 985 990ctg aac aag tac acg tac tag 2997Leu Asn Lys Tyr Thr Tyr 99537998PRTMus musculus 37Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr

Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Gly Val Arg Trp Glu Val Gln 565 570 575Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys 580 585 590Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val 595 600 605Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys 610 615 620Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala625 630 635 640Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn 645 650 655Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu 660 665 670Leu Pro Pro Asn Thr Asp Thr Lys Ser Met Ala Val Asp His Arg Gly 675 680 685Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val 690 695 700Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala705 710 715 720His Ser His Gly Ala Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser 725 730 735Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala 740 745 750Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn 755 760 765Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro 770 775 780Leu Thr Lys Ser Ser Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser785 790 795 800Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser 805 810 815Asn Pro Lys Ala Ile Leu Gly Glu Ile His Met Ala His Gln Thr Leu 820 825 830Met Leu Asp Pro Val Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro 835 840 845Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn 850 855 860Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met865 870 875 880Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg 885 890 895His Ser Ile Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val 900 905 910Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr 915 920 925Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val 930 935 940His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly945 950 955 960Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp 965 970 975Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg Pro 980 985 990Leu Asn Lys Tyr Thr Tyr 995383222DNAMus musculusCDS(1)..(3219) 38atg ggg ttc ctt ctg ctt tgg ttc tgc gtg ctg ttc ctt ctg gtc tcc 48Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15agg tta cgg gcg gtc agc ttc cca gaa gac gat gag ccc ctc aac acg 96Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30gtt gac tat cac tat tca agg caa tat ccg gtt ttt aga gga cgc cct 144Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45tca ggc aac gaa tcg cag cac agg ctg gac ttt cag ctg atg ttg aaa 192Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60att cga gac aca ctt tat att gct ggc agg gat caa gtc tat aca gtg 240Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80aac tta aat gaa atc ccc caa aca gag gtg ata cca agc aag aag ctg 288Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95acg tgg agg tcc aga cag cag gat cga gaa aat tgt gct atg aaa ggc 336Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110aag cat aaa gat gaa tgc cac aac ttc atc aaa gtc ttt gtc cca aga 384Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125aat gat gag atg gtt ttt gtc tgt ggt acc aat gct ttc aac ccg atg 432Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140tgc aga tac tat agg ttg aga acg tta gag tat gat ggg gaa gaa att 480Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160agt ggc ctg gca cga tgc ccg ttt gat gcc cga caa acc aat gtc gcc 528Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175ctc ttt gct gat gga aaa ctc tat tct gcc aca gtg gct gat ttc ctg 576Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190gcc agt gat gct gtc att tac aga agc atg gga gat gga tct gcc ctt 624Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205cgc aca ata aaa tac gat tcc aag tgg atc aaa gaa cca cac ttc ctt 672Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220cat gcc ata gaa tat gga aac tat gtc tat ttc ttc ttc aga gaa atc 720His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240gcc gtg gaa cat aat aac tta ggc aag gct gtg tat tcc cgc gtg gct 768Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255cgc att tgt aaa aac gac atg ggt ggc tca cag cgg gtc ctg gag aaa 816Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270cac tgg act tcc ttc ctt aag gct cgg ctg aac tgc tcc gtt cct gga 864His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285gat tcc ttt ttc tac ttc gac gtc ctg cag tct ata aca gac ata atc 912Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300caa atc aat ggc atc ccc act gtg gtt ggg gtc ttc acc aca cag ctc 960Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320aac agc att cct ggt tct gca gtc tgt gcc ttt agc atg gac gac att 1008Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335gag aaa gtg ttc aaa ggg cgg ttc aaa gag cag aaa acc cca gac tct 1056Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350gtt tgg aca gca gtt ccc gaa gac aaa gta cca aaa cca agg cct ggc 1104Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365tgt tgt gcc aaa cac ggc ctc gca gaa gct tac aag acc tcc atc gac 1152Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380ttt cca gat gac acc ctg gct ttc atc aag tcc cac ccg ctg atg gac 1200Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400tct gcc gtc cca ccc att gcc gat gag ccc tgg ttc aca aag aca cgg 1248Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415gtc agg tac agg ttg aca gcc atc gaa gtg gac cgt tca gca ggg cca 1296Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430tac caa aac tac aca gtc atc ttt gtt ggc tct gaa gct ggc gtg gta 1344Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445ctt aaa gtt ttg gca aag acc agt cct ttc tct ctg aat gac agt gta 1392Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460tta ctc gaa gag att gaa gct tat aac cca gcc aag tgc agc gcc gag 1440Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480agt gag gag gac aga aag gtg gtc tca tta cag ctg gac aag gat cac 1488Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495cat gct tta tac gtg gcc ttc tct agc tgc gtg gtc cgc atc ccc ctc 1536His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510agc cgc tgt gag cgc tac gga tcg tgt aaa aag tct tgc att gca tca 1584Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525cgt gac ccg tac tgt ggt tgg tta agc cag gga gtt tgt gag aga gtg 1632Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540acc cta ggg atg ctc cct gga gga tat gag cag gac acg gag tac ggc 1680Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly545 550 555 560aac aca gcc cac cta ggg gac tgc cac gaa agt ttg cct cct tca act 1728Asn Thr Ala His Leu Gly Asp Cys His Glu Ser Leu Pro Pro Ser Thr 565 570 575aca cca gat tac aaa ata ttt ggc ggt cca aca tct gac atg gag gta 1776Thr Pro Asp Tyr Lys Ile Phe Gly Gly Pro Thr Ser Asp Met Glu Val 580 585 590tcc tca tct tct gtt acc act gtg gca agt agc cca gaa att aca tct 1824Ser Ser Ser Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser 595 600 605aaa gtg att gat acc tgg aga cct aaa ctg acg agc tcc cgg aaa ttt 1872Lys Val Ile Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe 610 615 620gta gtt caa gat gac cca aat act tct gat ttt act gat act ata tca 1920Val Val Gln Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser625 630 635 640ggt atc cca aag ggt gta cgg tgg gaa gtc cag tct gga gaa tcc aat 1968Gly Ile Pro Lys Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn 645 650 655cag atg gtc cac atg aat gtc ctc atc acc tgc gtg ttt gcc gct ttt 2016Gln Met Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Phe 660 665 670gtc ttg ggc gcg ttc atc gca gga gtg gcc gtg tac tgc tac cgt gac 2064Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp 675 680 685atg ttc gtt cgg aag aac aga aag atc cat aaa gac gca gaa tcc gcc 2112Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser Ala 690 695 700cag tcg tgc aca gac tcc agc gga agc ttc gcc aag ctg aac ggc ctc 2160Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn Gly Leu705 710 715 720ttt gac agc ccc gtc aag gaa tac cag cag aac att gat tct ccc aaa 2208Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser Pro Lys 725 730 735ctc tac agc aac ctg ctg acc agt cgg aag gaa ctg cca cca aac acg 2256Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro Asn Thr 740 745 750gat aca aag tcc atg gcc gtg gac cac aga ggc cag cct ccc gag ctg 2304Asp Thr Lys Ser Met Ala Val Asp His Arg Gly Gln Pro Pro Glu Leu 755 760 765gct gct ctc ccc acg ccg gaa tcc aca cct gtc ctc cac cag aag acc 2352Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln Lys Thr 770 775 780ctg cag gcc atg aag agc cac tct gag aag gcc cac agc cac ggt gct 2400Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala His Ser His Gly Ala785 790 795 800tca agg aaa gaa cac ccc cag ttt ttt cct tct agt cct cca ccc cat 2448Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser Ser Pro Pro Pro His 805 810 815tcc cca ttg agt cac ggg cat atc ccc agt gcc atc gtt ctt cca aac 2496Ser Pro Leu Ser His Gly His Ile Pro Ser Ala Ile Val Leu Pro Asn 820 825 830gcc act cac gac tac aat aca tcc ttc tcc aac tcg aat gcc cac aaa 2544Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala His Lys 835 840 845gcc gaa aag aag ctt cag agc atg gat cac cct ctt acg aag tca tcc 2592Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro Leu Thr Lys Ser Ser 850 855 860agt aag cgg gag cac cgg cgg tct gtg gat tcc agg aat act ctc aat 2640Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn865 870 875 880gat ctc ctg aag cat cta aat gac cca aac agt aac ccc aaa gcc atc 2688Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys Ala Ile 885 890 895ctg gga gag atc cat atg gct cat caa acc ctc atg ctg gac ccg gtg 2736Leu Gly Glu Ile His Met Ala His Gln Thr Leu Met Leu Asp Pro Val 900 905 910gga cca atg gct gag gtc cca ccc aag gtc cct aac cgg gag gca tct 2784Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser 915 920 925cta tac tcc cct ccc tcc aca ctc ccc aga aat agt cca acc aag aga 2832Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys Arg 930 935 940gta gat gtc ccc acc act cct ggg gtg cca atg act tct ctg gaa aga 2880Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu Glu Arg945 950 955 960caa agg ggt tat cac aaa aat tcc tcc cag agg cac tct ata tct gcc 2928Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile Ser Ala 965 970 975gtg cct aaa aac tta aac tca cca aat ggt gtt ttg tta tct aga cag 2976Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser Arg Gln 980 985 990ccg agt atg aac cgt gga ggc tat atg ccc acc cca aca ggg gcg aag 3024Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly Ala Lys 995 1000 1005gtg gac tat att cag ggg aca ccg gtg agt gtt cat ctg cag ccc 3069Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val His Leu Gln Pro 1010 1015 1020tcc ctc tcc aga cag agc agc tat acc agt aat ggc acc ctc ccc 3114Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro 1025 1030 1035agg acg gga cta aag agg aca cca tcc tta aaa cct gat gtg cca 3159Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro 1040 1045 1050cca aag cct tcc ttt gtt ccg caa acc aca tct gtc aga cca ctg 3204Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg Pro Leu 1055 1060 1065aac aag tac acg tac tag 3222Asn Lys Tyr Thr Tyr 1070391073PRTMus musculus 39Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245

250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Glu Ser Leu Pro Pro Ser Thr 565 570 575Thr Pro Asp Tyr Lys Ile Phe Gly Gly Pro Thr Ser Asp Met Glu Val 580 585 590Ser Ser Ser Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser 595 600 605Lys Val Ile Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe 610 615 620Val Val Gln Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser625 630 635 640Gly Ile Pro Lys Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn 645 650 655Gln Met Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Phe 660 665 670Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp 675 680 685Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser Ala 690 695 700Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn Gly Leu705 710 715 720Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser Pro Lys 725 730 735Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro Asn Thr 740 745 750Asp Thr Lys Ser Met Ala Val Asp His Arg Gly Gln Pro Pro Glu Leu 755 760 765Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln Lys Thr 770 775 780Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala His Ser His Gly Ala785 790 795 800Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser Ser Pro Pro Pro His 805 810 815Ser Pro Leu Ser His Gly His Ile Pro Ser Ala Ile Val Leu Pro Asn 820 825 830Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala His Lys 835 840 845Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro Leu Thr Lys Ser Ser 850 855 860Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn865 870 875 880Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys Ala Ile 885 890 895Leu Gly Glu Ile His Met Ala His Gln Thr Leu Met Leu Asp Pro Val 900 905 910Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser 915 920 925Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys Arg 930 935 940Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu Glu Arg945 950 955 960Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile Ser Ala 965 970 975Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser Arg Gln 980 985 990Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly Ala Lys 995 1000 1005Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val His Leu Gln Pro 1010 1015 1020Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro1025 1030 1035Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro1040 1045 1050Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg Pro Leu1055 1060 1065Asn Lys Tyr Thr Tyr10704023DNAArtificialSequencing primer 40aaagcagaag gaaccccatg gtt 234125DNAArtificialSequencing primer 41accaggtagc taagtgggac ttctg 254223DNAArtificialSequencing primer 42tgacaccctg gctttcatca agt 234325DNAArtificialSequencing primer 43aaagtcttgc attgcatcac gtgac 254422DNAArtificialSequencing primer 44ccaatcagat ggtccacatg aa 224523DNAArtificialSequencing primer 45atgaagagcc actctgagaa ggc 234622DNAArtificialSequencing primer 46taaccgggag gcatctctat ac 22473093DNAMus musculusCDS(1)..(3090) 47atg ggg ttc ctt ctg ctt tgg ttc tgc gtg ctg ttc ctt ctg gtc tcc 48Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15agg tta cgg gcg gtc agc ttc cca gaa gac gat gag ccc ctc aac acg 96Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30gtt gac tat cac tat tca agg caa tat ccg gtt ttt aga gga cgc cct 144Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45tca ggc aac gaa tcg cag cac agg ctg gac ttt cag ctg atg ttg aaa 192Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60att cga gac aca ctt tat att gct ggc agg gat caa gtc tat aca gtg 240Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80aac tta aat gaa atc ccc caa aca gag gtg ata cca agc aag aag ctg 288Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95acg tgg agg tcc aga cag cag gat cga gaa aat tgt gct atg aaa ggc 336Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110aag cat aaa gat gaa tgc cac aac ttc atc aaa gtc ttt gtc cca aga 384Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125aat gat gag atg gtt ttt gtc tgt ggt acc aat gct ttc aac ccg atg 432Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140tgc aga tac tat agg ttg aga acg tta gag tat gat ggg gaa gaa att 480Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160agt ggc ctg gca cga tgc ccg ttt gat gcc cga caa acc aat gtc gcc 528Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175ctc ttt gct gat gga aaa ctc tat tct gcc aca gtg gct gat ttc ctg 576Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190gcc agt gat gct gtc att tac aga agc atg gga gat gga tct gcc ctt 624Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205cgc aca ata aaa tac gat tcc aag tgg atc aaa gaa cca cac ttc ctt 672Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220cat gcc ata gaa tat gga aac tat gtc tat ttc ttc ttc aga gaa atc 720His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240gcc gtg gaa cat aat aac tta ggc aag gct gtg tat tcc cgc gtg gct 768Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255cgc att tgt aaa aac gac atg ggt ggc tca cag cgg gtc ctg gag aaa 816Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270cac tgg act tcc ttc ctt aag gct cgg ctg aac tgc tcc gtt cct gga 864His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285gat tcc ttt ttc tac ttc gac gtc ctg cag tct ata aca gac ata atc 912Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300caa atc aat ggc atc ccc act gtg gtt ggg gtc ttc acc aca cag ctc 960Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320aac agc att cct ggt tct gca gtc tgt gcc ttt agc atg gac gac att 1008Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335gag aaa gtg ttc aaa ggg cgg ttc aaa gag cag aaa acc cca gac tct 1056Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350gtt tgg aca gca gtt ccc gaa gac aaa gta cca aaa cca agg cct ggc 1104Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365tgt tgt gcc aaa cac ggc ctc gca gaa gct tac aag acc tcc atc gac 1152Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380ttt cca gat gac acc ctg gct ttc atc aag tcc cac ccg ctg atg gac 1200Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400tct gcc gtc cca ccc att gcc gat gag ccc tgg ttc aca aag aca cgg 1248Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415gtc agg tac agg ttg aca gcc atc gaa gtg gac cgt tca gca ggg cca 1296Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430tac caa aac tac aca gtc atc ttt gtt ggc tct gaa gct ggc gtg gta 1344Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445ctt aaa gtt ttg gca aag acc agt cct ttc tct ctg aat gac agt gta 1392Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460tta ctc gaa gag att gaa gct tat aac cca gcc aag tgc agc gcc gag 1440Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480agt gag gag gac aga aag gtg gtc tca tta cag ctg gac aag gat cac 1488Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495cat gct tta tac gtg gcc ttc tct agc tgc gtg gtc cgc atc ccc ctc 1536His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510agc cgc tgt gag cgc tac gga tcg tgt aaa aag tct tgc att gca tca 1584Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525cgt gac ccg tac tgt ggt tgg tta agc cag gga gtt tgt gag aga gtg 1632Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540acc cta ggg atg ctg ctg tta acc gaa gac ttc ttt gct ttc cat aac 1680Thr Leu Gly Met Leu Leu Leu Thr Glu Asp Phe Phe Ala Phe His Asn545 550 555 560cac agc cct gga gga tat gag cag gac acg gag tac ggc aac aca gcc 1728His Ser Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly Asn Thr Ala 565 570 575cac cta ggg gac tgc cac gaa agt ttg cct cct tca act aca cca gat 1776His Leu Gly Asp Cys His Glu Ser Leu Pro Pro Ser Thr Thr Pro Asp 580 585 590tac aaa ata ttt ggc ggt cca aca tct ggt gta cgg tgg gaa gtc cag 1824Tyr Lys Ile Phe Gly Gly Pro Thr Ser Gly Val Arg Trp Glu Val Gln 595 600 605tct gga gaa tcc aat cag atg gtc cac atg aat gtc ctc atc acc tgc 1872Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys 610 615 620gtg ttt gcc gct ttt gtc ttg ggc gcg ttc atc gca gga gtg gcc gtg 1920Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val625 630 635 640tac tgc tac cgt gac atg ttc gtt cgg aag aac aga aag atc cat aaa 1968Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys 645 650 655gac gca gaa tcc gcc cag tcg tgc aca gac tcc agc gga agc ttc gcc 2016Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala 660 665 670aag ctg aac ggc ctc ttt gac agc ccc gtc aag gaa tac cag cag aac 2064Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn 675 680 685att gat tct ccc aaa ctc tac agc aac ctg ctg acc agt cgg aag gaa 2112Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu 690 695 700ctg cca cca aac acg gat aca aag tcc atg gcc gtg gac cac aga ggc 2160Leu Pro Pro Asn Thr Asp Thr Lys Ser Met Ala Val Asp His Arg Gly705 710 715 720cag cct ccc gag ctg gct gct ctc ccc acg ccg gaa tcc aca cct gtc 2208Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val 725 730 735ctc cac cag aag acc ctg cag gcc atg aag agc cac tct gag aag gcc 2256Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala 740 745 750cac agc cac ggt gct tca agg aaa gaa cac ccc cag ttt ttt cct tct 2304His Ser His Gly Ala Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser 755 760 765agt cct cca ccc cat tcc cca ttg agt cac ggg cat atc ccc agt gcc 2352Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala 770 775 780atc gtt ctt cca aac gcc act cac gac tac aat aca tcc ttc tcc aac 2400Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn785 790 795 800tcg aat gcc cac aaa gcc gaa aag aag ctt cag agc atg gat cac cct 2448Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro 805 810 815ctt acg aag tca tcc agt aag cgg gag cac cgg cgg tct gtg gat tcc 2496Leu Thr Lys Ser Ser Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser 820 825 830agg aat act ctc aat gat ctc ctg aag cat cta aat gac cca aac agt 2544Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser 835 840 845aac ccc aaa gcc atc ctg gga gag atc cat atg gct cat caa acc ctc 2592Asn Pro Lys Ala Ile Leu Gly Glu Ile His Met Ala His Gln Thr Leu 850 855 860atg ctg gac ccg gtg gga cca atg gct gag gtc cca ccc aag gtc cct 2640Met Leu Asp Pro Val Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro865 870 875 880aac cgg gag gca tct cta tac tcc cct ccc tcc aca ctc ccc aga aat 2688Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn 885 890 895agt cca acc aag aga gta gat gtc ccc acc act cct ggg gtg cca atg 2736Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met 900 905 910act tct ctg gaa aga caa agg ggt tat cac aaa aat tcc tcc cag agg 2784Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg 915 920 925cac tct ata tct gcc gtg cct aaa aac tta aac tca cca aat ggt gtt 2832His Ser Ile Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val 930 935 940ttg tta tct aga cag ccg agt atg aac cgt gga ggc tat atg ccc acc 2880Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr945 950 955 960cca aca ggg gcg

aag gtg gac tat att cag ggg aca ccg gtg agt gtt 2928Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val 965 970 975cat ctg cag ccc tcc ctc tcc aga cag agc agc tat acc agt aat ggc 2976His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly 980 985 990acc ctc ccc agg acg gga cta aag agg aca cca tcc tta aaa cct gat 3024Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp 995 1000 1005gtg cca cca aag cct tcc ttt gtt ccg caa acc aca tct gtc aga 3069Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg 1010 1015 1020cca ctg aac aag tac acg tac tag 3093Pro Leu Asn Lys Tyr Thr Tyr 1025 1030481030PRTMus musculus 48Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540Thr Leu Gly Met Leu Leu Leu Thr Glu Asp Phe Phe Ala Phe His Asn545 550 555 560His Ser Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly Asn Thr Ala 565 570 575His Leu Gly Asp Cys His Glu Ser Leu Pro Pro Ser Thr Thr Pro Asp 580 585 590Tyr Lys Ile Phe Gly Gly Pro Thr Ser Gly Val Arg Trp Glu Val Gln 595 600 605Ser Gly Glu Ser Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys 610 615 620Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val625 630 635 640Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys 645 650 655Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala 660 665 670Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn 675 680 685Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu 690 695 700Leu Pro Pro Asn Thr Asp Thr Lys Ser Met Ala Val Asp His Arg Gly705 710 715 720Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val 725 730 735Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala 740 745 750His Ser His Gly Ala Ser Arg Lys Glu His Pro Gln Phe Phe Pro Ser 755 760 765Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala 770 775 780Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn785 790 795 800Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Ser Met Asp His Pro 805 810 815Leu Thr Lys Ser Ser Ser Lys Arg Glu His Arg Arg Ser Val Asp Ser 820 825 830Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser 835 840 845Asn Pro Lys Ala Ile Leu Gly Glu Ile His Met Ala His Gln Thr Leu 850 855 860Met Leu Asp Pro Val Gly Pro Met Ala Glu Val Pro Pro Lys Val Pro865 870 875 880Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn 885 890 895Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met 900 905 910Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg 915 920 925His Ser Ile Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val 930 935 940Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr945 950 955 960Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser Val 965 970 975His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly 980 985 990Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp 995 1000 1005Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg 1010 1015 1020Pro Leu Asn Lys Tyr Thr Tyr 1025 1030493165DNAMus musculusCDS(1)..(3162) 49atg ggg ttc ctt ctg ctt tgg ttc tgc gtg ctg ttc ctt ctg gtc tcc 48Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15agg tta cgg gcg gtc agc ttc cca gaa gac gat gag ccc ctc aac acg 96Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30gtt gac tat cac tat tca agg caa tat ccg gtt ttt aga gga cgc cct 144Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45tca ggc aac gaa tcg cag cac agg ctg gac ttt cag ctg atg ttg aaa 192Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60att cga gac aca ctt tat att gct ggc agg gat caa gtc tat aca gtg 240Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80aac tta aat gaa atc ccc caa aca gag gtg ata cca agc aag aag ctg 288Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95acg tgg agg tcc aga cag cag gat cga gaa aat tgt gct atg aaa ggc 336Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110aag cat aaa gat gaa tgc cac aac ttc atc aaa gtc ttt gtc cca aga 384Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125aat gat gag atg gtt ttt gtc tgt ggt acc aat gct ttc aac ccg atg 432Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140tgc aga tac tat agg ttg aga acg tta gag tat gat ggg gaa gaa att 480Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160agt ggc ctg gca cga tgc ccg ttt gat gcc cga caa acc aat gtc gcc 528Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175ctc ttt gct gat gga aaa ctc tat tct gcc aca gtg gct gat ttc ctg 576Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190gcc agt gat gct gtc att tac aga agc atg gga gat gga tct gcc ctt 624Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205cgc aca ata aaa tac gat tcc aag tgg atc aaa gaa cca cac ttc ctt 672Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220cat gcc ata gaa tat gga aac tat gtc tat ttc ttc ttc aga gaa atc 720His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240gcc gtg gaa cat aat aac tta ggc aag gct gtg tat tcc cgc gtg gct 768Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255cgc att tgt aaa aac gac atg ggt ggc tca cag cgg gtc ctg gag aaa 816Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270cac tgg act tcc ttc ctt aag gct cgg ctg aac tgc tcc gtt cct gga 864His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285gat tcc ttt ttc tac ttc gac gtc ctg cag tct ata aca gac ata atc 912Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300caa atc aat ggc atc ccc act gtg gtt ggg gtc ttc acc aca cag ctc 960Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320aac agc att cct ggt tct gca gtc tgt gcc ttt agc atg gac gac att 1008Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335gag aaa gtg ttc aaa ggg cgg ttc aaa gag cag aaa acc cca gac tct 1056Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350gtt tgg aca gca gtt ccc gaa gac aaa gta cca aaa cca agg cct ggc 1104Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365tgt tgt gcc aaa cac ggc ctc gca gaa gct tac aag acc tcc atc gac 1152Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380ttt cca gat gac acc ctg gct ttc atc aag tcc cac ccg ctg atg gac 1200Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400tct gcc gtc cca ccc att gcc gat gag ccc tgg ttc aca aag aca cgg 1248Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415gtc agg tac agg ttg aca gcc atc gaa gtg gac cgt tca gca ggg cca 1296Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430tac caa aac tac aca gtc atc ttt gtt ggc tct gaa gct ggc gtg gta 1344Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445ctt aaa gtt ttg gca aag acc agt cct ttc tct ctg aat gac agt gta 1392Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460tta ctc gaa gag att gaa gct tat aac cca gcc aag tgc agc gcc gag 1440Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480agt gag gag gac aga aag gtg gtc tca tta cag ctg gac aag gat cac 1488Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495cat gct tta tac gtg gcc ttc tct agc tgc gtg gtc cgc atc ccc ctc 1536His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510agc cgc tgt gag cgc tac gga tcg tgt aaa aag tct tgc att gca tca 1584Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525cgt gac ccg tac tgt ggt tgg tta agc cag gga gtt tgt gag aga gtg 1632Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540acc cta ggg atg ctc cct gga gga tat gag cag gac acg gag tac ggc 1680Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly545 550 555 560aac aca gcc cac cta ggg gac tgc cac gac atg gag gta tcc tca tct 1728Asn Thr Ala His Leu Gly Asp Cys His Asp Met Glu Val Ser Ser Ser 565 570 575tct gtt acc act gtg gca agt agc cca gaa att aca tct aaa gtg att 1776Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser Lys Val Ile 580 585 590gat acc tgg aga cct aaa ctg acg agc tcc cgg aaa ttt gta gtt caa 1824Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe Val Val Gln 595 600 605gat gac cca aat act tct gat ttt act gat act ata tca ggt atc cca 1872Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser Gly Ile Pro 610 615 620aag ggt gta cgg tgg gaa gtc cag tct gga gaa tcc aat cag atg gtc 1920Lys Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn Gln Met Val625 630 635 640cac atg aat gtc ctc atc acc tgc gtg ttt gcc gct ttt gtc ttg ggc 1968His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Phe Val Leu Gly 645 650 655gcg ttc atc gca gga gtg gcc gtg tac tgc tac cgt gac atg ttc gtt 2016Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp Met Phe Val 660 665 670cgg aag aac aga aag atc cat aaa gac gca gaa tcc gcc cag tcg tgc 2064Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser Ala Gln Ser Cys 675 680 685aca gac tcc agc gga agc ttc gcc aag ctg aac ggc ctc ttt gac agc 2112Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn Gly Leu Phe Asp Ser 690 695 700ccc gtc aag gaa tac cag cag aac att gat tct ccc aaa ctc tac agc 2160Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser Pro Lys Leu Tyr Ser705 710 715 720aac ctg ctg acc agt cgg aag gaa ctg cca cca aac acg gat aca aag 2208Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro Asn Thr Asp Thr Lys 725 730 735tcc atg gcc gtg gac cac aga ggc cag cct ccc gag ctg gct gct ctc 2256Ser Met Ala Val Asp His Arg Gly Gln Pro Pro Glu Leu Ala Ala Leu 740 745 750ccc acg ccg gaa tcc aca cct gtc ctc cac cag aag acc ctg cag gcc 2304Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln Lys Thr Leu Gln Ala 755 760 765atg aag agc cac tct gag aag gcc cac agc cac ggt gct tca agg aaa 2352Met Lys Ser His Ser Glu Lys Ala His Ser His Gly Ala Ser Arg Lys 770 775 780gaa cac ccc cag ttt ttt cct tct agt cct cca ccc cat tcc cca ttg 2400Glu His Pro Gln Phe Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu785 790 795 800agt cac ggg cat atc ccc agt gcc atc gtt ctt cca aac gcc act cac 2448Ser His Gly His Ile Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His 805 810 815gac tac aat aca tcc ttc tcc aac tcg aat

gcc cac aaa gcc gaa aag 2496Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys 820 825 830aag ctt cag agc atg gat cac cct ctt acg aag tca tcc agt aag cgg 2544Lys Leu Gln Ser Met Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg 835 840 845gag cac cgg cgg tct gtg gat tcc agg aat act ctc aat gat ctc ctg 2592Glu His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu 850 855 860aag cat cta aat gac cca aac agt aac ccc aaa gcc atc ctg gga gag 2640Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys Ala Ile Leu Gly Glu865 870 875 880atc cat atg gct cat caa acc ctc atg ctg gac ccg gtg gga cca atg 2688Ile His Met Ala His Gln Thr Leu Met Leu Asp Pro Val Gly Pro Met 885 890 895gct gag gtc cca ccc aag gtc cct aac cgg gag gca tct cta tac tcc 2736Ala Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser Leu Tyr Ser 900 905 910cct ccc tcc aca ctc ccc aga aat agt cca acc aag aga gta gat gtc 2784Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys Arg Val Asp Val 915 920 925ccc acc act cct ggg gtg cca atg act tct ctg gaa aga caa agg ggt 2832Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu Glu Arg Gln Arg Gly 930 935 940tat cac aaa aat tcc tcc cag agg cac tct ata tct gcc gtg cct aaa 2880Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile Ser Ala Val Pro Lys945 950 955 960aac tta aac tca cca aat ggt gtt ttg tta tct aga cag ccg agt atg 2928Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser Arg Gln Pro Ser Met 965 970 975aac cgt gga ggc tat atg ccc acc cca aca ggg gcg aag gtg gac tat 2976Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly Ala Lys Val Asp Tyr 980 985 990att cag ggg aca ccg gtg agt gtt cat ctg cag ccc tcc ctc tcc aga 3024Ile Gln Gly Thr Pro Val Ser Val His Leu Gln Pro Ser Leu Ser Arg 995 1000 1005cag agc agc tat acc agt aat ggc acc ctc ccc agg acg gga cta 3069Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro Arg Thr Gly Leu 1010 1015 1020aag agg aca cca tcc tta aaa cct gat gtg cca cca aag cct tcc 3114Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro Pro Lys Pro Ser 1025 1030 1035ttt gtt ccg caa acc aca tct gtc aga cca ctg aac aag tac acg 3159Phe Val Pro Gln Thr Thr Ser Val Arg Pro Leu Asn Lys Tyr Thr 1040 1045 1050tac tag 3165Tyr501054PRTMus musculus 50Met Gly Phe Leu Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser1 5 10 15Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Arg Leu Arg Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 245 250 255Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 260 265 270His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly 275 280 285Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 290 295 300Gln Ile Asn Gly Ile Pro Thr Val Val Gly Val Phe Thr Thr Gln Leu305 310 315 320Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 325 330 335Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 340 345 350Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly 355 360 365Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 370 375 380Phe Pro Asp Asp Thr Leu Ala Phe Ile Lys Ser His Pro Leu Met Asp385 390 395 400Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 405 410 415Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 420 425 430Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val 435 440 445Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 450 455 460Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu465 470 475 480Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Lys Asp His 485 490 495His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 500 505 510Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser 515 520 525Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 530 535 540Thr Leu Gly Met Leu Pro Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly545 550 555 560Asn Thr Ala His Leu Gly Asp Cys His Asp Met Glu Val Ser Ser Ser 565 570 575Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser Lys Val Ile 580 585 590Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe Val Val Gln 595 600 605Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser Gly Ile Pro 610 615 620Lys Gly Val Arg Trp Glu Val Gln Ser Gly Glu Ser Asn Gln Met Val625 630 635 640His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Phe Val Leu Gly 645 650 655Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp Met Phe Val 660 665 670Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser Ala Gln Ser Cys 675 680 685Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn Gly Leu Phe Asp Ser 690 695 700Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp Ser Pro Lys Leu Tyr Ser705 710 715 720Asn Leu Leu Thr Ser Arg Lys Glu Leu Pro Pro Asn Thr Asp Thr Lys 725 730 735Ser Met Ala Val Asp His Arg Gly Gln Pro Pro Glu Leu Ala Ala Leu 740 745 750Pro Thr Pro Glu Ser Thr Pro Val Leu His Gln Lys Thr Leu Gln Ala 755 760 765Met Lys Ser His Ser Glu Lys Ala His Ser His Gly Ala Ser Arg Lys 770 775 780Glu His Pro Gln Phe Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu785 790 795 800Ser His Gly His Ile Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His 805 810 815Asp Tyr Asn Thr Ser Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys 820 825 830Lys Leu Gln Ser Met Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg 835 840 845Glu His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu 850 855 860Lys His Leu Asn Asp Pro Asn Ser Asn Pro Lys Ala Ile Leu Gly Glu865 870 875 880Ile His Met Ala His Gln Thr Leu Met Leu Asp Pro Val Gly Pro Met 885 890 895Ala Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser Leu Tyr Ser 900 905 910Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys Arg Val Asp Val 915 920 925Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu Glu Arg Gln Arg Gly 930 935 940Tyr His Lys Asn Ser Ser Gln Arg His Ser Ile Ser Ala Val Pro Lys945 950 955 960Asn Leu Asn Ser Pro Asn Gly Val Leu Leu Ser Arg Gln Pro Ser Met 965 970 975Asn Arg Gly Gly Tyr Met Pro Thr Pro Thr Gly Ala Lys Val Asp Tyr 980 985 990Ile Gln Gly Thr Pro Val Ser Val His Leu Gln Pro Ser Leu Ser Arg 995 1000 1005Gln Ser Ser Tyr Thr Ser Asn Gly Thr Leu Pro Arg Thr Gly Leu 1010 1015 1020Lys Arg Thr Pro Ser Leu Lys Pro Asp Val Pro Pro Lys Pro Ser 1025 1030 1035Phe Val Pro Gln Thr Thr Ser Val Arg Pro Leu Asn Lys Tyr Thr 1040 1045 1050Tyr513165DNAMus musculus 51atggggttcc ttctgctttg gttctgcgtg ctgttccttc tggtctccag gttacgggcg 60gtcagcttcc cagaagacga tgagcccctc aacacggttg actatcacta ttcaaggcaa 120tatccggttt ttagaggacg cccttcaggc aacgaatcgc agcacaggct ggactttcag 180ctgatgttga aaattcgaga cacactttat attgctggca gggatcaagt ctatacagtg 240aacttaaatg aaatccccca aacagaggtg ataccaagca agaagctgac gtggaggtcc 300agacagcagg atcgagaaaa ttgtgctatg aaaggcaagc ataaagatga atgccacaac 360ttcatcaaag tctttgtccc aagaaatgat gagatggttt ttgtctgtgg taccaatgct 420ttcaacccga tgtgcagata ctataggttg agaacgttag agtatgatgg ggaagaaatt 480agtggcctgg cacgatgccc gtttgatgcc cgacaaacca atgtcgccct ctttgctgat 540ggaaaactct attctgccac agtggctgat ttcctggcca gtgatgctgt catttacaga 600agcatgggag atggatctgc ccttcgcaca ataaaatacg attccaagtg gatcaaagaa 660ccacacttcc ttcatgccat agaatatgga aactatgtct atttcttctt cagagaaatc 720gccgtggaac ataataactt aggcaaggct gtgtattccc gcgtggctcg catttgtaaa 780aacgacatgg gtggctcaca gcgggtcctg gagaaacact ggacttcctt ccttaaggct 840cggctgaact gctccgttcc tggagattcc tttttctact tcgacgtcct gcagtctata 900acagacataa tccaaatcaa tggcatcccc actgtggttg gggtcttcac cacacagctc 960aacagcattc ctggttctgc agtctgtgcc tttagcatgg acgacattga gaaagtgttc 1020aaagggcggt tcaaagagca gaaaacccca gactctgttt ggacagcagt tcccgaagac 1080aaagtaccaa aaccaaggcc tggctgttgt gccaaacacg gcctcgcaga agcttacaag 1140acctccatcg actttccaga tgacaccctg gctttcatca agtcccaccc gctgatggac 1200tctgccgtcc cacccattgc cgatgagccc tggttcacaa agacacgggt caggtacagg 1260ttgacagcca tcgaagtgga ccgttcagca gggccatacc aaaactacac agtcatcttt 1320gttggctctg aagctggcgt ggtacttaaa gttttggcaa agaccagtcc tttctctctg 1380aatgacagtg tattactcga agagattgaa gcttataacc cagccaagtg cagcgccgag 1440agtgaggagg acagaaaggt ggtctcatta cagctggaca aggatcacca tgctttatac 1500gtggccttct ctagctgcgt ggtccgcatc cccctcagcc gctgtgagcg ctacggatcg 1560tgtaaaaagt cttgcattgc atcacgtgac ccgtactgtg gttggttaag ccagggagtt 1620tgtgagagag tgaccctagg gatgctccct ggaggatatg agcaggacac ggagtacggc 1680aacacagccc acctagggga ctgccacgac atggaggtat cctcatcttc tgttaccact 1740gtggcaagta gcccagaaat tacatctaaa gtgattgata cctggagacc taaactgacg 1800agctcccgga aatttgtagt tcaagatgac ccaaatactt ctgattttac tgatactata 1860tcaggtatcc caaagggtgt acggtgggaa gtccagtctg gagaatccaa tcagatggtc 1920cacatgaatg tcctcatcac ctgcgtgttt gccgcttttg tcttgggcgc gttcatcgca 1980ggagtggccg tgtactgcta ccgtgacatg ttcgttcgga agaacagaaa gatccataaa 2040gacgcagaat ccgcccagtc gtgcacagac tccagcggaa gcttcgccaa gctgaacggc 2100ctctttgaca gccccgtcaa ggaataccag cagaacattg attctcccaa actctacagc 2160aacctgctga ccagtcggaa ggaactgcca ccaaacacgg atacaaagtc catggccgtg 2220gaccacagag gccagcctcc cgagctggct gctctcccca cgccggaatc cacacctgtc 2280ctccaccaga agaccctgca ggccatgaag agccactctg agaaggccca cagccacggt 2340gcttcaagga aagaacaccc ccagtttttt ccttctagtc ctccacccca ttccccattg 2400agtcacgggc atatccccag tgccatcgtt cttccaaacg ccactcacga ctacaataca 2460tccttctcca actcgaatgc ccacaaagcc gaaaagaagc ttcagagcat ggatcaccct 2520cttacgaagt catccagtaa gcgggagcac cggcggtctg tggattccag gaatactctc 2580aatgatctcc tgaagcatct aaatgaccca aacagtaacc ccaaagccat cctgggagag 2640atccatatgg ctcatcaaac cctcatgctg gacccggtgg gaccaatggc tgaggtccca 2700cccaaggtcc ctaaccggga ggcatctcta tactcccctc cctccacact ccccagaaat 2760agtccaacca agagagtaga tgtccccacc actcctgggg tgccaatgac ttctctggaa 2820agacaaaggg gttatcacaa aaattcctcc cagaggcact ctatatctgc cgtgcctaaa 2880aacttaaact caccaaatgg tgttttgtta tctagacagc cgagtatgaa ccgtggaggc 2940tatatgccca ccccaacagg ggcgaaggtg gactatattc aggggacacc ggtgagtgtt 3000catctgcagc cctccctctc cagacagagc agctatacca gtaatggcac cctccccagg 3060acgggactaa agaggacacc atccttaaaa cctgatgtgc caccaaagcc ttcctttgtt 3120ccgcaaacca catctgtcag accactgaac aagtacacgt actag 3165523410DNADanio rerioCDS(122)..(2761) 52gactgaatgt acagctctgc tcttctgacg ctcagattta aagaaaacac gggaaatatg 60gaataagatg gtgttcgaag ccaaacggtt gacggaaaga acatggtgtt gctctgtcat 120c atg gcg atg gtc tta tta gcc tgg ctc ctc cca ctc att act tct gcc 169 Met Ala Met Val Leu Leu Ala Trp Leu Leu Pro Leu Ile Thr Ser Ala 1 5 10 15acg cct ttt cct aga gat ctg cag cca att agt gtg gtg gga ttg gac 217Thr Pro Phe Pro Arg Asp Leu Gln Pro Ile Ser Val Val Gly Leu Asp 20 25 30gac tcg tac ctg tac ccc agt ttt cag ggt ctg gtg tcc agc aat gag 265Asp Ser Tyr Leu Tyr Pro Ser Phe Gln Gly Leu Val Ser Ser Asn Glu 35 40 45acg gag cgt ctg ggt ctg gac tat cag cgc atg atg agg atc cag cac 313Thr Glu Arg Leu Gly Leu Asp Tyr Gln Arg Met Met Arg Ile Gln His 50 55 60atg ctg tac atc gcc gcc aga gac cat gtg ttt gtt gta aat ctc aca 361Met Leu Tyr Ile Ala Ala Arg Asp His Val Phe Val Val Asn Leu Thr65 70 75 80acg gca gta gat gaa att att cca cag cag atc ctg acg tgg aga tcc 409Thr Ala Val Asp Glu Ile Ile Pro Gln Gln Ile Leu Thr Trp Arg Ser 85 90 95aca gac gtg tcc aag tgc acc gtc aga gga aga aac agt gat gaa tgt 457Thr Asp Val Ser Lys Cys Thr Val Arg Gly Arg Asn Ser Asp Glu Cys 100 105 110tac aat tat atc aag gtt ctt gtt cct cgt aat gac gag act ctg ttt 505Tyr Asn Tyr Ile Lys Val Leu Val Pro Arg Asn Asp Glu Thr Leu Phe 115 120 125gcc tgt gga aca aac gcg ttg aat cct gcc tgc cgc aac tac aga ttg 553Ala Cys Gly Thr Asn Ala Leu Asn Pro Ala Cys Arg Asn Tyr Arg Leu 130 135 140agt tca ctg gag cag gtc gga cag gag ctc ttg ggt cag gca aga tgt 601Ser Ser Leu Glu Gln Val Gly Gln Glu Leu Leu Gly Gln Ala Arg Cys145 150 155 160cca ttt gag tct cga cag tcc aat gta gga gtg ttt gca ggt ggt cat 649Pro Phe Glu Ser Arg Gln Ser Asn Val Gly Val Phe Ala Gly Gly His 165 170 175ttc tat tca gcc aca gtg acg gac ttc cag gcg agt gat gct gtg atc 697Phe Tyr Ser Ala Thr Val Thr Asp Phe Gln Ala Ser Asp Ala Val Ile 180 185 190tac agg agt tta gga gga gag ggc cga cct gtt ctg cgc act gtc aaa 745Tyr Arg Ser Leu Gly Gly Glu Gly Arg Pro Val Leu Arg Thr Val Lys 195 200 205tac gac tcc aaa tgg ctc aga gag cct cat ttc ctg cac gct gtc gaa 793Tyr Asp Ser Lys Trp Leu Arg Glu Pro His Phe Leu His Ala Val Glu 210 215 220tac ggg aac tat gtg tat ttc ttc ttc agt gag att gct gtg gag cac 841Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Ser Glu Ile Ala Val Glu His225 230 235 240act gct gct ggg aag gtt gtg tat tct cgt gtg gcg cga gtg tgt aag 889Thr Ala Ala Gly Lys Val Val Tyr Ser Arg Val Ala Arg Val Cys Lys 245 250 255aat gat aac ggc ggc tcc acg cga gtg ttg gac cga cac tgg aca tca 937Asn Asp Asn Gly Gly Ser Thr Arg Val Leu Asp Arg His Trp Thr Ser 260 265 270ttt ctg aag gct cgg ctg aac tgc tcc gtt cct gga gac act ttc ttc 985Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly Asp Thr Phe Phe 275 280 285tac ttc gat gtg ctt cag tct ctg acc aat gtg ctg cag atc aac cag 1033Tyr Phe Asp Val Leu Gln Ser

Leu Thr Asn Val Leu Gln Ile Asn Gln 290 295 300aga ccc gct gta gtc gga gtg ttc acc aca cag acc aac agt att ccc 1081Arg Pro Ala Val Val Gly Val Phe Thr Thr Gln Thr Asn Ser Ile Pro305 310 315 320gga tcc gct gtt tgc ggt ttc tat ctg gat gac att gag cga gtg ttt 1129Gly Ser Ala Val Cys Gly Phe Tyr Leu Asp Asp Ile Glu Arg Val Phe 325 330 335aat ggg agg ttt aaa gag cag aag aac agt gac tcc atg tgg acg gca 1177Asn Gly Arg Phe Lys Glu Gln Lys Asn Ser Asp Ser Met Trp Thr Ala 340 345 350gta ccg gag gaa cag gtg ccc aaa cca cgt cca ggt tcg tgt gca ggt 1225Val Pro Glu Glu Gln Val Pro Lys Pro Arg Pro Gly Ser Cys Ala Gly 355 360 365gag ggt tcg gcc tcc tcc tat tcc tct tct gtt cag ttt cca gac tct 1273Glu Gly Ser Ala Ser Ser Tyr Ser Ser Ser Val Gln Phe Pro Asp Ser 370 375 380gtg ctg tcg ttc atc aaa aca cac ccg ctg atg gag gag agc gtg ccg 1321Val Leu Ser Phe Ile Lys Thr His Pro Leu Met Glu Glu Ser Val Pro385 390 395 400tca gtc aac agc caa ccg ctg atc acc aac acc gcc agc agg tat aag 1369Ser Val Asn Ser Gln Pro Leu Ile Thr Asn Thr Ala Ser Arg Tyr Lys 405 410 415ctg act cag att gtg gtg gac act gct gct ggg cct cat aag aac cgc 1417Leu Thr Gln Ile Val Val Asp Thr Ala Ala Gly Pro His Lys Asn Arg 420 425 430acc gta gtg ttt ctg ggc tct gaa gac gga cgc gtg ctg aag atc ctg 1465Thr Val Val Phe Leu Gly Ser Glu Asp Gly Arg Val Leu Lys Ile Leu 435 440 445acc aac aca cac tcc aac agc tca cac aca tcc cag ctg ctg gag gac 1513Thr Asn Thr His Ser Asn Ser Ser His Thr Ser Gln Leu Leu Glu Asp 450 455 460atc gac gtg ttt aat ccc aca cgg tgt gtt ggt gag cgt gca gtg ttg 1561Ile Asp Val Phe Asn Pro Thr Arg Cys Val Gly Glu Arg Ala Val Leu465 470 475 480ggt ctg gag ctg gat aag gag cat cac gct ctg ttt gtg gcc ttc tcc 1609Gly Leu Glu Leu Asp Lys Glu His His Ala Leu Phe Val Ala Phe Ser 485 490 495agc tgt gtg atc aga gtt cct ctc agc cgc tgc gct cag cac gcc acc 1657Ser Cys Val Ile Arg Val Pro Leu Ser Arg Cys Ala Gln His Ala Thr 500 505 510tgc agg aga cgc tgc ctc tac aca cat gac cca tac tgc atc tgg ctg 1705Cys Arg Arg Arg Cys Leu Tyr Thr His Asp Pro Tyr Cys Ile Trp Leu 515 520 525cgg acg gga cgc tgt gct gac atg gcc cca ggg ttc aag gcg gga ttt 1753Arg Thr Gly Arg Cys Ala Asp Met Ala Pro Gly Phe Lys Ala Gly Phe 530 535 540gaa cag gac att gat ggt gaa caa aca cat tta ttt gac aca tgc act 1801Glu Gln Asp Ile Asp Gly Glu Gln Thr His Leu Phe Asp Thr Cys Thr545 550 555 560gat gtg atg tca tca gca gga agt gat gtc aaa tca gct gtg gat tcg 1849Asp Val Met Ser Ser Ala Gly Ser Asp Val Lys Ser Ala Val Asp Ser 565 570 575gcc tct gga gta aag cag ctt ccc gac gcc gac agt ctg agc gac ggc 1897Ala Ser Gly Val Lys Gln Leu Pro Asp Ala Asp Ser Leu Ser Asp Gly 580 585 590tat cac ttc act ctt ctg ggc gcg tgt gtg ttg cta gcg ttt gtg ttg 1945Tyr His Phe Thr Leu Leu Gly Ala Cys Val Leu Leu Ala Phe Val Leu 595 600 605ggg gcg atc gcg tca ggt ttg ctg gtg tcg tgt tac tgc aga cag agc 1993Gly Ala Ile Ala Ser Gly Leu Leu Val Ser Cys Tyr Cys Arg Gln Ser 610 615 620tct ccg cca acg cca gag cct gaa gca aca ctc gca cac aca cat gca 2041Ser Pro Pro Thr Pro Glu Pro Glu Ala Thr Leu Ala His Thr His Ala625 630 635 640cac aca ctc tcg ctc agc agc ctc gct aag atc aac ctg ctg atg gac 2089His Thr Leu Ser Leu Ser Ser Leu Ala Lys Ile Asn Leu Leu Met Asp 645 650 655aac aaa cca gag aaa aag agc gag tct cca tcc gca cac atc tac tcg 2137Asn Lys Pro Glu Lys Lys Ser Glu Ser Pro Ser Ala His Ile Tyr Ser 660 665 670ccc gct aaa cct cca gaa gag ctg cca ccc acg ccc gac tcg acc cca 2185Pro Ala Lys Pro Pro Glu Glu Leu Pro Pro Thr Pro Asp Ser Thr Pro 675 680 685gaa ctg cca atc aaa aac atc aaa gcc atc agc agc caa tgg gag aga 2233Glu Leu Pro Ile Lys Asn Ile Lys Ala Ile Ser Ser Gln Trp Glu Arg 690 695 700agc cac acc cac aac tcc acc ctc cag ctc att ccg acc aat cag agt 2281Ser His Thr His Asn Ser Thr Leu Gln Leu Ile Pro Thr Asn Gln Ser705 710 715 720cat cca atg ctt tca gaa aat ccc agt gat gat ata agc agt agc agt 2329His Pro Met Leu Ser Glu Asn Pro Ser Asp Asp Ile Ser Ser Ser Ser 725 730 735caa cgt tct gat gcc acc ctt atg tca cct gct gga tta aag tca tac 2377Gln Arg Ser Asp Ala Thr Leu Met Ser Pro Ala Gly Leu Lys Ser Tyr 740 745 750aat cgg act tta tta ccg aag tcg tat tac agc tgt ctg aaa gag ccg 2425Asn Arg Thr Leu Leu Pro Lys Ser Tyr Tyr Ser Cys Leu Lys Glu Pro 755 760 765tca gaa tgt tcc acg ctt cag cag att ccc gaa cag ccc tcc gca cag 2473Ser Glu Cys Ser Thr Leu Gln Gln Ile Pro Glu Gln Pro Ser Ala Gln 770 775 780cgc cac gtc ctc att aaa atg ggt aac ggg atc acc agc gcg cgc cag 2521Arg His Val Leu Ile Lys Met Gly Asn Gly Ile Thr Ser Ala Arg Gln785 790 795 800cac acc ttc aac ccc aag atg aac tcc aat acg ggg aat att tac gag 2569His Thr Phe Asn Pro Lys Met Asn Ser Asn Thr Gly Asn Ile Tyr Glu 805 810 815atc cag cgg ccg ctc gtc gcc ggc ggc tcg tgt ttg acg cgg cag cac 2617Ile Gln Arg Pro Leu Val Ala Gly Gly Ser Cys Leu Thr Arg Gln His 820 825 830agt tac agc gag ccg cca cag ctc cag cgc agc gct atc gtc aga cgc 2665Ser Tyr Ser Glu Pro Pro Gln Leu Gln Arg Ser Ala Ile Val Arg Arg 835 840 845acc gca tcg cta aaa cca cag ata ccg ccc aaa cca ctg aac ata cct 2713Thr Ala Ser Leu Lys Pro Gln Ile Pro Pro Lys Pro Leu Asn Ile Pro 850 855 860gct aaa aca ctg ccc tct gct ggc aca cac aac cac aca cac aac tac 2761Ala Lys Thr Leu Pro Ser Ala Gly Thr His Asn His Thr His Asn Tyr865 870 875 880tgacacacac acacacacac acacacacac acacacaact actgacccca aggtcacatg 2821acacacacaa ctactgacac acacacacat acacaaatac tgaccccgta gtcacgtcac 2881acacacaatt acctaccagc acacacatac acaactattg actccacggt cacaagacgc 2941gcacaactac tgactctctc acacacacac acacacacac acacacacac acacaaaaat 3001actgacctcg cgctcacatt acacacacaa ctattgacta cacagtcaca tggcatacac 3061acacaactat tgaccctgtg ggacaacact ggtcacacaa cacacacatg caattactaa 3121ccccgcgatc acgacacaca actactgacc ccgcgatcac atgacacaaa cacaactact 3181gaccatgtgt tcacatgaca cacaaacgac acacaactga gcccacacac tcaggggtca 3241gaataccagc acattgatga ctgcagtgtg taaatatagt gtgtatatag tgtaaatata 3301agagatggga tgttattatg gtgcacactg aatgattatg cagtggtgga gggttatttt 3361tgtcaataaa tctggtttct tgcatttgtt aaaaaaaaaa aaaaaaaaa 341053880PRTDanio rerio 53Met Ala Met Val Leu Leu Ala Trp Leu Leu Pro Leu Ile Thr Ser Ala1 5 10 15Thr Pro Phe Pro Arg Asp Leu Gln Pro Ile Ser Val Val Gly Leu Asp 20 25 30Asp Ser Tyr Leu Tyr Pro Ser Phe Gln Gly Leu Val Ser Ser Asn Glu 35 40 45Thr Glu Arg Leu Gly Leu Asp Tyr Gln Arg Met Met Arg Ile Gln His 50 55 60Met Leu Tyr Ile Ala Ala Arg Asp His Val Phe Val Val Asn Leu Thr65 70 75 80Thr Ala Val Asp Glu Ile Ile Pro Gln Gln Ile Leu Thr Trp Arg Ser 85 90 95Thr Asp Val Ser Lys Cys Thr Val Arg Gly Arg Asn Ser Asp Glu Cys 100 105 110Tyr Asn Tyr Ile Lys Val Leu Val Pro Arg Asn Asp Glu Thr Leu Phe 115 120 125Ala Cys Gly Thr Asn Ala Leu Asn Pro Ala Cys Arg Asn Tyr Arg Leu 130 135 140Ser Ser Leu Glu Gln Val Gly Gln Glu Leu Leu Gly Gln Ala Arg Cys145 150 155 160Pro Phe Glu Ser Arg Gln Ser Asn Val Gly Val Phe Ala Gly Gly His 165 170 175Phe Tyr Ser Ala Thr Val Thr Asp Phe Gln Ala Ser Asp Ala Val Ile 180 185 190Tyr Arg Ser Leu Gly Gly Glu Gly Arg Pro Val Leu Arg Thr Val Lys 195 200 205Tyr Asp Ser Lys Trp Leu Arg Glu Pro His Phe Leu His Ala Val Glu 210 215 220Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Ser Glu Ile Ala Val Glu His225 230 235 240Thr Ala Ala Gly Lys Val Val Tyr Ser Arg Val Ala Arg Val Cys Lys 245 250 255Asn Asp Asn Gly Gly Ser Thr Arg Val Leu Asp Arg His Trp Thr Ser 260 265 270Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly Asp Thr Phe Phe 275 280 285Tyr Phe Asp Val Leu Gln Ser Leu Thr Asn Val Leu Gln Ile Asn Gln 290 295 300Arg Pro Ala Val Val Gly Val Phe Thr Thr Gln Thr Asn Ser Ile Pro305 310 315 320Gly Ser Ala Val Cys Gly Phe Tyr Leu Asp Asp Ile Glu Arg Val Phe 325 330 335Asn Gly Arg Phe Lys Glu Gln Lys Asn Ser Asp Ser Met Trp Thr Ala 340 345 350Val Pro Glu Glu Gln Val Pro Lys Pro Arg Pro Gly Ser Cys Ala Gly 355 360 365Glu Gly Ser Ala Ser Ser Tyr Ser Ser Ser Val Gln Phe Pro Asp Ser 370 375 380Val Leu Ser Phe Ile Lys Thr His Pro Leu Met Glu Glu Ser Val Pro385 390 395 400Ser Val Asn Ser Gln Pro Leu Ile Thr Asn Thr Ala Ser Arg Tyr Lys 405 410 415Leu Thr Gln Ile Val Val Asp Thr Ala Ala Gly Pro His Lys Asn Arg 420 425 430Thr Val Val Phe Leu Gly Ser Glu Asp Gly Arg Val Leu Lys Ile Leu 435 440 445Thr Asn Thr His Ser Asn Ser Ser His Thr Ser Gln Leu Leu Glu Asp 450 455 460Ile Asp Val Phe Asn Pro Thr Arg Cys Val Gly Glu Arg Ala Val Leu465 470 475 480Gly Leu Glu Leu Asp Lys Glu His His Ala Leu Phe Val Ala Phe Ser 485 490 495Ser Cys Val Ile Arg Val Pro Leu Ser Arg Cys Ala Gln His Ala Thr 500 505 510Cys Arg Arg Arg Cys Leu Tyr Thr His Asp Pro Tyr Cys Ile Trp Leu 515 520 525Arg Thr Gly Arg Cys Ala Asp Met Ala Pro Gly Phe Lys Ala Gly Phe 530 535 540Glu Gln Asp Ile Asp Gly Glu Gln Thr His Leu Phe Asp Thr Cys Thr545 550 555 560Asp Val Met Ser Ser Ala Gly Ser Asp Val Lys Ser Ala Val Asp Ser 565 570 575Ala Ser Gly Val Lys Gln Leu Pro Asp Ala Asp Ser Leu Ser Asp Gly 580 585 590Tyr His Phe Thr Leu Leu Gly Ala Cys Val Leu Leu Ala Phe Val Leu 595 600 605Gly Ala Ile Ala Ser Gly Leu Leu Val Ser Cys Tyr Cys Arg Gln Ser 610 615 620Ser Pro Pro Thr Pro Glu Pro Glu Ala Thr Leu Ala His Thr His Ala625 630 635 640His Thr Leu Ser Leu Ser Ser Leu Ala Lys Ile Asn Leu Leu Met Asp 645 650 655Asn Lys Pro Glu Lys Lys Ser Glu Ser Pro Ser Ala His Ile Tyr Ser 660 665 670Pro Ala Lys Pro Pro Glu Glu Leu Pro Pro Thr Pro Asp Ser Thr Pro 675 680 685Glu Leu Pro Ile Lys Asn Ile Lys Ala Ile Ser Ser Gln Trp Glu Arg 690 695 700Ser His Thr His Asn Ser Thr Leu Gln Leu Ile Pro Thr Asn Gln Ser705 710 715 720His Pro Met Leu Ser Glu Asn Pro Ser Asp Asp Ile Ser Ser Ser Ser 725 730 735Gln Arg Ser Asp Ala Thr Leu Met Ser Pro Ala Gly Leu Lys Ser Tyr 740 745 750Asn Arg Thr Leu Leu Pro Lys Ser Tyr Tyr Ser Cys Leu Lys Glu Pro 755 760 765Ser Glu Cys Ser Thr Leu Gln Gln Ile Pro Glu Gln Pro Ser Ala Gln 770 775 780Arg His Val Leu Ile Lys Met Gly Asn Gly Ile Thr Ser Ala Arg Gln785 790 795 800His Thr Phe Asn Pro Lys Met Asn Ser Asn Thr Gly Asn Ile Tyr Glu 805 810 815Ile Gln Arg Pro Leu Val Ala Gly Gly Ser Cys Leu Thr Arg Gln His 820 825 830Ser Tyr Ser Glu Pro Pro Gln Leu Gln Arg Ser Ala Ile Val Arg Arg 835 840 845Thr Ala Ser Leu Lys Pro Gln Ile Pro Pro Lys Pro Leu Asn Ile Pro 850 855 860Ala Lys Thr Leu Pro Ser Ala Gly Thr His Asn His Thr His Asn Tyr865 870 875 880544317DNARattus norvegicusCDS(1)..(4314) 54atg aag gcg agg agc cag agt gaa cta ggg ata aag tat cca ctc ttc 48Met Lys Ala Arg Ser Gln Ser Glu Leu Gly Ile Lys Tyr Pro Leu Phe1 5 10 15agt aga cta gga aat aag gac act ctg cta tgt gga caa ccg agg gag 96Ser Arg Leu Gly Asn Lys Asp Thr Leu Leu Cys Gly Gln Pro Arg Glu 20 25 30tgt aaa aat aac tgc tac ttc tcc ttg aga gct tgc act gtg cca aac 144Cys Lys Asn Asn Cys Tyr Phe Ser Leu Arg Ala Cys Thr Val Pro Asn 35 40 45agc gta atg ata gtc ata cta gca ggc aac tgc gtc atg agg acc ctg 192Ser Val Met Ile Val Ile Leu Ala Gly Asn Cys Val Met Arg Thr Leu 50 55 60agc caa acg ctg ctt gaa aca gta cca gtg tgg ata cat aga aga tgc 240Ser Gln Thr Leu Leu Glu Thr Val Pro Val Trp Ile His Arg Arg Cys65 70 75 80cta aca ccc tct ggt gat gtc aca cat gag tct ccc agc cgc cct gca 288Leu Thr Pro Ser Gly Asp Val Thr His Glu Ser Pro Ser Arg Pro Ala 85 90 95gca tgc acg tgc aca gac aat gca cat ctc cat agc agt aag ggg tct 336Ala Cys Thr Cys Thr Asp Asn Ala His Leu His Ser Ser Lys Gly Ser 100 105 110ccc ttc tgc agg agg aga ctg gca gaa agg ctg gct aca ctg tca tcc 384Pro Phe Cys Arg Arg Arg Leu Ala Glu Arg Leu Ala Thr Leu Ser Ser 115 120 125atg tgg att act gca gcc ctg gct agt ggc aag tct cag cag ttc tgc 432Met Trp Ile Thr Ala Ala Leu Ala Ser Gly Lys Ser Gln Gln Phe Cys 130 135 140cag gct ggc agc tgt acc agg gca gct ccc aag gtt gac gac tta caa 480Gln Ala Gly Ser Cys Thr Arg Ala Ala Pro Lys Val Asp Asp Leu Gln145 150 155 160atg aga cct ctg gaa ccg tct tta gaa aat ata cgt tct gag tca aca 528Met Arg Pro Leu Glu Pro Ser Leu Glu Asn Ile Arg Ser Glu Ser Thr 165 170 175tgg tta ata gtg tgc ctt ggt gtg aaa act aag aca aaa ctt cgg ggt 576Trp Leu Ile Val Cys Leu Gly Val Lys Thr Lys Thr Lys Leu Arg Gly 180 185 190aca act gcg ccc acc gca cca ctg ggc tgc agc cat ttg tcc tcc gat 624Thr Thr Ala Pro Thr Ala Pro Leu Gly Cys Ser His Leu Ser Ser Asp 195 200 205cgt cta ggg tgg ctg gct ggg aga gta gtg agg gcg cct gga gga agg 672Arg Leu Gly Trp Leu Ala Gly Arg Val Val Arg Ala Pro Gly Gly Arg 210 215 220gag agg cgg ctt tgc agg cta cag agg cgg cgc cag ctg ggc gac ccg 720Glu Arg Arg Leu Cys Arg Leu Gln Arg Arg Arg Gln Leu Gly Asp Pro225 230 235 240gct cgg aga ggc gcg gga gga gcg gct ccg cta agg tgg gag agc ctg 768Ala Arg Arg Gly Ala Gly Gly Ala Ala Pro Leu Arg Trp Glu Ser Leu 245 250 255ggc gcg cgg ccg agc gcg atc agg gac gcg gcg gcc act ggg gtc gag 816Gly Ala Arg Pro Ser Ala Ile Arg Asp Ala Ala Ala Thr Gly Val Glu 260 265 270gcc gcg gcg cgc gta gga ctc tgg gcg gcg ctg gcc gcg gtg gga gct 864Ala Ala Ala Arg Val Gly Leu Trp Ala Ala Leu Ala Ala Val Gly Ala 275 280 285gca gag cgg cga ggg agc cgg gat ctc agg gag cga ctc gga gat gga 912Ala Glu Arg Arg Gly Ser Arg Asp Leu Arg Glu Arg Leu Gly Asp Gly 290 295 300tcg aat tac acc att tgc cga gca gcg gac ctc gtt cag act ctt gag 960Ser Asn Tyr Thr Ile Cys Arg Ala Ala Asp Leu Val Gln Thr Leu Glu305 310 315 320gtc aac ctg gca gtc cac agc gct aac ttt gct cag aat cca cgg aag 1008Val Asn Leu Ala Val His Ser Ala Asn Phe Ala Gln Asn Pro Arg Lys 325 330

335cta agt ggg act tct gag gag gga gct cag ata cct tct cgg cca acc 1056Leu Ser Gly Thr Ser Glu Glu Gly Ala Gln Ile Pro Ser Arg Pro Thr 340 345 350atg agg ttc ttt ctg ctg tgg ttc tgt gtg ctg ttc ctt ctg gtc tcc 1104Met Arg Phe Phe Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser 355 360 365agg tta cgg gcc gtc agc ttc cct gag gac gat gag ccc ctt aac acg 1152Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 370 375 380gtt gac tac cac tat tca agg caa tat ccg gtt ttt aga gga cgc cct 1200Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro385 390 395 400tca ggc aac gaa tcg cag cat agg ctg gac ttt cag ctg atg ttg aaa 1248Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 405 410 415att cga gac aca ctt tat att gct ggc agg gat caa gtc tat aca gtg 1296Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val 420 425 430aac tta aat gac atc ccc caa aca gag gtg atc ccg agc aag aag ctg 1344Asn Leu Asn Asp Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 435 440 445aca tgg agg tcc aga cag cag gat cga gaa aat tgt gct atg aaa ggc 1392Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 450 455 460aag cat aaa gat gaa tgt cac aac ttc atc aaa gtc ttt gtc cca aga 1440Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg465 470 475 480aat gat gag atg gtt ttt gtc tgt ggc acc aac gct ttc aac ccg atg 1488Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 485 490 495tgc aga tac tat agg ttg agt acc tta gag tat gat ggg gaa gaa att 1536Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile 500 505 510agt ggc ctg gca cgg tgc ccg ttt gat gcc cga caa acc aat gtt gcc 1584Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 515 520 525ctc ttt gct gat ggg aaa ctg tat tct gcc aca gtg gct gat ttc ctg 1632Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 530 535 540gcc agt gat gct gtc att tac aga agc atg ggt gat gga tcg gcc ctc 1680Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu545 550 555 560cgc aca ata aaa tac gac tcc aaa tgg atc aaa gaa cca cac ttt ctt 1728Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 565 570 575cac gcc ata gaa tat gga aac tat gtc tat ttc ttc ttc aga gaa atc 1776His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile 580 585 590gcc gtg gaa cat aat aac tta ggc aag gct gtg tac tcc cga gtg gcc 1824Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 595 600 605cgc att tgt aaa aac gac atg ggt ggc tca cag cgg gtc ctg gag aaa 1872Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 610 615 620cac tgg act tcc ttc ctg aag gct cgg ctt aac tgc tca gtc cct gga 1920His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly625 630 635 640gat tcc ttt ttc tac ttc gat gtt ctg cag tcc atc aca gac atc atc 1968Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 645 650 655caa atc aat ggc atc ccc acc gtg atc ggg gtc ttc acc acg cag ctc 2016Gln Ile Asn Gly Ile Pro Thr Val Ile Gly Val Phe Thr Thr Gln Leu 660 665 670aac agc att cct ggc tct gca gtc tgt gcc ttt agc atg gac gac att 2064Asn Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 675 680 685gag aaa gtg ttc aaa ggg cgg ttc aaa gag cag aaa acc cca gac tct 2112Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 690 695 700gtt tgg aca gcg gtt cct gaa gac aaa gta cca aaa cca agg cct ggc 2160Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly705 710 715 720tgt tgt gcc aaa cat ggc ctc gcg gaa gct tac aaa acc tcc atc gac 2208Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 725 730 735ttt cca gat gat acc ctg tct ttc atc aag tcc cac ccg ctg atg gac 2256Phe Pro Asp Asp Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp 740 745 750tcc gct gtc cca ccc att gct gat gag ccc tgg ttc aca aag act cgg 2304Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 755 760 765gtc cgg tac agg ctg aca gcc atc gaa gtg gac cgt tcg gca ggg ccg 2352Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 770 775 780tac caa aac tac aca gtc atc ttt gtt ggc tct gag gcc ggc gtg gtg 2400Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val785 790 795 800ctt aaa gtt ttg gca aag acc agt cct ttc tct ttg aac gac agt gta 2448Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 805 810 815tta ctc gaa gag atc gaa gct tat aac cca gcc aag tgc agc gcc gag 2496Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu 820 825 830agt gag gag gac agg aag gtc gtc tcg tta cag ctg gac agg gat cac 2544Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Arg Asp His 835 840 845cat gct tta tac gtg gcc ttc tcc agc tgc gtg gtc cgc atc ccc ctc 2592His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 850 855 860agc cgc tgt gag cgc tat ggc tcc tgt aaa aag tct tgc att gca tca 2640Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser865 870 875 880cga gac ccg tac tgt ggt tgg tta agc cag gga gtg tgt gag aga gtg 2688Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 885 890 895acc tta ggg atg ctg ctg tta acc gaa gac ttc ttt gct ttc cat aac 2736Thr Leu Gly Met Leu Leu Leu Thr Glu Asp Phe Phe Ala Phe His Asn 900 905 910cac agt gct gga gga tat gag cag gac acc gag tat ggc aac acg gcc 2784His Ser Ala Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly Asn Thr Ala 915 920 925cac cta ggg gac tgc cac gaa agt ttg cct act tca act aca cca gat 2832His Leu Gly Asp Cys His Glu Ser Leu Pro Thr Ser Thr Thr Pro Asp 930 935 940tac aaa ata ttt ggc ggt cca aca tct gac atg gag gta ccc tca tct 2880Tyr Lys Ile Phe Gly Gly Pro Thr Ser Asp Met Glu Val Pro Ser Ser945 950 955 960tct gtt acc act gtg gca agt agc cca gaa att aca tct aaa gtg att 2928Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser Lys Val Ile 965 970 975gat acc tgg aga cct aaa ctg acg agc tcc cgg aaa ttt gta gtt caa 2976Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe Val Val Gln 980 985 990gat gac cca aac act tcc gat ttt act gat act ata tca ggt atc cca 3024Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser Gly Ile Pro 995 1000 1005aag ggt gta cgg tgg gaa gtc cag tct gga gat tcc aac cag atg 3069Lys Gly Val Arg Trp Glu Val Gln Ser Gly Asp Ser Asn Gln Met 1010 1015 1020gtc cac atg aat gtc ctc atc acc tgc gtg ttt gca gct ttt gtc 3114Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Phe Val 1025 1030 1035ttg ggc gcg ttc atc gca gga gtg gct gtg tac tgc tat cgt gac 3159Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp 1040 1045 1050atg ttt gtt cgg aag aac aga aag atc cat aaa gat gca gaa tcg 3204Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser 1055 1060 1065gcc cag tca tgc aca gat tcc agt gga agc ttt gcc aag ctg aat 3249Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn 1070 1075 1080ggt ctc ttt gac agc ccc gtc aag gag tac cag cag aac atc gat 3294Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp 1085 1090 1095tca ccc aaa ctg tac agc aac ctg ctg acc agt cgg aag gag ctg 3339Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu 1100 1105 1110cct ccc aac acg gat cca aag tcc atg gcc atg gac cat cga ggc 3384Pro Pro Asn Thr Asp Pro Lys Ser Met Ala Met Asp His Arg Gly 1115 1120 1125cag cct cca gag ctg gct gct ctc ccc acg cca gag tct aca cct 3429Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro 1130 1135 1140gta ctc cac cag aag acc ctg cag gcc atg aag agc cac tcc gat 3474Val Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Asp 1145 1150 1155aag gcc cat ggc cat ggt gct tca agg aag gaa cac ccc cag ttt 3519Lys Ala His Gly His Gly Ala Ser Arg Lys Glu His Pro Gln Phe 1160 1165 1170ttt cct tct agt cct cca ccc cat tcc ccg tta agt cac ggg cat 3564Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His 1175 1180 1185att ccc agt gcc atc gtt ctt cca aac gcc act cat gac tac aac 3609Ile Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn 1190 1195 1200aca tcc ttc tca aac tct aac gct cac aaa gcc gaa aag aag ctt 3654Thr Ser Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys Lys Leu 1205 1210 1215cag aac gtt gat cac cct ctc aca aag tca tcc agt aag agg gaa 3699Gln Asn Val Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg Glu 1220 1225 1230cac cgg cgc tct gtg gac tcc aga aac acc ctc aat gat ctc ttg 3744His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu 1235 1240 1245aag cat ctc aat gac cca aac agt aac gcc aaa gcc atc atg gga 3789Lys His Leu Asn Asp Pro Asn Ser Asn Ala Lys Ala Ile Met Gly 1250 1255 1260gaa atc cac atg gcc cat cag acc ctc atg ctg gac cca gtg gga 3834Glu Ile His Met Ala His Gln Thr Leu Met Leu Asp Pro Val Gly 1265 1270 1275cca atg tct gag gtc cca ccc aag gtt cct aac cgg gag gca tcc 3879Pro Met Ser Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser 1280 1285 1290cta tac tcc ccc ccc tca aca ctc ccc aga aat agt cca acc aag 3924Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys 1295 1300 1305aga gta gat gtc ccc acc act cct ggg gtc cca atg act tct ctg 3969Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu 1310 1315 1320gaa aga caa agg ggt tat cac aaa aac tcc tcc cag agg cac tct 4014Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser 1325 1330 1335ata tct gcc gtg cct aaa aac tta aac tca cca aac ggt gtt ttg 4059Ile Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu 1340 1345 1350tta tct aga cag ccg agt atg aac cgt gga gga tat atg ccc acc 4104Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr 1355 1360 1365cca aca ggg gcg aag gtg gac tat att cag ggg aca ccg gtg agt 4149Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser 1370 1375 1380gtc cat ctg cag ccc tcc ctc tcc aga cag agc agc tac acc agt 4194Val His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser 1385 1390 1395aat ggt acc cta ccc agg acg gga cta aag agg aca cca tcc tta 4239Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu 1400 1405 1410aaa cct gat gtg cca cca aag cct tcc ttt gtt cct caa acc aca 4284Lys Pro Asp Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr 1415 1420 1425tct gtc aga cca ctg aac aaa tac act tac tag 4317Ser Val Arg Pro Leu Asn Lys Tyr Thr Tyr 1430 1435551438PRTRattus norvegicus 55Met Lys Ala Arg Ser Gln Ser Glu Leu Gly Ile Lys Tyr Pro Leu Phe1 5 10 15Ser Arg Leu Gly Asn Lys Asp Thr Leu Leu Cys Gly Gln Pro Arg Glu 20 25 30Cys Lys Asn Asn Cys Tyr Phe Ser Leu Arg Ala Cys Thr Val Pro Asn 35 40 45Ser Val Met Ile Val Ile Leu Ala Gly Asn Cys Val Met Arg Thr Leu 50 55 60Ser Gln Thr Leu Leu Glu Thr Val Pro Val Trp Ile His Arg Arg Cys65 70 75 80Leu Thr Pro Ser Gly Asp Val Thr His Glu Ser Pro Ser Arg Pro Ala 85 90 95Ala Cys Thr Cys Thr Asp Asn Ala His Leu His Ser Ser Lys Gly Ser 100 105 110Pro Phe Cys Arg Arg Arg Leu Ala Glu Arg Leu Ala Thr Leu Ser Ser 115 120 125Met Trp Ile Thr Ala Ala Leu Ala Ser Gly Lys Ser Gln Gln Phe Cys 130 135 140Gln Ala Gly Ser Cys Thr Arg Ala Ala Pro Lys Val Asp Asp Leu Gln145 150 155 160Met Arg Pro Leu Glu Pro Ser Leu Glu Asn Ile Arg Ser Glu Ser Thr 165 170 175Trp Leu Ile Val Cys Leu Gly Val Lys Thr Lys Thr Lys Leu Arg Gly 180 185 190Thr Thr Ala Pro Thr Ala Pro Leu Gly Cys Ser His Leu Ser Ser Asp 195 200 205Arg Leu Gly Trp Leu Ala Gly Arg Val Val Arg Ala Pro Gly Gly Arg 210 215 220Glu Arg Arg Leu Cys Arg Leu Gln Arg Arg Arg Gln Leu Gly Asp Pro225 230 235 240Ala Arg Arg Gly Ala Gly Gly Ala Ala Pro Leu Arg Trp Glu Ser Leu 245 250 255Gly Ala Arg Pro Ser Ala Ile Arg Asp Ala Ala Ala Thr Gly Val Glu 260 265 270Ala Ala Ala Arg Val Gly Leu Trp Ala Ala Leu Ala Ala Val Gly Ala 275 280 285Ala Glu Arg Arg Gly Ser Arg Asp Leu Arg Glu Arg Leu Gly Asp Gly 290 295 300Ser Asn Tyr Thr Ile Cys Arg Ala Ala Asp Leu Val Gln Thr Leu Glu305 310 315 320Val Asn Leu Ala Val His Ser Ala Asn Phe Ala Gln Asn Pro Arg Lys 325 330 335Leu Ser Gly Thr Ser Glu Glu Gly Ala Gln Ile Pro Ser Arg Pro Thr 340 345 350Met Arg Phe Phe Leu Leu Trp Phe Cys Val Leu Phe Leu Leu Val Ser 355 360 365Arg Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 370 375 380Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro385 390 395 400Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 405 410 415Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val 420 425 430Asn Leu Asn Asp Ile Pro Gln Thr Glu Val Ile Pro Ser Lys Lys Leu 435 440 445Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 450 455 460Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg465 470 475 480Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 485 490 495Cys Arg Tyr Tyr Arg Leu Ser Thr Leu Glu Tyr Asp Gly Glu Glu Ile 500 505 510Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 515 520 525Leu Phe Ala Asp Gly Lys Leu Tyr Ser Ala Thr Val Ala Asp Phe Leu 530 535 540Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu545 550 555 560Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 565 570 575His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile 580 585 590Ala Val Glu His Asn Asn Leu Gly Lys Ala Val Tyr Ser Arg Val Ala 595 600 605Arg Ile Cys Lys Asn Asp Met Gly Gly Ser Gln Arg Val Leu Glu Lys 610 615 620His Trp Thr Ser Phe Leu Lys Ala Arg Leu Asn Cys Ser Val Pro Gly625 630 635 640Asp Ser Phe Phe Tyr Phe Asp Val Leu Gln Ser Ile Thr Asp Ile Ile 645 650 655Gln Ile Asn Gly Ile Pro Thr Val Ile Gly Val Phe Thr Thr Gln Leu 660 665 670Asn

Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp Asp Ile 675 680 685Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro Asp Ser 690 695 700Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg Pro Gly705 710 715 720Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser Ile Asp 725 730 735Phe Pro Asp Asp Thr Leu Ser Phe Ile Lys Ser His Pro Leu Met Asp 740 745 750Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys Thr Arg 755 760 765Val Arg Tyr Arg Leu Thr Ala Ile Glu Val Asp Arg Ser Ala Gly Pro 770 775 780Tyr Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly Val Val785 790 795 800Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp Ser Val 805 810 815Leu Leu Glu Glu Ile Glu Ala Tyr Asn Pro Ala Lys Cys Ser Ala Glu 820 825 830Ser Glu Glu Asp Arg Lys Val Val Ser Leu Gln Leu Asp Arg Asp His 835 840 845His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Val Arg Ile Pro Leu 850 855 860Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile Ala Ser865 870 875 880Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Val Cys Glu Arg Val 885 890 895Thr Leu Gly Met Leu Leu Leu Thr Glu Asp Phe Phe Ala Phe His Asn 900 905 910His Ser Ala Gly Gly Tyr Glu Gln Asp Thr Glu Tyr Gly Asn Thr Ala 915 920 925His Leu Gly Asp Cys His Glu Ser Leu Pro Thr Ser Thr Thr Pro Asp 930 935 940Tyr Lys Ile Phe Gly Gly Pro Thr Ser Asp Met Glu Val Pro Ser Ser945 950 955 960Ser Val Thr Thr Val Ala Ser Ser Pro Glu Ile Thr Ser Lys Val Ile 965 970 975Asp Thr Trp Arg Pro Lys Leu Thr Ser Ser Arg Lys Phe Val Val Gln 980 985 990Asp Asp Pro Asn Thr Ser Asp Phe Thr Asp Thr Ile Ser Gly Ile Pro 995 1000 1005Lys Gly Val Arg Trp Glu Val Gln Ser Gly Asp Ser Asn Gln Met 1010 1015 1020Val His Met Asn Val Leu Ile Thr Cys Val Phe Ala Ala Phe Val 1025 1030 1035Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr Cys Tyr Arg Asp 1040 1045 1050Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp Ala Glu Ser 1055 1060 1065Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys Leu Asn 1070 1075 1080Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile Asp 1085 1090 1095Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu 1100 1105 1110Pro Pro Asn Thr Asp Pro Lys Ser Met Ala Met Asp His Arg Gly 1115 1120 1125Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro 1130 1135 1140Val Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Asp 1145 1150 1155Lys Ala His Gly His Gly Ala Ser Arg Lys Glu His Pro Gln Phe 1160 1165 1170Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His 1175 1180 1185Ile Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn 1190 1195 1200Thr Ser Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys Lys Leu 1205 1210 1215Gln Asn Val Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg Glu 1220 1225 1230His Arg Arg Ser Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu 1235 1240 1245Lys His Leu Asn Asp Pro Asn Ser Asn Ala Lys Ala Ile Met Gly 1250 1255 1260Glu Ile His Met Ala His Gln Thr Leu Met Leu Asp Pro Val Gly 1265 1270 1275Pro Met Ser Glu Val Pro Pro Lys Val Pro Asn Arg Glu Ala Ser 1280 1285 1290Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser Pro Thr Lys 1295 1300 1305Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr Ser Leu 1310 1315 1320Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His Ser 1325 1330 1335Ile Ser Ala Val Pro Lys Asn Leu Asn Ser Pro Asn Gly Val Leu 1340 1345 1350Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Met Pro Thr 1355 1360 1365Pro Thr Gly Ala Lys Val Asp Tyr Ile Gln Gly Thr Pro Val Ser 1370 1375 1380Val His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser 1385 1390 1395Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu 1400 1405 1410Lys Pro Asp Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr 1415 1420 1425Ser Val Arg Pro Leu Asn Lys Tyr Thr Tyr 1430 1435565634DNABos taurusCDS(344)..(3202) 56cggcgcccgg gtttctcttc ccagccactc tcccccgcaa ctttccgtgc tttgttctcc 60cgctggaaat gatttacgga agcgtcttgg acagggtctc cgccaggcgg caagagccca 120gcgctgagat gtgttacgtt ctcatctacc catcaattat ggatggaaac aaataaggaa 180gagtcaattt tgcatgagcc ccttctccgg cggctagagg catccgcagc cgggagggag 240ccgccgcgcg cgtcggcagc tgctggcaag ggggatggtg aggagaaggt agctaagtgg 300actctctgag gaggggctgc tctgccttca cgttggccca acc atg agg ttc ttc 355 Met Arg Phe Phe 1ctg ctc tgt gcc tac atg ctg ctg cta ctg att tcc cag ttg agg gca 403Leu Leu Cys Ala Tyr Met Leu Leu Leu Leu Ile Ser Gln Leu Arg Ala5 10 15 20gtc agc ttt cct gaa gat gat gaa ccc ctt aat act gtt gac tat cac 451Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr Val Asp Tyr His 25 30 35tat tca agg caa tat ccg gtt ttt aga gga cgt cct tca ggc aat gaa 499Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro Ser Gly Asn Glu 40 45 50tca cag cac agg ctg gac ttt cag ctg atg ttg aaa att cga gac aca 547Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys Ile Arg Asp Thr 55 60 65ctt tat att gct ggc agg gat caa gtt tat aca gta aac tta aat gaa 595Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val Asn Leu Asn Glu 70 75 80atc ccc aaa aca gaa gta ata cca aac aag aaa ctg aca tgg cgg tca 643Ile Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu Thr Trp Arg Ser85 90 95 100aga caa cag gat cga gaa aac tgt gct atg aaa ggc aag cat aaa gat 691Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly Lys His Lys Asp 105 110 115gaa tgc cac aac ttt att aaa gta ttt gtt cca aga aac gat gag atg 739Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg Asn Asp Glu Met 120 125 130gtt ttt gtt tgt ggc acc aat gcg ttt aat ccc atg tgt aga tac tat 787Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met Cys Arg Tyr Tyr 135 140 145aag ttg aat acc tta gag tat gat gga gaa gaa att agt ggc ctg gca 835Lys Leu Asn Thr Leu Glu Tyr Asp Gly Glu Glu Ile Ser Gly Leu Ala 150 155 160aga tgc cca ttt gat gcc aga caa act aat gtt gcc ctt ttt gct ggt 883Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala Leu Phe Ala Gly165 170 175 180ggc gct gct gta tct gcc aca gtg gct gac ttc ttg gcc agt gat gct 931Gly Ala Ala Val Ser Ala Thr Val Ala Asp Phe Leu Ala Ser Asp Ala 185 190 195gtt att tat cga agc atg ggt gat gga tct gct ctt cgt aca ata aaa 979Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu Arg Thr Ile Lys 200 205 210tat gat tcc aaa tgg atc aaa gag cca cac ttt ctg cat gct ata gaa 1027Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu His Ala Ile Glu 215 220 225tac gga aac tac gtc tat ttc ttc ttt cga gaa att gct gta gaa cat 1075Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile Ala Val Glu His 230 235 240aac aac tta ggc aag gca aaa cag gtc cgc cgt ccc ctg atg ctg ttc 1123Asn Asn Leu Gly Lys Ala Lys Gln Val Arg Arg Pro Leu Met Leu Phe245 250 255 260ctc ttt ttc agc att cct ggt tcc gca gtc tgt gcg ttt agc atg gat 1171Leu Phe Phe Ser Ile Pro Gly Ser Ala Val Cys Ala Phe Ser Met Asp 265 270 275gac att gaa aaa gta ttc aaa gga cgg ttt aaa gaa cag aaa act cca 1219Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu Gln Lys Thr Pro 280 285 290gat tct gtt tgg aca gcg gtc cct gaa gac aaa gta cca aag cca agg 1267Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val Pro Lys Pro Arg 295 300 305cct ggg tgt tgt gca aag cac ggt ctt gcg gaa gca tat aaa acc tcc 1315Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala Tyr Lys Thr Ser 310 315 320atc gat ttc ccg gat gaa acc ctg tca ttc atc aaa tcc cac ccc ctg 1363Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys Ser His Pro Leu325 330 335 340atg gac tcg gcc gtc cca ccc att gcc gac gaa ccc tgg ttc aca aag 1411Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro Trp Phe Thr Lys 345 350 355act cgg atc agg tac aga ctg acg gcc atc gcc gtc gac cat tct gcc 1459Thr Arg Ile Arg Tyr Arg Leu Thr Ala Ile Ala Val Asp His Ser Ala 360 365 370gga ccc cac cag aac tac aca gtc atc ttt gtt ggc tca gaa gct ggc 1507Gly Pro His Gln Asn Tyr Thr Val Ile Phe Val Gly Ser Glu Ala Gly 375 380 385gtg gtg ctt aaa gtt ttg gcg aag acc agc cct ttc tct ttg aat gac 1555Val Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe Ser Leu Asn Asp 390 395 400agc gta tta ctg gaa gag att gaa gca tac aac cat gca aag tgc agt 1603Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His Ala Lys Cys Ser405 410 415 420gct gaa aat gag gag gac aga aag gtc atc tca tta cag ttg gat aaa 1651Ala Glu Asn Glu Glu Asp Arg Lys Val Ile Ser Leu Gln Leu Asp Lys 425 430 435gac cat cat gct tta tat gtg gcg ttc tct agc tgc gtt atc cgc atc 1699Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys Val Ile Arg Ile 440 445 450ccc ctc agt cgc tgt gag cgt tat gga tca tgt aaa aag tct tgt att 1747Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys Lys Ser Cys Ile 455 460 465gca tct cga gac cca tac tgt ggc tgg tta agc caa ggg gcc tgt ggt 1795Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln Gly Ala Cys Gly 470 475 480cga gtg agc cca gcg atg ctg ctg tta act gaa gac ttg ttt gct ttc 1843Arg Val Ser Pro Ala Met Leu Leu Leu Thr Glu Asp Leu Phe Ala Phe485 490 495 500cat aac cac agc gct gga gga ttt gaa caa gac aca gaa tat ggc aac 1891His Asn His Ser Ala Gly Gly Phe Glu Gln Asp Thr Glu Tyr Gly Asn 505 510 515acg gcc cat cta ggg gac tgc cac ggt gta cgg tgg gaa gtc cag tct 1939Thr Ala His Leu Gly Asp Cys His Gly Val Arg Trp Glu Val Gln Ser 520 525 530gga gag gcc aac cag atg gtc cac atg aat gtc ctc atc acc tgt gtc 1987Gly Glu Ala Asn Gln Met Val His Met Asn Val Leu Ile Thr Cys Val 535 540 545ttt gca gct ttt gtc ttg ggt gcg ttc att gca ggt gtg gca gtc tac 2035Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly Val Ala Val Tyr 550 555 560tgt tac cgt gac atg ttt gtt cgg aaa aac aga aag atc cat aaa gat 2083Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys Ile His Lys Asp565 570 575 580gca gaa tct gcc cag tca tgc aca gac tcc agt gga agt ttt gcc aag 2131Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly Ser Phe Ala Lys 585 590 595ctg aat ggt ctc ttt gac agc ccc gtc aag gaa tac caa cag aat att 2179Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr Gln Gln Asn Ile 600 605 610gat tct ccc aaa tta tat agt aac ctg ctg acc agt cgg aaa gag ctg 2227Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser Arg Lys Glu Leu 615 620 625cca ccc aat gga gat aca aaa tcc atg gtc atg gac cat cga ggc caa 2275Pro Pro Asn Gly Asp Thr Lys Ser Met Val Met Asp His Arg Gly Gln 630 635 640cct cct gag ttg gct gct ctc ccc act cct gag tct acg cct gtg ctt 2323Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser Thr Pro Val Leu645 650 655 660cac cag aag acc ctg cag gcc atg aag agc cac tca gaa aag gcc cat 2371His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser Glu Lys Ala His 665 670 675ggc cat gga gct tca agg aaa gaa acc ccc cag ttt ttt cct tct agt 2419Gly His Gly Ala Ser Arg Lys Glu Thr Pro Gln Phe Phe Pro Ser Ser 680 685 690cct cca cca cat tcc cca cta agt cac ggg cat atc ccc agc gcc att 2467Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile Pro Ser Ala Ile 695 700 705gtt ctt cct aat gct acc cat gac tac aac act tct ttc tca aac tcc 2515Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser Phe Ser Asn Ser 710 715 720aat gct cac aaa gct gaa aag aag ctt caa aac att gac cat cct ctt 2563Asn Ala His Lys Ala Glu Lys Lys Leu Gln Asn Ile Asp His Pro Leu725 730 735 740aca aag tca tcc agt aaa aga gat cac cgg cgt tct gtg gat tcc aga 2611Thr Lys Ser Ser Ser Lys Arg Asp His Arg Arg Ser Val Asp Ser Arg 745 750 755aat acc ctc aat gat ctc ctg aag cat cta aat gac cca aac agt aac 2659Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp Pro Asn Ser Asn 760 765 770ccc aaa gcc atc atg gga gac atc cag atg gcc cac cag acc cta atg 2707Pro Lys Ala Ile Met Gly Asp Ile Gln Met Ala His Gln Thr Leu Met 775 780 785ctg gat ccc gtg gga cct atg tct gaa gtc ccg ccc aag gtc cct aac 2755Leu Asp Pro Val Gly Pro Met Ser Glu Val Pro Pro Lys Val Pro Asn 790 795 800cgc gag gca tct ctc tac tct cct ccc tcg act ctt ccc aga aat agc 2803Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu Pro Arg Asn Ser805 810 815 820cca acc aag cga gtg gat gtt ccc acc act cct gga gtt ccg atg act 2851Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly Val Pro Met Thr 825 830 835tct ttg gaa aga cag agg ggt tac cat aaa aat tcc tcc cag agg cac 2899Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser Ser Gln Arg His 840 845 850tct ata tcg gct atg cct aaa aac tta agt tca cca aat ggt gtt ttg 2947Ser Ile Ser Ala Met Pro Lys Asn Leu Ser Ser Pro Asn Gly Val Leu 855 860 865tta tct aga cag cct agt atg aac cgt gga ggg tac gtg ccc acc cct 2995Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr Val Pro Thr Pro 870 875 880gca ggg cca aag gtg gac tat att cag gga gca cca gtg agt gct cac 3043Ala Gly Pro Lys Val Asp Tyr Ile Gln Gly Ala Pro Val Ser Ala His885 890 895 900cta cag cct tcc ctc tcc aga cag agc agc tac acc agt aat ggc acc 3091Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr Ser Asn Gly Thr 905 910 915ctt ccc cgg acg gga cta aag agg aca ccg tcc tta aaa cct gac gtg 3139Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu Lys Pro Asp Val 920 925 930ccg cca aag cct tca ttt gtt cct caa acc acc tcc gtc aga cca ctg 3187Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser Val Arg Pro Leu 935 940 945aac aaa tac act tac taggcctcaa gtgtgccctt ccttgtgtgg ctttatcctg 3242Asn Lys Tyr Thr Tyr 950tctatgttgt tgagaggatg atatggtaag ggtaccttaa gaaaagagac tcgcttgtat 3302ttcaagagaa gcaagtggcc aaagaaactc ttcctaactt tggcaacatc agaacttgcc 3362atatgtagct actgcagcaa ggcttctgtg tacttgcctg aaaacaaagg aaggtgctgg 3422tcattccatt tcttttgttt gaagctaaag agatgtgtgg ctctgagggg ctacctgtaa 3482ccagtataaa gagctgatcc agtgctcaga agaatctgtc tgtgagcaaa tacttgaaaa 3542tgggttcaac ttagactgcc attttgtgtg gtcttcccat taaatgtgaa cattttaata 3602tgtatgcatt caccttgcct cttgcacaaa tgtcaaaaaa aaaaaaaatg gtaatgtctc 3662aaagaaacga acttgtagat taccaaacaa tttgctaaaa attcagtctt tgacccaaac 3722tgtagcatct ttttcatgtg tggcattttt ttccgtgcca ccaaggaact gtgttgtgtg 3782tgcatgtgtg tgtgagtgtg tgtgagtgtg tgtgagtgtg tgtgtgttct

gtccccacta 3842gcatttgttt cggtgcccat tgcatctttt tgtgctatgg agttgtttac atcgcgcatg 3902actgaacaag agacaataat ttcttcccac agcagtccat tgggttcagc tttgagaaag 3962aaaaccaagg ctgattttga cagtcaaaat gattaactcg acttccatgt tacccagtgc 4022cagaatgtaa gagtactaag taattttgtg ctgctattca ctgaaacttc aattacagtc 4082ttgccagctt aaggagatag agacgttaag aggtatcctt aatttatcca ccagtttcag 4142tagtaaaatt caccagtcca ctgtgaatcc aagccccagt gactctgtta accttggaca 4202cactaacaag gttttatttt tactgtgttt ggtttctccc ctgtagtaaa attcctcttg 4262ttttaattcc cctctaaccc caagatggaa aaaaaaaaga accacacaca catacaaaac 4322agaagacaaa agaagggaat gtgagaggct catagttggc ttaacaggaa cagtctatgg 4382gaacctaaca gtggtgcaat catgttgtct gtgttgtgtg atgtgagaac tttctcctaa 4442gtcatgcagg taacgacagt atactgtaaa tattacatgt gagtttacct gaatctgtgc 4502attttgtgcc ttattcatga gaatgataga agtactcaaa tacgtcaagt gttttcagta 4562tagcacatca tttactgagt gccagttgta catgtttttc aaccagcacc tgaaaagact 4622tttcaaaaaa atcataacaa cgacctagaa caattaactg taaagcaatc catccagata 4682gccgcattac atcctttgcc atgataaaca ttccactcct gctttcacta aggatgaatc 4742agtgataatg tgaagtcaaa tgaggtttcc cgggtaatgt gacacctgca gaaaccatat 4802agagtcattt attcgtagtt ttgcagaagc cacttacagt tgatgatgtg caaccctgac 4862gactgtttca gttaatatgc tgcacaccac ggtttattga acctcatcta gaaagtatca 4922aggcagagga atgctcctga cttagtcaga caaataagtt caactgattt cctgtgatga 4982tatcttatta cttgggggag gatgggttgc aaaagaccag agcattttta tacagaatat 5042agaatacgga tgcagttatt cttttctttt gagaatattg ttttataaag aacatgattc 5102cctgaggtct ctggaagctc aaaagctaaa acttctgttt ttgcaacact tcagctttga 5162aactaaaata atacagattg ataataaatt aaaccaacca acgataaaca ctactcagtc 5222cactgccgac aaacctgttt gaattcaccc tgccaatatt aatcctggcg tgcggaaaat 5282ggaacagtaa ctgtatgtga acccggataa cattttgtga cattgtgctg ccttgtagtt 5342tgtaatgtga gttctatcag tatttatgtt gagatttcta acacaaaatc tagtctctat 5402cctgttaatt taatctttaa atgctttatt catttgtgca aaggtaaaca cagattgtat 5462cttttttaat ggtacggcat aaaaagtaac cctaaagtga agtggctcta tactgtttta 5522tagagtactt taacatgtat agatatcttg taaacttgta ttgtggatgt gtaaataata 5582tgtactttgg gtttttaaca ccgcatgtaa agtcaaaata aaatatacaa at 563457953PRTBos taurus 57Met Arg Phe Phe Leu Leu Cys Ala Tyr Met Leu Leu Leu Leu Ile Ser1 5 10 15Gln Leu Arg Ala Val Ser Phe Pro Glu Asp Asp Glu Pro Leu Asn Thr 20 25 30Val Asp Tyr His Tyr Ser Arg Gln Tyr Pro Val Phe Arg Gly Arg Pro 35 40 45Ser Gly Asn Glu Ser Gln His Arg Leu Asp Phe Gln Leu Met Leu Lys 50 55 60Ile Arg Asp Thr Leu Tyr Ile Ala Gly Arg Asp Gln Val Tyr Thr Val65 70 75 80Asn Leu Asn Glu Ile Pro Lys Thr Glu Val Ile Pro Asn Lys Lys Leu 85 90 95Thr Trp Arg Ser Arg Gln Gln Asp Arg Glu Asn Cys Ala Met Lys Gly 100 105 110Lys His Lys Asp Glu Cys His Asn Phe Ile Lys Val Phe Val Pro Arg 115 120 125Asn Asp Glu Met Val Phe Val Cys Gly Thr Asn Ala Phe Asn Pro Met 130 135 140Cys Arg Tyr Tyr Lys Leu Asn Thr Leu Glu Tyr Asp Gly Glu Glu Ile145 150 155 160Ser Gly Leu Ala Arg Cys Pro Phe Asp Ala Arg Gln Thr Asn Val Ala 165 170 175Leu Phe Ala Gly Gly Ala Ala Val Ser Ala Thr Val Ala Asp Phe Leu 180 185 190Ala Ser Asp Ala Val Ile Tyr Arg Ser Met Gly Asp Gly Ser Ala Leu 195 200 205Arg Thr Ile Lys Tyr Asp Ser Lys Trp Ile Lys Glu Pro His Phe Leu 210 215 220His Ala Ile Glu Tyr Gly Asn Tyr Val Tyr Phe Phe Phe Arg Glu Ile225 230 235 240Ala Val Glu His Asn Asn Leu Gly Lys Ala Lys Gln Val Arg Arg Pro 245 250 255Leu Met Leu Phe Leu Phe Phe Ser Ile Pro Gly Ser Ala Val Cys Ala 260 265 270Phe Ser Met Asp Asp Ile Glu Lys Val Phe Lys Gly Arg Phe Lys Glu 275 280 285Gln Lys Thr Pro Asp Ser Val Trp Thr Ala Val Pro Glu Asp Lys Val 290 295 300Pro Lys Pro Arg Pro Gly Cys Cys Ala Lys His Gly Leu Ala Glu Ala305 310 315 320Tyr Lys Thr Ser Ile Asp Phe Pro Asp Glu Thr Leu Ser Phe Ile Lys 325 330 335Ser His Pro Leu Met Asp Ser Ala Val Pro Pro Ile Ala Asp Glu Pro 340 345 350Trp Phe Thr Lys Thr Arg Ile Arg Tyr Arg Leu Thr Ala Ile Ala Val 355 360 365Asp His Ser Ala Gly Pro His Gln Asn Tyr Thr Val Ile Phe Val Gly 370 375 380Ser Glu Ala Gly Val Val Leu Lys Val Leu Ala Lys Thr Ser Pro Phe385 390 395 400Ser Leu Asn Asp Ser Val Leu Leu Glu Glu Ile Glu Ala Tyr Asn His 405 410 415Ala Lys Cys Ser Ala Glu Asn Glu Glu Asp Arg Lys Val Ile Ser Leu 420 425 430Gln Leu Asp Lys Asp His His Ala Leu Tyr Val Ala Phe Ser Ser Cys 435 440 445Val Ile Arg Ile Pro Leu Ser Arg Cys Glu Arg Tyr Gly Ser Cys Lys 450 455 460Lys Ser Cys Ile Ala Ser Arg Asp Pro Tyr Cys Gly Trp Leu Ser Gln465 470 475 480Gly Ala Cys Gly Arg Val Ser Pro Ala Met Leu Leu Leu Thr Glu Asp 485 490 495Leu Phe Ala Phe His Asn His Ser Ala Gly Gly Phe Glu Gln Asp Thr 500 505 510Glu Tyr Gly Asn Thr Ala His Leu Gly Asp Cys His Gly Val Arg Trp 515 520 525Glu Val Gln Ser Gly Glu Ala Asn Gln Met Val His Met Asn Val Leu 530 535 540Ile Thr Cys Val Phe Ala Ala Phe Val Leu Gly Ala Phe Ile Ala Gly545 550 555 560Val Ala Val Tyr Cys Tyr Arg Asp Met Phe Val Arg Lys Asn Arg Lys 565 570 575Ile His Lys Asp Ala Glu Ser Ala Gln Ser Cys Thr Asp Ser Ser Gly 580 585 590Ser Phe Ala Lys Leu Asn Gly Leu Phe Asp Ser Pro Val Lys Glu Tyr 595 600 605Gln Gln Asn Ile Asp Ser Pro Lys Leu Tyr Ser Asn Leu Leu Thr Ser 610 615 620Arg Lys Glu Leu Pro Pro Asn Gly Asp Thr Lys Ser Met Val Met Asp625 630 635 640His Arg Gly Gln Pro Pro Glu Leu Ala Ala Leu Pro Thr Pro Glu Ser 645 650 655Thr Pro Val Leu His Gln Lys Thr Leu Gln Ala Met Lys Ser His Ser 660 665 670Glu Lys Ala His Gly His Gly Ala Ser Arg Lys Glu Thr Pro Gln Phe 675 680 685Phe Pro Ser Ser Pro Pro Pro His Ser Pro Leu Ser His Gly His Ile 690 695 700Pro Ser Ala Ile Val Leu Pro Asn Ala Thr His Asp Tyr Asn Thr Ser705 710 715 720Phe Ser Asn Ser Asn Ala His Lys Ala Glu Lys Lys Leu Gln Asn Ile 725 730 735Asp His Pro Leu Thr Lys Ser Ser Ser Lys Arg Asp His Arg Arg Ser 740 745 750Val Asp Ser Arg Asn Thr Leu Asn Asp Leu Leu Lys His Leu Asn Asp 755 760 765Pro Asn Ser Asn Pro Lys Ala Ile Met Gly Asp Ile Gln Met Ala His 770 775 780Gln Thr Leu Met Leu Asp Pro Val Gly Pro Met Ser Glu Val Pro Pro785 790 795 800Lys Val Pro Asn Arg Glu Ala Ser Leu Tyr Ser Pro Pro Ser Thr Leu 805 810 815Pro Arg Asn Ser Pro Thr Lys Arg Val Asp Val Pro Thr Thr Pro Gly 820 825 830Val Pro Met Thr Ser Leu Glu Arg Gln Arg Gly Tyr His Lys Asn Ser 835 840 845Ser Gln Arg His Ser Ile Ser Ala Met Pro Lys Asn Leu Ser Ser Pro 850 855 860Asn Gly Val Leu Leu Ser Arg Gln Pro Ser Met Asn Arg Gly Gly Tyr865 870 875 880Val Pro Thr Pro Ala Gly Pro Lys Val Asp Tyr Ile Gln Gly Ala Pro 885 890 895Val Ser Ala His Leu Gln Pro Ser Leu Ser Arg Gln Ser Ser Tyr Thr 900 905 910Ser Asn Gly Thr Leu Pro Arg Thr Gly Leu Lys Arg Thr Pro Ser Leu 915 920 925Lys Pro Asp Val Pro Pro Lys Pro Ser Phe Val Pro Gln Thr Thr Ser 930 935 940Val Arg Pro Leu Asn Lys Tyr Thr Tyr945 950582633DNAArtificialMurine Sema6D-Ig fusion protein CDS 58atggggttcc ttctgctttg gttctgcgtg ctgttccttc tggtctccag gttacgggcg 60gtcagcttcc cagaagacga tgagcccctc aacacggttg actatcacta ttcaaggcaa 120tatccggttt ttagaggacg cccttcaggc aacgaatcgc agcacaggct ggactttcag 180ctgatgttga aaattcgaga cacactttat attgctggca gggatcaagt ctatacagtg 240aacttaaatg aaatccccca aacagaggtg ataccaagca agaagctgac gtggaggtcc 300agacagcagg atcgagaaaa ttgtgctatg aaaggcaagc ataaagatga atgccacaac 360ttcatcaaag tctttgtccc aagaaatgat gagatggttt ttgtctgtgg taccaatgct 420ttcaacccga tgtgcagata ctataggttg agaacgttag agtatgatgg ggaagaaatt 480agtggcctgg cacgatgccc gtttgatgcc cgacaaacca atgtcgccct ctttgctgat 540ggaaaactct attctgccac agtggctgat ttcctggcca gtgatgctgt catttacaga 600agcatgggag atggatctgc ccttcgcaca ataaaatacg attccaagtg gatcaaagaa 660ccacacttcc ttcatgccat agaatatgga aactatgtct atttcttctt cagagaaatc 720gccgtggaac ataataactt aggcaaggct gtgtattccc gcgtggctcg catttgtaaa 780aacgacatgg gtggctcaca gcgggtcctg gagaaacact ggacttcctt ccttaaggct 840cggctgaact gctccgttcc tggagattcc tttttctact tcgacgtcct gcagtctata 900acagacataa tccaaatcaa tggcatcccc actgtggttg gggtcttcac cacacagctc 960aacagcattc ctggttctgc agtctgtgcc tttagcatgg acgacattga gaaagtgttc 1020aaagggcggt tcaaagagca gaaaacccca gactctgttt ggacagcagt tcccgaagac 1080aaagtaccaa aaccaaggcc tggctgttgt gccaaacacg gcctcgcaga agcttacaag 1140acctccatcg actttccaga tgacaccctg gctttcatca agtcccaccc gctgatggac 1200tctgccgtcc cacccattgc cgatgagccc tggttcacaa agacacgggt caggtacagg 1260ttgacagcca tcgaagtgga ccgttcagca gggccatacc aaaactacac agtcatcttt 1320gttggctctg aagctggcgt ggtacttaaa gttttggcaa agaccagtcc tttctctctg 1380aatgacagtg tattactcga agagattgaa gcttataacc cagccaagtg cagcgccgag 1440agtgaggagg acagaaaggt ggtctcatta cagctggaca aggatcacca tgctttatac 1500gtggccttct ctagctgcgt ggtccgcatc cccctcagcc gctgtgagcg ctacggatcg 1560tgtaaaaagt cttgcattgc atcacgtgac ccgtactgtg gttggttaag ccagggagtt 1620tgtgagagag tgaccctagg gatgctccct ggaggatatg agcaggacac ggagtacggc 1680aacacagccc acctagggga ctgccacgac atggaggtat cctcatcttc tgttaccact 1740gtggcaagta gcccagaaat tacatctaaa gtgattgata cctggagacc taaactgacg 1800agctcccgga aatttgtagt tcaagatgac ccaaatactt ctgattttac tgatactata 1860tcaggtatcc caaagggtgt acggtgggaa gtccagtctg gagaatccaa tcagatggtc 1920cacatgaatg tcctcatcac ctgcgtgttt gccgctggat ccgagcccaa atcttgtgac 1980aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc gtcagtcttc 2040ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacatgc 2100gtggtggtgg acgtgagcca cgaagaccct gaggtcaagt tcaactggta cgtggacggc 2160gtggaggtgc ataatgccaa gacaaagccg cgggaggagc agtacaacag cacgtaccgt 2220gtggtcagcg tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc 2280aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa agccaaaggg 2340cagccccgag aaccacaggt gtacaccctg cccccatccc gggatgagct gaccaagaac 2400caggtcagcc tgacctgcct ggtcaaaggc ttctatccca gcgacatcgc cgtggagtgg 2460gagagcaatg ggcagccgga gaacaactac aagaccacgc ctcccgtgct ggactccgac 2520ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 2580gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaa 2633

Claims

1. A method of reducing T cell activation in a subject, comprising administering to a subject in need of reduced T cell activation an effective amount of an inhibitor of Semaphorin 6D (Sema6D) activity on T cells.

2. The method of claim 1, wherein the subject is a transplantation patient, a subject having an autoimmune disease or at risk of having an autoimmune-disease (e.g., SLE, MS, RA, type I diabetes), and/or a subject having an inflammatory response or at risk of having an inflammatory response.

3. The method of claim 1, wherein the inhibitor of Sema6D activity is an antibody that specifically binds Sema6D.

4. The method of claim 1, wherein the inhibitor of Sema6D activity is administered in combination with another anti-T cell therapeutic, either simultaneously, before and/or after administration of the inhibitor of Sema6D activity.

5. A method of increasing T cell activation in a subject, comprising administering to a subject in need of increased T cell activation an effective amount of an enhancer of Semaphorin 6D (Sema6D) activity on T cells.

6. The method of claim 5, wherein the enhancer of Sema6D activity is administered in combination with another T cell activating therapeutic, either simultaneously, before and/or after administration of the enhancer of Sema6D activity.

7. A method of identifying an activated T cell, comprising detecting Sema6D on the surface of the T cell.

8. A method of identifying an activated T cell, comprising detecting messenger RNA encoding Sema6D in the T cell.

9. A method of monitoring T cell activation over time, comprising detecting Sema6D on the surface of a T cell over time and measuring changes in the amount of Sema6D on the surface of a T cell over time.

10. A method of monitoring T cell activation over time, comprising detecting messenger RNA encoding. Sema6D in a T cell over time and measuring changes in the amount of messenger RNA encoding Sema6D in the T cell over time.

11. A method of identifying a substance having an inhibitory effect on Sema6D activity and/or having an inhibitory effect on T cell activation, comprising contacting the substance with T cells under conditions whereby Sema6D activity and/or T cell activation can occur and measuring the amount of Sema6D activity and/or T cell activation in the presence and in the absence of the substance; whereby a decrease in Sema6D activity and/or T cell activation in the presence of the substance as compared to the amount of Sema6D activity and or/T cell activation in the absence of the substance identifies a substance having the ability to inhibit Sema6D activity and/or T cell activation.

12. A method of identifying a substance having an enhancing effect on Sema6D activity and/or T cell activation, comprising contacting the substance with T cells under conditions whereby Sema6D activity and/or T cell activation can occur and measuring the amount of Sema6D activity and/or T cell activation in the presence and in the absence of the substance; whereby an increase in Sema6D activity and/or T cell activation in the presence of the substance as compared to the amount of Sema6D activity and/or T cell activation in the absence of the substance identifies a substance having the ability to enhance Sema6D activity and/or T cell activation.

13. A method of reducing B cell activation in a subject, comprising administering to a subject in need of reduced B cell activation an effective amount of an inhibitor of Semaphorin 6D (Sema6D) activity on B cells.

14. The method of claim 13, wherein the subject is a transplantation patient, a subject having an autoimmune disease or at risk of having an autoimmune disease (e.g., SLE, MS, RA, type I diabetes), and/or a subject having an inflammatory response or at risk of having an inflammatory response.

15. The method of claim 13, wherein the inhibitor of Sema6D activity is an antibody that specifically binds Sema6D.

16. The method of claim 13, wherein the inhibitor of Sema6D activity is administered in combination with another anti-B cell therapeutic, either simultaneously, before and/or after administration of the inhibitor of Sema6D activity.

17. A method of increasing B cell activation in a subject, comprising administering to a subject in need of increased B cell activation an effective amount of an enhancer of Semaphorin 6D (Sema6D) activity on B cells.

18. The method of claim 17, wherein the enhancer of Sema6D activity is administered in combination with another B cell activating therapeutic, either simultaneously, before and/or after administration of the enhancer of Sema6D activity.

19. A method of identifying an activated B cell, comprising detecting Sema6D on the surface of the B cell.

20. A method of identifying an activated B cell, comprising detecting messenger RNA encoding Sema6D in the B cell.

21. A method of monitoring B cell activation over time, comprising detecting Sema6D on the surface of a B cell over time and measuring changes in the amount of Sema6D on the surface of a B cell over time.

22. A method of monitoring B cell activation over time, comprising detecting messenger RNA encoding Sema6D in a B cell over time and measuring changes in the amount of messenger RNA encoding Sema6D in the B cell over time.

23. A method of identifying a substance having an inhibitory effect on Sema6D activity and/or having an inhibitory effect on B cell activation, comprising contacting the substance with B cells under conditions whereby Sema6D activity and/or B cell activation can occur and measuring the amount of Sema6D activity and/or B cell activation in the presence and in the absence of the substance; whereby a decrease in Sema6D activity and/or B cell activation in the presence of the substance as compared to the amount of Sema6D activity and or/B cell activation in the absence of the substance identifies a substance having the ability to inhibit Sema6D activity and/or B cell activation.

24. A method of identifying a substance having an enhancing effect on Sema6D activity and/or B cell activation, comprising contacting the substance with B cells under conditions whereby Sema6D activity and/or B cell activation can occur and measuring the amount of Sema6D activity and/or B cell activation in the presence and in the absence of the substance; whereby an increase in Sema6D activity and/or B cell activation in the presence of the substance as compared to the amount of Sema6D activity and/or B cell activation in the absence of the substance identifies a substance having the ability to enhance Sema6D activity and/or B cell activation.

25. A method of treating a B cell-related disorder in a subject, comprising administering to the subject a therapeutic amount of an inhibitor of Semaphorin 6D (Sema6D) activity on B cells.

26. The method of claim 25, wherein the disorder is selected from the group consisting of leukemia, lymphoma, an autoimmune disorder, inflammatory response, transplantation rejection and any combination thereof.

27. A method of treating a T cell-related disorder in a subject, comprising administering to the subject a therapeutic amount of an inhibitor of Semaphorin 6D (Sema6D) activity on B cells.

28. The method of claim 27, wherein the disorder is selected from the group consisting of leukemia, lymphoma, autoimmune disease, inflammatory response, transplantation rejection and any combination thereof.

29. A method of treating a white blood cell-related disorder in a subject, comprising administering to the subject a therapeutic amount of an inhibitor of Semaphorin 6D (Sema6D) activity on white blood cells.

30. The method of claim 29, wherein the disorder is selected from the group consisting of leukemia (e.g., chronic myelogenous leukemia; promyelocytic leukemia), lymphoma, an autoimmune disorder and any combination thereof.