Patent application title: METHODS FOR DIFFERENTIATION
Inventors:
IPC8 Class: AC12N50793FI
USPC Class:
1 1
Class name:
Publication date: 2017-04-20
Patent application number: 20170107487
Abstract:
Described herein are methods relating to the differentiation of stem
cells to more differentiated phenotypes, e.g. to terminally
differentiated cell types and/or precursors thereof. In some embodiments,
the methods relate to contacting the stem cells with differentiation
factors and halting the cell cycle, thereby increasing the rate of
differentiation.Claims:
1. A method of differentiating a stem cell, the method comprising: i)
contacting the stem cell with one or more ectopic differentiation
factors; and ii) inhibiting the cell cycle of the stem cell; wherein
steps i) and ii) occur within 15 days of each other.
2.-15. (canceled)
16. The method of claim 1, wherein steps i) and ii) occur simultaneously.
17. The method of claim 1, wherein the differentiation factor is a terminal transcription factor.
18. The method of claim 17, wherein the terminal transcription factor is selected from Table 1.
19. The method of claim 17, wherein the stem cell is to be differentiated to a skeletal muscle phenotype and is contacted with the terminal transcription factor MyoD.
20. The method of claim 17, wherein the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with a terminal transcription factor selected from the group consisting of: Ngn2; Isl1; and Lhx3.
21. The method of claim 17, wherein the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with the terminal transcription factors Ngn2; Isl1; and Lhx3.
22. The method of claim 17, wherein the stem cell is to be differentiated to a cardiomyocyte phenotype and is contacted with the terminal transcription factor Gata5.
23. The method of claim 17, wherein the stem cell is to be differentiated to a hepatocyte or hepatoblast phenotype and is contacted with the terminal transcription factor Hnf4.alpha..
24. The method of claim 1, wherein the cell cycle is inhibited by one or more of the following: reducing or removing growth factors; reducing serum levels; reducing serum levels below 5%; contacting the cell with a PI3K inhibitor; contacting the cell with an E2F family transcription factor inhibitor; contacting the cell with a Myc inhibitor; contacting the cell with a MAPK inhibitor; contacting the cell with a MEK1/2 inhibitor; contacting the cell with a CDK inhibitor; contacting the cell with an Id inhibitor; contacting the cell with a Rb agonist; contacting the cell with a Ink family agonist; contacting the cell with a Cip/Kip family agonist; and culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta..
25.-27. (canceled)
28. The method of claim 24, wherein the PI3K inhibitor is LY294002.
29. The method of claim 24, wherein the E2F transcription factor inhibitor is HLM006474.
30. The method of claim 24, wherein the Myc inhibitor is JQ1 or 10058-F4.
31. The method of claim 24, wherein the MAPK inhibitor is PD98059.
32. The method of claim 24, wherein the CDK inhibitor is a CDK4 or CDK2 inhibitor.
33. The method of claim 24, wherein the CDK inhibitor is p16, p15, p18, p19, p21, p27, or p57.
34. (canceled)
35. The method of claim 1, wherein the stem cell is an embryonic stem cell.
36. The method of claim 1, wherein steps i) and ii) result in a population of cells comprising one or more terminally-differentiated cell types.
37. The method of claim 1, wherein steps i) and ii) result in a population of cells comprising no more than 2 terminally-differentiated cell types.
38. The method of claim 1, wherein steps i) and ii) result in a population of cells of which at least 50% are terminally-differentiated cells.
39.-41. (canceled)
Description:
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit under 35 U.S.C. .sctn.119(e) of U.S. Provisional Application No. 62/010,244 filed Jun. 10, 2014, the contents of which are incorporated herein by reference in their entirety.
SEQUENCE LISTING
[0003] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 28, 2015, is named 002806-081571-PCT_SL.txt and is 314,859 bytes in size.
TECHNICAL FIELD
[0004] The technology described herein relates to methods of differentiation, e.g. differentiating stem cells.
BACKGROUND
[0005] As cells differentiate during embryonic development, they progress through a sequence of events, starting with stem cells, to intermediate cell types, and finally, to terminally differentiated cell types. This differentiation process can be induced in vitro. However, in vitro differentiation can be a time-consuming process with a significant lag time before differentiated cells are obtained.
SUMMARY
[0006] Described herein are methods relating to the inventors' discovery that early and simultaneous inhibition of the cell cycle as well as the introduction of differentiation factors can significantly reduce the time required for cells to differentiate in vitro.
[0007] In one aspect, described herein is a method of differentiating a stem cell, the method comprising: i) contacting the stem cell with one or more ectopic differentiation factors; and ii) inhibiting the cell cycle of the stem cell; wherein steps i) and ii) occur within 15 days of each other.
[0008] In some embodiments, steps i) and ii) occur within 14 days of each other. In some embodiments, steps i) and ii) occur within 13 days of each other. In some embodiments, steps i) and ii) occur within 12 days of each other. In some embodiments, steps i) and ii) occur within 11 days of each other. In some embodiments, steps i) and ii) occur within 10 days of each other. In some embodiments, steps i) and ii) occur within 9 days of each other. In some embodiments, steps i) and ii) occur within 8 days of each other. In some embodiments, steps i) and ii) occur within 7 days of each other. In some embodiments, steps i) and ii) occur within 6 days of each other. In some embodiments, steps i) and ii) occur within 5 days of each other. In some embodiments, steps i) and ii) occur within 4 days of each other. In some embodiments, steps i) and ii) occur within 3 days of each other. In some embodiments, steps i) and ii) occur within 2 days of each other. In some embodiments, steps i) and ii) occur within 24 hours of each other. In some embodiments, steps i) and ii) occur simultaneously.
[0009] In some embodiments, the differentiation factor is a terminal transcription factor. In some embodiments, the terminal transcription factor is selected from Table 1.
[0010] In some embodiments, the cell cycle is inhibited by one or more of the following: reducing or removing growth factors; reducing serum levels; reducing serum levels below 5%; contacting the cell with a PI3K inhibitor; contacting the cell with an E2F family transcription factor inhibitor; contacting the cell with a Myc inhibitor; contacting the cell with a MAPK inhibitor; contacting the cell with a MEK1/2 inhibitor; contacting the cell with a CDK inhibitor; contacting the cell with an Id inhibitor; contacting the cell with a Rb agonist; contacting the cell with a Ink family agonist; contacting the cell with a Cip/Kip family agonist; and culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta.. In some embodiments, the PI3K inhibitor is LY294002. In some embodiments, the E2F transcription factor inhibitor is HLM006474. In some embodiments, the Myc inhibitor is JQ1 or 10058-F4. In some embodiments, the MAPK inhibitor is PD98059. In some embodiments, the CDK inhibitor is a CDK4 or CDK2 inhibitor. In some embodiments, the CDK inhibitor is p16, p15, p18, or p19. In some embodiments, the CDK inhibitor is p21, p27, or p57.
[0011] In some embodiments, the stem cell is an embryonic stem cell.
[0012] In some embodiments, steps i) and ii) result in a population of cells comprising one or more terminally-differentiated cell types. In some embodiments, steps i) and ii) result in a population of cells comprising no more than 2 terminally-differentiated cell types. In some embodiments, steps i) and ii) result in a population of cells of which at least 50% are terminally-differentiated cells. In some embodiments, steps i) and ii) result in a population of cells of which at least 60% are terminally-differentiated cells. In some embodiments, steps i) and ii) result in a population of cells of which at least 70% are terminally-differentiated cells. In some embodiments, steps i) and ii) result in a population of cells of which at least 80% are terminally-differentiated cells.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIGS. 1A-1C depict an illustrative summary of the proliferation/differentiation network adapted for ES cells. FIG. 1A depicts a schematic reconstructed summary of main network components and interactions in normal somatic cycling cells. Extracellular growth factors (GFs) either purified or in serum activate downstream signaling pathways (PI3K, MAPK), which then trigger a transcriptional activation (Myc, E2F) that drives the core cell cycle machinery (Cyclins and Cyclin-dependent kinases). For a full explanation and justification of the summary see FIGS. 7A-7C. The cellular behavior associated with this model is normal oscillatory cycling. FIG. 1B depicts a schematic of changes to the network that occur during terminal division arrest and differentiation. Cells switch to insulin signaling for survival and growth, and shut down cycling activity. Terminal transcription factors become fully active, leading to complete differentiation. FIG. 1C depicts a schematic composite adaptation of network for ES cells. ES cells are normally maintained by LIF and high serum or LIF and Bmp4. This hyper-activates PI3K, Myc, E2F, CDK2, and Id family activities. Meanwhile, MAPK, CDK4, p16 family, p21 family, and Rb family activities are highly suppressed. This leads to an ultra-rapid proliferation and short G1 phase.
[0014] FIGS. 2A-2B demonstrate that gfactor/serum reduction drives a direct terminal skeletal muscle differentiation program. FIG. 2A depicts a differentiation time course of ES cells to skeletal muscle when exposed to low serum vs high serum conditions. MyoD overexpression was initially induced with tamoxifen starting at Day -1 for 24 hours under ES conditions. LIF was removed at Day 0. Low serum was then initiated at different starting times beginning with Day 0. Cells were then fixed and immunostained for myosin heavy chain (MHC) expression. Differentiating cells in high serum were continuously split to prevent overgrowth. FIG. 2B depicts a comparison of differentiation efficiency generated by two types of defined media (N2B27) and 20% KOSR, low serum media (2% horse serum+insulin), and high serum media (15% FBS). Cells were removed from standard ES media (LIF and serum) and incubated in the specified media starting from Day 0 to Day 4. Continuation of LIF (1000 U/ml) or addition of Bmp4 (10 ng/ml) results in a strong block to muscle differentiation.
[0015] FIG. 3 demonstrates that growth factor/serum withdrawal drives a condensed gene expression program of early Pax3 expression and subsequent MyoG expression, but does not affect kinetics of Oct4 or Nanog loss. Gene expression time courses of differentiation over 7 days. In this experiment, low serum was initiated at Day 0, one day after induction of MyoD expression in ES media, and maintained over the course of differentiation. The rate of decline of Oct4 and Nanog mRNA levels are not strongly affected by cell cycle inhibition. In the muscle regulatory hierarchy, only Pax3 and MyoG are strongly upregulated. Upregulation of additional terminal markers of skeletal muscle terminal differentiation can be found in FIG. 9. Ct values were normalized to glyceraldehyde 3-phosphate dehydrogenase (GADPH). Error values reflect S.E.M. (n=3).
[0016] FIG. 4 demonstrates that specific cell cycle inhibitors have stage and condition-specific effects on Pax3 and MyoG expression. Time courses of differentiation were run for 7 days similarly to the previous growth factor withdrawal experiments. MyoD was induced at Day -1, and LIF was removed at Day 0. Cells were kept in either high serum (15% FBS) or low serum (2% HS+Insulin) media throughout the time course. Drug treatments were applied continuously at the designated concentrations for the entire duration of the time course, with daily media change. mRNA expression levels were measured by qRT-PCR. Pax3 was measured on Day 3 (since it is upregulated early) and MyoG was measured on Day 7 (since it is upregulated late). All measurements are relative to a DMSO control for the specific condition (i.e. low serum values are still higher than in high serum). L=lethal; drug had strong anti-survival effects so no data was collected. Error bars indicate S.E.M. (n=2).
[0017] FIG. 5 demonstrates that in an unguided or heterogeneous differentiation setting, growth factor/serum withdrawal upregulates the expression of numerous genes associated with differentiated cell types. Gene expression time courses of unguided (without MyoD) differentiation after release from ES cell media at Day 0. Low or high serum was applied at Day 0 for the full time course. Upregulated factors include Dll1, Sox6, GATA1, PPAR.gamma., Sox9, Runx2, Mitf, Sox17, and Nkx2.2 (continued in FIG. 10). These genes are involved in the differentiation of multiple cell types, including neurons, chondrocytes, erythrocytes, adipocytes, cardiomyocytes, osteoblasts, melanocytes, and beta-cells. Error values indicate S.E.M. (n=2).
[0018] FIG. 6 demonstrates that use of network-based cell cycle manipulation may provide an alternative strategy to generating terminal cell types that is more efficient than recapitulating embryogenesis. (Top Box) Analytical scheme of how cell cycle states drive activation of a terminal transcription factor. Without wishing to be bound by theory, it is contemplated that in the MyoD overexpression system, transitions from the 3 states of ES to somatic cycling to a terminally differentiated state influence the subsequent activation of MyoD and hence the progression of differentiation. The first transition is correlated with Pax3 activation and the second transition is correlated with MyoG activation. Accelerating the cell cycle transitions accelerates the differentiation process. (Lower Box) Current strategies of differentiating ES cells into cells involves growth-factor based recapitulation of embryogenesis. The alternative strategy described herein (and shown in the case of skeletal muscle), is to artificially induce differentiation by accelerating cell cycle inhibition combined with addition of a terminal transcription factor. Since ES cells are susceptible to cell cycle-related pathways, this permits a faster, more efficient differentiation.
[0019] FIGS. 7A-7C depict schematics of cell cycle control. Schematics are adapted from Morgan, D.O. The cell cycle: principles of control. Sinauer associates, Sunderland, 2007 p. 207-210; which is incorporated by reference herein in its entirety. 1. Growth factors (GFs)/mitogens are received in G1 before the restriction point 2. The immediate-early response genes are initiated in response to mitogens. Myc then induces Cyclin D transcription and E2F activity. Entry into S-phase by Myc requires E2F activity. Myc also can induce Inhibitor of differentiation (Id) family proteins. 3. E2F activity reciprocally promotes Myc activity. Box represents that Myc and E2F share a transcriptional function to activate pro-proliferative genes. 4. MyoD interacts with G1/S transition components in several ways. MyoD directly interacts with Cyclin D/Cdk4, suppressing its activity. MyoD is also phosphorylated by CDKs leading to its ubiquitination and destruction. Rb interacts with MyoD as a co-factor on DNA. Finally, MyoD transcriptionally increases the expression of Rb RNA. 5. Grouped together are family members of the Ink4 CDK inhibitors, Cip/Kip CDK inhibitors, Rb pocket proteins (Rb1, p107, p130), Inhibitor of DNA binding (Id) proteins, and E2F transcription factors. It is recognized that individual family members have unique features, however this complexity is not represented in this model. 6. In mES cells, LIF drives Myc activity through Jak/Stat signaling. LIF also increases PI3K activity. 7. Bmp signaling leads to upregulation of Inhibitor of differentiation (Id) proteins, which are predicted to inhibit Rb and MyoD 8. c-Myc has been observed to bind Rb in vitro, but not in vivo. On the other hand, p107 does interact with Myc in vivo. In mES cells, Myc is expressed at high levels and may be inhibiting Rb family members. 9. In certain cases, Myc or E2F overexpression leads to a reduction in Cyclin D1 levels. It is contemplated that the extra activation of these factors in mES cells decreases Cyclin D1 levels. 10. c-Myc has been suspected to independently suppress myod outside of cell transformation.
[0020] FIG. 8 depicts microscopy images demonstrating the morphology of differentiated muscle myotubes stained for myosin heavy chain and sarcomeric a-actinin. FIG. 8A depicts myosin heavy chain staining is in white coloring in the cytoplasm. Myotubes exhibit an elongated, multinucleated morphology. Arrows point to nuclei in a binucleate myotube. This particular image was taken on day 8 of the low serum time course started on day 0. FIGS. 8B-8D depict sarcomeric a-actinin staining of myofibrillar striations in differentiated myotubes. These particular images were taken on day 13.
[0021] FIG. 9 demonstrates additional muscle genes upregulated by growth factor/serum removal. Microarray data confirm expression of skeletal muscle genes during MyoD differentiation by low serum Desmin (Des), Myosin light chain (Myl1), skeletal muscle actin (Acta1), troponin (Tnnc1), tropomyosin (Tpm1), Mirk/Dyrk1b, and titin (Ttn) get upregulated during the differentiation time course. In this experiment, MyoD overexpression is activated at Day -1 in ES media. LIF is then removed at Day 0 and the media is switched to low serum.
[0022] FIG. 10 demonstrates additional time courses of lineage-specific factors differentiated by low serum and LIF removal (no MyoD).
[0023] FIGS. 11A-11B depict spinal motor neurons. FIG. 11A demonstrates rapid neuron formation from iNIL ES cells Beta-3 tubulin (terminal neuron marker) mRNA expression after 4 days in media of different growth factor content. FIG. 11B depicts a time course of gene expression for neuronal lineage factors and motor neuron terminal differentiation markers in growth factor-free (N2B27) media.
[0024] FIGS. 12A-12B depict cardiomyocytes. FIG. 12A demonstrates rapid kinetics of cardiomyocyte formation from GATA5-overexpressing ES cells. Cardiac troponin (terminal cardiomyocyte marker) mRNA expression after 4 days in media of different growth factor content. FIG. 12B depicts a time course of gene expression for cardiac lineage factors and cardiomyocyte terminal differentiation markers in growth factor-free (N2B27) media.
[0025] FIGS. 13A-13B depict hepatoblast-like cells. FIG. 13A demonstrates hepatoblast formation from Hnf4.alpha.-overexpressing ES cells. Alpha-fetoprotein mRNA expression after 4 days in media of different growth factor content. FIG. 13B depicts a time course of gene expression for hepatic lineage factors and hepatocyte markers in growth factor-free (N2B27) media.
[0026] FIG. 14 depicts pictures of spinal motor neurons. Top: Phase contrast image of Day 5 neurons differentiated in growth factor-free N2B27 media. Bottom: Same neurons immunostained with antibody against neuronal beta3-tubulin (Tubb3).
[0027] FIG. 15 depicts an image of a cluster of cardiomyocytes differentiated after 9 days beating in the dish.
[0028] FIG. 16 depicts pictures of hepatoblast-like cells. Top: Phase contrast image of Day 5 hepatoblast-like cells differentiated in growth factor-free N2B27 media. Image is crowded due to the continued proliferation of these cells in growth factor-free media. Bottom: Same hepatoblast-like cells immunostained with antibody against alpha fetoprotein (AFP
DETAILED DESCRIPTION
[0029] As described herein, the inventors's have found that inhibiting the cell cycle and introducing differentiation factors, when both steps are performed early in the differentiation process, significantly increases the rate of differentiation (e.g. the differentiation of stem cells to terminally differentiated cells). In one aspect, described herein is a method of differentiating a stem cell, the method comprising (i) contacting the stem cell with one or more ectopic differentiation factors and (ii) inhibiting the cell cycle of the stem cell. In some embodiments, the stem cell can be an embryonic stem cell. In some embodiments, the stem cell can be an adult stem cell. In some embodiments, the stem cell can be an induced pluripotent stem cell.
[0030] Accordingly, in some embodiments, step (i) (i.e., contacting the stem cell with one or more ectopic differentiation factors) and step (ii) (i.e., inhibiting the cell cycle of the stem cell) are performed within about 15 days or less of each other, e.g. within about 14 days or less of each other, within about 13 days or less of each other, within about 12 days or less of each other, within about 11 days or less of each other, within about 10 days or less of each other, within about 9 days or less of each other, within about 8 days or less of each other, within about 7 days or less of each other, within about 6 days or less of each other, within about 5 days or less of each other, within about 4 days or less of each other, within about 3 days or less of each other, within about 2 days or less of each other, or within about 1 day or less of each other. In some embodiments, steps (i) and (ii) can be performed about simultaneously.
[0031] In some embodiments, step (i) (i.e., contacting the stem cell with one or more ectopic differentiation factors) and step (ii) (i.e., inhibiting the cell cycle of the stem cell) are performed within 15 days of each other, e.g. within 14 days of each other, within 13 days of each other, within 12 days of each other, within 11 days of each other, within 10 days of each other, within 9 days of each other, within 8 days of each other, within 7 days of each other, within 6 days of each other, within 5 days of each other, within 4 days of each other, within 3 days of each other, within 2 days of each other, or within 1 day (e.g. within 24 hours) of each other. In some embodiments, steps (i) and (ii) can be performed simultaneously.
[0032] In some embodiments, steps (i) and (ii) can both be performed before the stem cell differentiates to an intermediate and/or terminally differentiated cell, e.g. while the stem cell still evidences a stem cell phenotype. In some embodiments, a stem cell can be an undifferentiated cell exhibiting both pluripotency (or totipotent) and capable of self-renewal. In some embodiments, a stem cell can be a cell expressing stem cell markers. Stem cell markers are known in the art and can include, by way of non-limiting example, Nanog, SSEA-1, TDGF-1, Sox2, Oct4, (for further detail see, e.g., Pazhianisamy MATER METHODS 2013 3:200 and Zhao et al. Molecules 2013 17:6196-6236; each of which is incorporated by reference herein in its entirety). Kits for determining if a cell expresses stem cell markers are commercially available, e.g. Cat No. ab109884 from AbCam, Cambridge, Mass.
[0033] As used herein, "ectopic differentiation factor" refers to an ectopic agent that increases and/or promotes the process of differentiation. Ectopic differentiation factors are known in the art and can include, e.g. nucleic acids encoding polypeptides, polypeptides, small molecules, growth factors, cytokines, and the like. The identity of the ectopic differentiation factor will vary according to the type of differentiated cell that is desired. Appropriate ectopic differentiation factors that permit the differentiation of specific differentiated cell types are known in the art, see, e.g. Examples of various differentiation agents are disclosed in U.S. Patent Application Serial No. 2003/0022367, or Gimble et al., 1995; Lennon et al., 1995; Majumdar et al., 1998; Caplan and Goldberg, 1999; Ohgushi and Caplan, 1999; Pittenger et al., 1999; Caplan and Bruder, 2001; Fukuda, 2001; Worster et al., 2001; Zuk et al., 2001; Rosenbauer and Tenen Nature Reviews Immunology 2007 7:105-117; Hughes et al. Periodontology 2006 41:48-72; Loregger et al. Placenta 2003 A:S104-110; Florini et al. Ann Rev of Physiology 1991 53:201-216; Yamamizu et al. Stem Cell Reports 2013 1:545-559; James. Scientifica 2013 684736; and Mummery et al. Circulation Research 2012 111:344-358; each of which is incorporated by reference herein in its entirety.
[0034] In some embodiments, the ectopic differentiation factor can be a terminal transcription factor. As used herein, the term "terminal transcription factor" refers to a transcription factor that promotes the differentiation of a stem cell and/or intermediate or partially differentiated cell into a terminally differentiated cell. A cell that is contacted with a terminal transcription factor can be contacted with either an ectopic nucleic acid encoding a terminal transcription factor and/or an ectopic terminal transcription factor polypeptide.
[0035] Terminal transcription factors, and the differentiated phenotypes they promote are known in the art. Non-limiting examples of terminal transcription factors can include MyoD; MyoG, Myf5, Mrf4, Ngn family (e.g. Ngn1-3), NeuroD family (e.g. NeuroD1-3), Ascl family (e.g. Ascl1-2), Hb9, Zic1, Brn2, Mytl1, Nurr1, Lmx1a, Gata family (e.g. Gata1, 2, 4, 5, 6), Tbx5, Mef2 family (e.g. Mef2a,b,c), Mesp1, Hnf/FoxA family (e.g. Hnf4.alpha., FoxA2), Pdx1, MafA, Runx family (e.g. Runx2, Runx1t1), Mitf, Spi1, Nkx family (e.g. Nkx2.1, 2.2), C/EBP family (e.g. C/EBP.alpha., .beta.) Prdm family (e.g. Prdm1, 16), PPAR.gamma., Scl, Lmo2, Ldb1, E2A, Ebf, Sox9, Hlf, Prdm5, Pbx1, Zfp37, Isl1, Lhx3, Phox2a, Fezf2, Olig family (e.g. 1 and 2), Elf5, Irf2, Elf1, Tgif1, Ets1, Sox family (e.g. Sox4, 6, 9, 17), Bach2, Cdx2, Smyd1, Pax family (e.g. Pax3, 6, 7), Klf family (e.g. Klf4), basic helix-loop-helix factors. A non-limiting list of exemplary terminal transcription factors is provided in Table 1.
TABLE-US-00001 TABLE 1 Exemplary Terminal Transcription Factors Exemplary Associated Terminal Transcription NCBI Gene ID for Differentiated Cell Type Factor Human Gene Myoblast MyoD 4654 MyoG 4656 Myf5 4617 Mrf4 4618 Gata4 2626 Tbx5 6910 Mef2a 4205 Mef2b 100271849 Mef2c 4208 Mesp1 55897 Pax7 5081 Smyd1 150572 Neuron Ngn1 4762 Ngn2 63973 Ngn3 50674 NeuroD1 4760 NeuroD2 4761 NeuroD3 4762 Ascl1 429 Ascl2 430 Zic1 7545 Brn2 5454 Nurr1 4929 Mytl1 23040 Lmx1a 4009 Hlf 3131 Zfp37 7539 Phox2a 401 Fezf2 55079 Motor neurons/Pancreatic Hb9 3110 cells Isl1 3670 Erythroid Gata1 2623 Ldb1 8861 Haemotopoietic and Gata2 2624 Endocrine lineages Myocardial and endodermal Gata5 140628 lineages Endodermal and Gata6 2627 Mesodermal lineages Hepatocyte (also liver, Hnf4.alpha. 3172 kidney, & intestinal cells) Hepatocytes FoxA2 3170 Pancreatic Pdx1 3651 MafA 389692 Osteoblast Runx2 860 Prdm5 11107 Pbx1 5087 Melanocytes Mitf 4286 Myeloid, B lymphoid Spi1 6688 Thyroid Nkx2.1 7080 Central Nervous System Nkx2.2 4821 Adipocytes C/EBP.alpha. 1050 Prdm16 63976 C/EBP.beta. 1051 PPAR.gamma. 5468 Trophoblasts, plasma cells Prdm1 639 Osteoblast, neurons, Scl 6886 haemotopoietic lineages Haemotopoietic Lmo2 4005 Runx1t1 862 Bach2 60468 Irf2 3660 Sox4 6659 Lymphocytes E2A 6929 Elf1 1997 B cells Ebf 1879 Chondrocytes Sox9 6662 Motor Neurons Lhx3 8022 Oligodendrocytes Olig1 116448 Olig2 10215 Epithelial lineage Elf5 2001 Klf4 9314 Myeloid Tgif1 7050 Haemotopoietic and Ets1 2113 Epithelial lineages Neurons and chondrocytes Sox6 55553 Endoderm and Sox17 64321 Haemotopoietic lineages Intestinal Cdx2 1045 Muscle cells Pax3 5077 Nervous system and eye Pax6 5080 cells Skeletal muscle cells MyoD 4654 Spinal motor neurons Ngn2 63973 Isl1 3670 Lhx3 8022 Cardiomyocytes Gata5 140628 Hepatocytes/Hepatoblasts Hnf4.alpha. 3172
[0036] In some embodiments, the stem cell is to be differentiated to a skeletal muscle phenotype and is contacted with the terminal transcription factor MyoD. In some embodiments, the stem cell is to be differentiated to a skeletal muscle phenotype and is contacted with the terminal transcription factor MyoD and the cell cycle is inhibited by reducing or removing growth factors. In some embodiments, the stem cell is to be differentiated to a skeletal muscle phenotype and is contacted with the terminal transcription factor MyoD and the cell cycle is inhibited by culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta.. In some embodiments, the stem cell is to be differentiated to a skeletal muscle phenotype and is contacted with the terminal transcription factor MyoD and the cell cycle is inhibited by culturing the cell in a media lacking LIF.
[0037] In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with a terminal transcription factor selected from the group consisting of: Ngn2; Isl1; and Lhx3. In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with a terminal transcription factor selected from the group consisting of: Ngn2; Isl1; and Lhx3 and the cell cycle is inhibited by reducing or removing growth factors. In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with a terminal transcription factor selected from the group consisting of: Ngn2; Isl1; and Lhx3 and the cell cycle is inhibited by culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta.. In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with a terminal transcription factor selected from the group consisting of: Ngn2; Isl1; and Lhx3 and the cell cycle is inhibited by culturing the cell in a media lacking LIF. In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with the terminal transcription factors Ngn2; Isl1; and Lhx3. In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with the terminal transcription factors Ngn2; Isl1; and Lhx3 and the cell cycle is inhibited by reducing or removing growth factors. In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with the terminal transcription factors Ngn2; Isl1; and Lhx3 and the cell cycle is inhibited by culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta.. In some embodiments, the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with the terminal transcription factors Ngn2; Isl1; and Lhx3 and the cell cycle is inhibited by culturing the cell in a media lacking LIF.
[0038] In some embodiments, the stem cell is to be differentiated to a cardiomyocyte phenotype and is contacted with the terminal transcription factor Gata5. In some embodiments, the stem cell is to be differentiated to a cardiomyocyte phenotype and is contacted with the terminal transcription factor Gata5 and the cell cycle is inhibited by reducing or removing growth factors. In some embodiments, the stem cell is to be differentiated to a cardiomyocyte phenotype and is contacted with the terminal transcription factor Gata5 and the cell cycle is inhibited by culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta.. In some embodiments, the stem cell is to be differentiated to a cardiomyocyte phenotype and is contacted with the terminal transcription factor Gata5 and the cell cycle is inhibited by culturing the cell in a media lacking LIF.
[0039] In some embodiments, the stem cell is to be differentiated to a hepatocyte or hepatoblast phenotype and is contacted with the terminal transcription factor Hnf4.alpha.. In some embodiments, the stem cell is to be differentiated to a hepatocyte or hepatoblast phenotype and is contacted with the terminal transcription factor Hnf4.alpha. and the cell cycle is inhibited by reducing or removing growth factors. In some embodiments, the stem cell is to be differentiated to a hepatocyte or hepatoblast phenotype and is contacted with the terminal transcription factor Hnf4.alpha. and the cell cycle is inhibited by culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta.. In some embodiments, the stem cell is to be differentiated to a hepatocyte or hepatoblast phenotype and is contacted with the terminal transcription factor Hnf4.alpha. and the cell cycle is inhibited by culturing the cell in a media lacking LIF.
[0040] In some embodiments, the ectopic differentiation factor can be a polypeptide. In some embodiments, the ectopic differentiation factor can be a terminal transcription factor polypeptide. In some embodiments, the ectopic differentiation factor can be a variant of a terminal transcription factor polypeptide. In some embodiments, the ectopic differentiation factor can be a functional fragment of a terminal transcription factor polypeptide.
[0041] As used herein, a given "polypeptide" can include the human polypeptide, as well as homologs from other species, including but not limited to bovine, dog, cat chicken, murine, rat, porcine, ovine, turkey, horse, fish, baboon and other primates. The terms also refer to fragments or variants of a polypeptide that maintain at least 50% of the activity or effect, e.g. transcriptional activation and/or suppression of a full-length polypeptide. Conservative substitution variants that maintain the activity of wildtype polypeptides will include a conservative substitution as defined herein. The identification of amino acids most likely to be tolerant of conservative substitution while maintaining at least 50% of the activity of the wildtype is guided by, for example, sequence alignment with homologs or paralogs from other species Amino acids that are identical between homologs are less likely to tolerate change, while those showing conservative differences are obviously much more likely to tolerate conservative change in the context of an artificial variant. Similarly, positions with non-conservative differences are less likely to be critical to function and more likely to tolerate conservative substitution in an artificial variant. Variants, fragments, and/or fusion proteins can be tested for activity, for example, by transcriptional activity assays and/or differentiation assays.
[0042] In some embodiments, the variant is a conservative substitution variant. Variants can be obtained by mutations of native nucleotide sequences, for example. A "variant," as referred to herein, is a polypeptide substantially homologous to a native or reference polypeptide, but which has an amino acid sequence different from that of the native or reference polypeptide because of one or a plurality of deletions, insertions or substitutions. Polypeptide-encoding DNA sequences encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to a native or reference DNA sequence, but that encode a variant protein or fragment thereof that retains the relevant biological activity relative to the reference protein, e.g., at least 50% of an activity of the wildtype polypeptide. As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters a single amino acid or a small percentage, (i.e. 5% or fewer, e.g. 4% or fewer, or 3% or fewer, or 1% or fewer) of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. It is contemplated that some changes can potentially improve the relevant activity, such that a variant, whether conservative or not, has more than 100% of the activity of the wildtype polypeptide, e.g. 110%, 125%, 150%, 175%, 200%, 500%, 1000% or more.
[0043] One method of identifying amino acid residues which can be substituted is to align, for example, a human polypeptide with a homolog from one or more non-human species. Alignment can provide guidance regarding not only residues likely to be necessary for function but also, conversely, those residues likely to tolerate change. Where, for example, an alignment shows two identical or similar amino acids at corresponding positions, it is more likely that that site is important functionally. Where, conversely, alignment shows residues in corresponding positions to differ significantly in size, charge, hydrophobicity, etc., it is more likely that that site can tolerate variation in a functional polypeptide. The variant amino acid or DNA sequence can be at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more, identical to a native or reference sequence, or a nucleic acid encoding one of those amino acid sequences. The degree of homology (percent identity) between a native and a mutant sequence can be determined, for example, by comparing the two sequences using freely available computer programs commonly employed for this purpose on the world wide web. The variant amino acid or DNA sequence can be at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more, similar to the sequence from which it is derived (referred to herein as an "original" sequence). The degree of similarity (percent similarity) between an original and a mutant sequence can be determined, for example, by using a similarity matrix. Similarity matrices are well known in the art and a number of tools for comparing two sequences using similarity matrices are freely available online, e.g. BLASTp (available on the world wide web at http://blast.ncbi.nlm.nih.gov), with default parameters set.
[0044] A given amino acid can be replaced by a residue having similar physiochemical characteristics, e.g., substituting one aliphatic residue for another (such as Ile, Val, Leu, or Ala for one another), or substitution of one polar residue for another (such as between Lys and Arg; Glu and Asp; or Gln and Asn). Other such conservative substitutions, e.g., substitutions of entire regions having similar hydrophobicity characteristics, are well known. Polypeptides comprising conservative amino acid substitutions can be tested in any one of the assays described herein to confirm that a desired activity of a native or reference polypeptide is retained. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles consistent with the disclosure. Typically conservative substitutions for one another include: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).
[0045] Any cysteine residue not involved in maintaining the proper conformation of the polypeptide also can be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Conversely, cysteine bond(s) can be added to the polypeptide to improve its stability or facilitate oligomerization.
[0046] In some embodiments, a polypeptide, can comprise one or more amino acid substitutions or modifications. In some embodiments, the substitutions and/or modifications can prevent or reduce proteolytic degradation and/or prolong half-life of the polypeptide. In some embodiments, a polypeptide can be modified by conjugating or fusing it to other polypeptide or polypeptide domains such as, by way of non-limiting example, transferrin (WO06096515A2), albumin (Yeh et al., 1992), growth hormone (US2003104578AA); cellulose (Levy and Shoseyov, 2002); and/or Fc fragments (Ashkenazi and Chamow, 1997). The references in the foregoing paragraph are incorporated by reference herein in their entireties.
[0047] In some embodiments, a polypeptide as described herein can comprise at least one peptide bond replacement. A polypeptide as described herein can comprise one type of peptide bond replacement or multiple types of peptide bond replacements, e.g. 2 types, 3 types, 4 types, 5 types, or more types of peptide bond replacements. Non-limiting examples of peptide bond replacements include urea, thiourea, carbamate, sulfonyl urea, trifluoroethylamine, ortho-(aminoalkyl)-phenylacetic acid, para-(aminoalkyl)-phenylacetic acid, meta-(aminoalkyl)-phenylacetic acid, thioamide, tetrazole, boronic ester, olefinic group, and derivatives thereof.
[0048] In some embodiments, a polypeptide, as described herein can comprise naturally occurring amino acids commonly found in polypeptides and/or proteins produced by living organisms, e.g. Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M), Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q), Asp (D), Glu (E), Lys (K), Arg (R), and His (H). In some embodiments, a polypeptide as described herein can comprise alternative amino acids. Non-limiting examples of alternative amino acids include, D-amino acids; beta-amino acids; homocysteine, phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine (3-mercapto-D-valine), ornithine, citruline, alpha-methyl-alanine, para-benzoylphenylalanine, para-amino phenylalanine, p-fluorophenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine), diaminobutyric acid, 7-hydroxy-tetrahydroisoquinoline carboxylic acid, naphthylalanine, biphenylalanine, cyclohexylalanine, amino-isobutyric acid, norvaline, norleucine, tert-leucine, tetrahydroisoquinoline carboxylic acid, pipecolic acid, phenylglycine, homophenylalanine, cyclohexylglycine, dehydroleucine, 2,2-diethylglycine, 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1-cyclohexanecarboxylic acid, amino-benzoic acid, amino-naphthoic acid, gamma-aminobutyric acid, difluorophenylalanine, nipecotic acid, alpha-amino butyric acid, thienyl-alanine, t-butylglycine, trifluorovaline; hexafluoroleucine; fluorinated analogs; azide-modified amino acids; alkyne-modified amino acids; cyano-modified amino acids; and derivatives thereof.
[0049] In some embodiments, a polypeptide can be modified, e.g. by addition of a moiety to one or more of the amino acids that together comprise the peptide. In some embodiments, a polypeptide as described herein can comprise one or more moiety molecules, e.g. 1 or more moiety molecules per polypeptide, 2 or more moiety molecules per polypeptide, 5 or more moiety molecules per polypeptide, 10 or more moiety molecules per polypeptide or more moiety molecules per polypeptide. In some embodiments, a polypeptide as described herein can comprise one more types of modifications and/or moieties, e.g. 1 type of modification, 2 types of modifications, 3 types of modifications or more types of modifications. Non-limiting examples of modifications and/or moieties include PEGylation; glycosylation; HESylation; ELPylation; lipidation; acetylation; amidation; end-capping modifications; cyano groups; phosphorylation; albumin, and cyclization. In some embodiments, an end-capping modification can comprise acetylation at the N-terminus, N-terminal acylation, and N-terminal formylation. In some embodiments, an end-capping modification can comprise amidation at the C-terminus, introduction of C-terminal alcohol, aldehyde, ester, and thioester moieties. The half-life of a polypeptide can be increased by the addition of moieties, e.g. PEG, albumin, or other fusion partners (e.g. Fc fragment of an immunoglobin).
[0050] In some embodiments, the polypeptide can be a functional fragment of one of the amino acid sequences described herein. As used herein, a "functional fragment" is a fragment or segment of a polypeptide which retains the activity, e.g. the transcriptional activity, of the wildtype polypeptide. A functional fragment can comprise conservative substitutions of the sequences disclosed herein.
[0051] Alterations of the original amino acid sequence can be accomplished by any of a number of techniques known to one of skill in the art. Mutations can be introduced, for example, at particular loci by synthesizing oligonucleotides containing a mutant sequence, flanked by restriction sites permitting ligation to fragments of the native sequence. Following ligation, the resulting reconstructed sequence encodes an analog having the desired amino acid insertion, substitution, or deletion. Alternatively, oligonucleotide-directed site-specific mutagenesis procedures can be employed to provide an altered nucleotide sequence having particular codons altered according to the substitution, deletion, or insertion required. Techniques for making such alterations include those disclosed by Khudyakov et al. "Artificial DNA: Methods and Applications" CRC Press, 2002; Braman "In Vitro Mutagenesis Protocols" Springer, 2004; and Rapley "The Nucleic Acid Protocols Handbook" Springer 2000; which are herein incorporated by reference in their entireties. In some embodiments, a polypeptide as described herein can be chemically synthesized and mutations can be incorporated as part of the chemical synthesis process.
[0052] In some embodiments, a cell can be contacted with multiple ectopic differentiation factors, e.g. two or more terminal transcription factors, or a terminal transcription factor and cytokine.
[0053] As used herein "cell cycle" refers to the series of events involving the growth, replication, and division of a eukaryotic cell. A "phase of a cell cycle" or "cell cycle phase" refers to a distinct phase or period of the cell cycle, such as the mitosis phase (M phase), the first gap phase (G1 phase), the DNA synthesis phase (S phase), and the second gap phase (G2 phase). A "complete cell cycle" refers to entire single cell cycle including a G1 phase, S phase, G2 phase, and an M phase. Analysis of a complete cell cycle does not require beginning at a particular phase within the cell cycle. For example, a "complete cellcycle phase" may begin with an S phase and end at completion of G1 phase, or likewise, a "complete cell cycle phase" may begin with an M phase and end with completion of G2 phase Inhibition of the cell cycle can comprise slowing the progression of a cell through the cycle, slowing the progression of a cell through a particular stage of the cell cycle, and/or arresting the cell at a particular point in the cell cycle. Slowing the progression of the cell constitutes a decrease in the rate at which the cell progresses through the cell cycle.
[0054] Methods of inhibiting the cell cycle can comprise contacting the cell with an agent that inhibits the cell cycle and/or removing an agent that promotes progression through the cell cycle. Agents for promoting or inhibiting cell cycle progression are known in the art. By way of non-limiting example, the cell cycle can be inhibited by: reducing or removing growth factors; reducing serum levels; reducing serum levels below about 5%; reducing serum levels below 5%; contacting the cell with a PI3K inhibitor; contacting the cell with an E2F family transcription factor inhibitor; contacting the cell with a Myc inhibitor; contacting the cell with a MAPK inhibitor; contacting the cell with a MEK1/2 inhibitor; contacting the cell with a CDK inhibitor; contacting the cell with an Id inhibitor; contacting the cell with a Rb agonist; contacting the cell with a Ink family agonist; contacting the cell with a Cip/Kip family agonist; culturing the cell in a media lacking a factor selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta..
[0055] As used herein, the term "inhibitor" refers to an agent which can decrease the expression and/or activity of the targeted expression product (e.g. mRNA encoding the target or a target polypeptide), e.g. by at least 10% or more, e.g. by 10% or more, 50% or more, 70% or more, 80% or more, 90% or more, 95% or more, or 98% or more. The efficacy of an inhibitor, e.g. its ability to decrease the level and/or activity of the target, can be determined, e.g. by measuring the level of an expression product of and/or the activity of the target. Methods for measuring the level of a given mRNA and/or polypeptide are known to one of skill in the art, e.g. RTPCR can be used to determine the level of RNA and Western blotting with an antibody can be used to determine the level of a polypeptide. The activity of a target can be determined using methods known in the art and described herein, e.g. transcriptional activity assays. In some embodiments, the inhibitor can be an inhibitory nucleic acid; an aptamer; an antibody reagent; an antibody; or a small molecule.
[0056] As used herein, the term "agonist" refers to any agent that increases the level and/or activity of the target, e.g, of Rb, Ink family polypeptides, and/or Cip/Kip family polypeptides. As used herein, the term "agonist" refers to an agent which increases the expression and/or activity of the target by at least 10% or more, e.g. by 10% or more, 50% or more, 100% or more, 200% or more, 500% or more, or 1000% or more.
[0057] Phosphoinositide 3-kinases are a family of related enzymes that are capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol. They are also known as phosphatidylinositol-3-kinases. PI3Ks interact with the IRS (Insulin receptor substrate) in order to regulate glucose uptake through a series of phosphorylation events. The phosphoinositol-3-kinase family is composed of Class I, II and Class III, with Class I the only ones able to convert PI(4,5)P2 to PI(3,4,5)P3 on the inner leaflet of the plasma membrane. As used herein, a "PI3K inhibitor" refers to an agent that inhibits the activity of PI3K, as measured by the level of phosphorylation of the 3 position hydroxyl group of the inositol ring of phosphatidylinositol, or as measured by the activity and/or phosphorylation (where increased phosphorylation indicates PI3K activity) of molecules downstream of PI3K. Examples of such downstream molecules are known in the art and can include, but are not limited to AKT, SGK, mTOR, GSK3.beta., PSD-95, S6, and 4EBP1. Methods of measuring the activity of PI3K, directly or indirectly are well known in the art, and include, by way of non-limiting example determining the level of phosphorylation of a molecule downstream of PI3K using phospho-isoform specific antibodies, which are commercially available (e.g. anti-phospho-AKT antibody, Cat No. ab66138 Abcam, Cambridge, Mass.). Non-limiting examples of PI3K inhibitors can include LY294002; BGT226; BEZ235; PI103, PI828. wortmannin, demethoxyviridin, IC486068, IC87114, GDC-0941, perifosine, CAL101, PX-866, IPI-145, BAY 80-6946, P6503, TGR1202, SF1126, INK1117, BKM120, IL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, TG100-115, CAL263, GNE-447, CUDC-907, and AEZS-136.
[0058] An inhibitor of E2F family transcription factors can be an agent that inhibits the activity of a E2F transcription factor, as measured by the level of transcription of E2F targets (e.g. CCNA1, MYB, EB1, BRCA1, and TP53). Assays for E2F activity are known in the art and are commercially available (e.g. Cat. No. CCS-003L, Qiagen Valencia, Calif.). Non-limiting examples of E2F family transcription factors can include HLM006474.
[0059] An inhibitor of Myc can be an agent that inhibits the activity and/or level of Myc. Myc is a transcription factor that participates in cell proliferation and DNA replication. The sequence of Myc is known in a number of species, e.g. human Myc (NCBI Gene ID: 4609) mRNA (NCBI Ref Seq: NM 002467 (SEQ ID NO: 85)) and polypeptide (NP 002458 (SEQ ID NO: 86)) sequences. Myc activity can be measured, e.g. by the level of transcription of genes activated (e.g. CDK or MNT) or suppressed (e.g. Miz1) by Myc. Assays for Myc activity are known in the art and are commercially available (e.g. Cat. No. CCS-012L; Qiagen Valencia, Calif.). Non-limiting examples of Myc inhibitors can include JQ1; 10058-F4; and CAS 403811-55-21.
[0060] An inhibitor of MAPK can be an agent that inhibits the activity of a mitogen-activated protein kinase (MAPK), as measured by the level of phosphorylation of MAPK targets (e.g. ELK1 is a substrate of ERK1 and MK2 and MK3 are targets of p38 kinases). Assays for MAPK activity are known in the art and are commercially available (e.g. Cat. No. CS0250 from Sigma-Aldrich, St. Louis, Mo.). Non-limiting examples of MAPK inhibitors can include PD98059; SB203580; SB202190; and SP600125.
[0061] An inhibitor of CDK can be an agent that inhibits the activity of a cyclin-dependent kinase (CDK), as measured by the level of phosphorylation of CDK targets (e.g. CDK2 targets Rb, p53 and E2F are substrates of CDK2 and RB1 and MEP50 are substrates of CDK4). Assays for CDK activity are known in the art and are commercially available (e.g. Cat. No. PV3343 Invitrogen, Carlsbad, Calif.). In some embodiments, an inhibitor of CDK can inhibit CDK4 and/or CDK2. In some embodiments, an inhibitor of CDK can specifically inhibit CDK4 and/or CDK2. Non-limiting examples of CDK inhibitors can include p16; p15; p18; p19; p21; p27; p57; p1446A-05; PD-0332991; flavopiridol; aloisine A; AT7519; BS-181; butyrolactone I; purvalanol A; pruvalanol B; roscovitine; and WHI-P180.
[0062] An inhibitor of Id can be an agent that inhibits the level and/or activity of inhibitor of DNA binding 1 (Id). Id forms heterodimers with helix-loop-helix transcription factors and inhibits their activity. The sequence of Id is known in a number of species, e.g. human Id (NCBI Gene ID: 3397) mRNA (NCBI Ref Seq: NM_002165 (SEQ ID NO: 87)) and polypeptide (NP_002156 (SEQ ID NO: 88)) sequences. Id activity can be measured, e.g. by measuring the inhibition of DNA binding and/or transcriptional activation of helix-loop-helix transcription factors that can bind with Id. Non-limiting examples of Id inhibitors can include caveolin-1.
[0063] An agonist of Rb can be an agent that increases the level and/or activity of retinoblastoma 1 (Rb). Rb binds to and inhibits E2F transcription factors, thereby preventing progress through the cell cycle. The sequence of Rb is known in a number of species, e.g. human Rb (NCBI Gene ID: 5925) mRNA (NCBI Ref Seq: NM_000321 (SEQ ID NO: 89)) and polypeptide (NP_000312 (SEQ ID NO: 90)) sequences. Rb activity can be measured, e.g., by measuring binding to E2F transcription factors and/or transcription of E2F factors. Non-limiting examples of agonists of Rb can include Rb polypeptides or agonist fragments thereof and nucleic acids encoding a Rb polypeptide.
[0064] An agonist of Ink family proteins can be an agent that increase the level and/or activity of Ink family proteins (e.g. INK4 family, INK4A (NCBI Gene ID: 1029 (SEQ ID NOS 91-92)), INK4B (NCBI Gene ID: 1030 (SEQ ID NOS 93-94)), INK4C (NCBI Gene ID: 1031 (SEQ ID NOS 95-96)), and INK4D (NCBI Gene ID: 1032 (SEQ ID NOS 97-98))). INK family proteins bind and inhibit CDK4 and CDK6. Ink protein activity can be measured by measuring, e.g. the activity of CDK4 and/or CDK6 as described elsewhere herein and/or binding to CDK4 and/or CDK6. Non-limiting examples of agonists of Ink family polypeptides can include Ink family polypeptides or agonist fragments thereof and nucleic acids encoding an Ink family polypeptide.
[0065] An agonist of Cip/Kip family proteins can be an agent that increase the level and/or activity of Cip/Kip family proteins (e.g. Cip/Kip family, KIP1 (NCBI Gene ID: 1027 (SEQ ID NOS 99-100)), KIP2 (NCBI Gene ID: 1028 (SEQ ID NOS 101-102)), and CIP1 (NCBI Gene ID: 1026 (SEQ ID NOS 103-104))). Cip/Kip family proteins bind and inhibit CDK2. Cip/Kip protein activity can be measured by measuring, e.g. the activity of CDK2 as described elsewhere herein. Non-limiting examples of agonists of Cip/Kip family polypeptides can include Cip/Kip family polypeptides or agonist fragments thereof and nucleic acids encoding an Cip/Kip family polypeptide.
[0066] In some embodiments, inhibition of the cell cycle can be accomplished by removing and/or reducing the level of growth and/or signaling factors, e.g. by culturing the cell in media lacking or having reduced levels of one or more growth and/or signaling factors that promote the cell cycle. Non-limiting examples of such growth and/or signaling factors can include LIF (e.g., NCBI Gene ID: 3976 (SEQ ID NOS 105-106)), Bmp (e.g. NCBI Gene ID: 649 (SEQ ID NOS 107-108), 650 (SEQ ID NOS 109-110), 651 (SEQ ID NOS 111-112), 652 (SEQ ID NOS 113-114), 653 (SEQ ID NOS 115-116), 654 (SEQ ID NOS 117-118), 655 (SEQ ID NOS 119-120), 6565 (SEQ ID NOS 121-122), 51423 (SEQ ID NOS 123-124), and 27302 (SEQ ID NOS 125-126)), Fgf (e.g. one or more of NCBI Gene IDs: 2252 (SEQ ID NOS 127-128), 2255 (SEQ ID NOS 129-130), 9965 (SEQ ID NOS 131-132), 2249 (SEQ ID NOS 133-134), 2248 (SEQ ID NOS 135-136), 2257 (SEQ ID NOS 137-138), 8822 (SEQ ID NOS 139-140), 2251 (SEQ ID NOS 141-142), 27006 (SEQ ID NOS 143-144), 2256 (SEQ ID NOS 145-146), 2247 (SEQ ID NOS 147-148), 8074 (SEQ ID NOS 149-150), 2246 (SEQ ID NOS 151-152), 26291 (SEQ ID NOS 153-154), 2253 (SEQ ID NOS 155-156), 2254 (SEQ ID NOS 157-158), 2250 (SEQ ID NOS 159-160), 2258 (SEQ ID NOS 161-162), 8817 (SEQ ID NOS 163-164), 26281 (SEQ ID NOS 165-166), and 2259 (SEQ ID NOS 167-168)) Avtivin (e.g., NBCI Gene ID: 3624 (SEQ ID NOS 169-170)), and TGF.beta. (e.g. one or more of NCBI Gene IDs: 7040 (SEQ ID NOS 171-172), 7042 (SEQ ID NOS 173-174), 7043 (SEQ ID NOS 175-176), and 7044 (SEQ ID NOS 177-178)). In some embodiments, inhibiting the cell cycle can comprise culturing the cell in a media lacking one or more factors selected from the group consisting of: LIF; Bmp; Fgf; Activin; or TGF.beta., e.g. lacking 1 of the factors, 2 of the factors, 3 of the factors, 4 of the factors, 5 of the factors, or more of the factors.
[0067] In some embodiments, contacting a cell with an agent can comprise contacting the cell with one dose of the agent. In some embodiments, contacting a cell with an agent can comprise contacting the cell with repeated doses of the agent. In some embodiments, contacting a cell with an agent can comprise maintaining a given concentration of the agent in the cell's environment, e.g. in the culture media. In some embodiments, contacting a cell with an agent can comprise maintaining at least a given minimum concentration of the agent in the cell's environment, e.g. in the culture media.
[0068] In some embodiments, the methods described herein can result in a population of cells comprising one or more terminally-differentiated cell types, e.g. 1 terminally-differentiated cell type, 2 terminally-differentiated cell types, 3 terminally-differentiated cell types, 4 terminally-differentiated cell types, 5 terminally-differentiated cell types, or more terminally-differentiated cell types. When discussing a population of cells that results from the methods described herein, the resulting population can be the population of cells existing at about 1 day to about 30 days after both steps (i) and (ii) have been performed.
[0069] In some embodiments, the methods described herein can result in a population of cells comprising no more than 2 terminally-differentiated cell types, e.g. 1 terminally-differentiated cell type or 2 terminally-differentiated cell types.
[0070] In some embodiments, the methods described herein can result in a population of cells of which at least about 50% of the cells are terminally-differentiated cell, e.g. about 50% or more of the cells are terminally-differentiated cells, about 60% or more of the cells are terminally-differentiated cells, about 70% or more of the cells are terminally-differentiated cells, about 80% or more of the cells are terminally-differentiated cells, about 90% or more of the cells are terminally-differentiated cells, about 95% or more of the cells are terminally-differentiated cells, or about 98% or more of the cells are terminally-differentiated cells. In some embodiments, the methods described herein can result in a population of cells of which at least 50% of the cells are terminally-differentiated cell, e.g. 50% or more of the cells are terminally-differentiated cells, 60% or more of the cells are terminally-differentiated cells, 70% or more of the cells are terminally-differentiated cells, 80% or more of the cells are terminally-differentiated cells, 90% or more of the cells are terminally-differentiated cells, 95% or more of the cells are terminally-differentiated cells, or 98% or more of the cells are terminally-differentiated cells.
[0071] Differentiated cells obtained in accordance with the methods described herein can be used, e.g. for cell therapy, autologous cell therapy, transplantation, wound healing or repair, in vitro studies of cell function, cell growth, cell differentiation, and/or screens for modulators of cell function and behavior (e.g. therapeutics, drug candidates, inhibitors or agonists of growth, function, and differentiation).
[0072] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. 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. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.
[0073] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here.
[0074] The terms "decrease", "reduced", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. In some embodiments, "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reduction" or "inhibition" does not encompass a complete inhibition or reduction as compared to a reference level. "Complete inhibition" is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.
[0075] The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, an "increase" is a statistically significant increase in such level.
[0076] As used herein, "contacting" refers to any suitable means for delivering, or exposing, an agent to at least one cell. Exemplary delivery methods include, but are not limited to, direct delivery to cell culture medium, perfusion, injection, or other delivery method well known to one skilled in the art.
[0077] The term "agent" refers generally to any entity which is normally not present or not present at the levels being administered to a cell, tissue or subject. An agent can be selected from a group including but not limited to: polynucleotides; polypeptides; small molecules; and antibodies or antigen-binding fragments thereof. A polynucleotide can be RNA or DNA, and can be single or double stranded, and can be selected from a group including, for example, nucleic acids and nucleic acid analogues that encode a polypeptide. A polypeptide can be, but is not limited to, a naturally-occurring polypeptide, a mutated polypeptide or a fragment thereof that retains the function of interest. Further examples of agents include, but are not limited to a nucleic acid aptamer, peptide-nucleic acid (PNA), locked nucleic acid (LNA), small organic or inorganic molecules; saccharide; oligosaccharides; polysaccharides; biological macromolecules, peptidomimetics; nucleic acid analogs and derivatives; extracts made from biological materials such as bacteria, plants, fungi, or mammalian cells or tissues and naturally occurring or synthetic compositions. An agent can be applied to the media, where it contacts the cell and induces its effects. Alternatively, an agent can be intracellular as a result of introduction of a nucleic acid sequence encoding the agent into the cell and its transcription resulting in the production of the nucleic acid and/or protein environmental stimuli within the cell. In some embodiments, the agent is any chemical, entity or moiety, including without limitation synthetic and naturally-occurring non-proteinaceous entities. In certain embodiments the agent is a small molecule having a chemical moiety selected, for example, from unsubstituted or substituted alkyl, aromatic, or heterocyclyl moieties including macrolides, leptomycins and related natural products or analogues thereof. Agents can be known to have a desired activity and/or property, or can be selected from a library of diverse compounds. As used herein, the term "small molecule" can refer to compounds that are "natural product-like," however, the term "small molecule" is not limited to "natural product-like" compounds. Rather, a small molecule is typically characterized in that it contains several carbon-carbon bonds, and has a molecular weight more than about 50, but less than about 5000 Daltons (5 kD). Preferably the small molecule has a molecular weight of less than 3 kD, still more preferably less than 2 kD, and most preferably less than 1 kD. In some cases it is preferred that a small molecule have a molecular mass equal to or less than 700 Daltons.
[0078] As used herein, "ectopic" refers to a substance that is found in an unusual location and/or amount. An ectopic substance can be one that is normally found in a given cell, but at a much lower amount and/or at a different time.
[0079] As used herein, the terms "protein" and "polypeptide" are used interchangeably herein to designate a series of amino acid residues, connected to each other by peptide bonds between the alpha-amino and carboxy groups of adjacent residues. The terms "protein", and "polypeptide" refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of its size or function. "Protein" and "polypeptide" are often used in reference to relatively large polypeptides, whereas the term "peptide" is often used in reference to small polypeptides, but usage of these terms in the art overlaps. The terms "protein" and "polypeptide" are used interchangeably herein when referring to a gene product and fragments thereof. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing.
[0080] The polypeptides of the present invention can be synthesized by using well known methods including recombinant methods and chemical synthesis. Recombinant methods of producing a polypeptide through the introduction of a vector including nucleic acid encoding the polypeptide into a suitable host cell are well known in the art, e.g., as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d Ed, Vols 1 to 8, Cold Spring Harbor, N.Y. (1989); M. W. Pennington and B. M. Dunn, Methods in Molecular Biology: Peptide Synthesis Protocols, Vol 35, Humana Press, Totawa, N.J. (1994), contents of both of which are herein incorporated by reference. Peptides can also be chemically synthesized using methods well known in the art. See for example, Merrifield et al., J. Am. Chem. Soc. 85:2149 (1964); Bodanszky, M., Principles of Peptide Synthesis, Springer-Verlag, New York, N.Y. (1984); Kimmerlin, T. and Seebach, D. J. Pept. Res. 65:229-260 (2005); Nilsson et al., Annu. Rev. Biophys. Biomol. Struct. (2005) 34:91-118; W. C. Chan and P. D. White (Eds.) Fmoc Solid Phase Peptide Synthesis: A Practical Approach, Oxford University Press, Cary, N.C. (2000); N. L. Benoiton, Chemistry of Peptide Synthesis, CRC Press, Boca Raton, Fla. (2005); J. Jones, Amino Acid and Peptide Synthesis, 2.sup.nd Ed, Oxford University Press, Cary, N.C. (2002); and P. Lloyd-Williams, F. Albericio, and E. Giralt, Chemical Approaches to the synthesis of peptides and proteins, CRC Press, Boca Raton, Fla. (1997), contents of all of which are herein incorporated by reference. Peptide derivatives can also be prepared as described in U.S. Pat. Nos. 4,612,302; 4,853,371; and 4,684,620, and U.S. Pat. App. Pub. No. 2009/0263843, contents of all which are herein incorporated by reference.
[0081] As used herein, the term "nucleic acid" or "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid or an analog thereof. The nucleic acid can be either single-stranded or double-stranded. A single-stranded nucleic acid can be one nucleic acid strand of a denatured double-stranded DNA. Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA. In one aspect, the nucleic acid can be DNA. In another aspect, the nucleic acid can be RNA. Suitable nucleic acid molecules are DNA, including genomic DNA or cDNA. Other suitable nucleic acid molecules are RNA, including mRNA.
[0082] In some embodiments, the technology described herein relates to a nucleic acid encoding a polypeptide as described herein. As used herein, the term "nucleic acid" or "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid or an analog thereof. The nucleic acid can be either single-stranded or double-stranded. A single-stranded nucleic acid can be one strand nucleic acid of a denatured double-stranded DNA. Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA. In one aspect, the template nucleic acid is DNA. In another aspect, the template is RNA. Suitable nucleic acid molecules include DNA, including genomic DNA or cDNA. Other suitable nucleic acid molecules include RNA, including mRNA. The nucleic acid molecule can be naturally occurring, as in genomic DNA, or it may be synthetic, i.e., prepared based upon human action, or may be a combination of the two. The nucleic acid molecule can also have certain modification(s) such as 2'-deoxy, 2'-deoxy-2'-fluoro, 2'-O-methyl, 2'-O-methoxyethyl (2'-O-MOE), 2'-O-aminopropyl (2'-O-AP), 2'-O-dimethylaminoethyl (2'-O-DMAOE), 2'-O-dimethylaminopropyl (2'-O-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-O-DMAEOE), or 2'-O--N-methylacetamido (2'-O-NMA), cholesterol addition, and phosphorothioate backbone as described in US Patent Application 20070213292; and certain ribonucleoside that are linked between the 2'-oxygen and the 4'-carbon atoms with a methylene unit as described in U.S. Pat. No. 6,268,490, wherein both patent and patent application are incorporated herein by reference in their entirety.
[0083] In some embodiments, a nucleic acid encoding a polypeptide as described herein is comprised by a vector. In some of the aspects described herein, a nucleic acid sequence encoding a polypeptide as described herein is operably linked to a vector. The term "vector", as used herein, refers to a nucleic acid construct designed for delivery to a host cell or for transfer between different host cells. As used herein, a vector can be viral or non-viral. The term "vector" encompasses any genetic element that is capable of replication when associated with the proper control elements and that can transfer gene sequences to cells. A vector can include, but is not limited to, a cloning vector, an expression vector, a plasmid, phage, transposon, cosmid, chromosome, virus, virion, etc.
[0084] As used herein, the term "expression vector" refers to a vector that directs expression of an RNA or polypeptide from sequences linked to transcriptional regulatory sequences on the vector. The sequences expressed will often, but not necessarily, be heterologous to the cell. An expression vector may comprise additional elements, for example, the expression vector may have two replication systems, thus allowing it to be maintained in two organisms, for example in human cells for expression and in a prokaryotic host for cloning and amplification. The term "expression" refers to the cellular processes involved in producing RNA and proteins and as appropriate, secreting proteins, including where applicable, but not limited to, for example, transcription, transcript processing, translation and protein folding, modification and processing. "Expression products" include RNA transcribed from a gene, and polypeptides obtained by translation of mRNA transcribed from a gene. The term "gene" means the nucleic acid sequence which is transcribed (DNA) to RNA in vitro or in vivo when operably linked to appropriate regulatory sequences. The gene may or may not include regions preceding and following the coding region, e.g. 5' untranslated (5'UTR) or "leader" sequences and 3' UTR or "trailer" sequences, as well as intervening sequences (introns) between individual coding segments (exons).
[0085] As used herein, the term "viral vector" refers to a nucleic acid vector construct that includes at least one element of viral origin and has the capacity to be packaged into a viral vector particle. The viral vector can contain a nucleic acid encoding a polypeptide as described herein in place of non-essential viral genes. The vector and/or particle may be utilized for the purpose of transferring nucleic acids into cells either in vitro or in vivo. Numerous forms of viral vectors are known in the art.
[0086] By "recombinant vector" is meant a vector that includes a heterologous nucleic acid sequence, or "transgene" that is capable of expression in vivo. It should be understood that the vectors described herein can, in some embodiments, be combined with other suitable compositions and therapies. In some embodiments, the vector is episomal. The use of a suitable episomal vector provides a means of maintaining the nucleotide of interest in the subject in high copy number extra chromosomal DNA thereby eliminating potential effects of chromosomal integration.
[0087] The term "progenitor cell" is used herein to refers to cells that have a cellular phenotype that is more primitive (e.g., is at an earlier step along a developmental pathway or progression than is a fully differentiated cell) relative to a cell which it can give rise to by differentiation. Often, progenitor cells also have significant or very high proliferative potential. Progenitor cells can give rise to multiple distinct differentiated cell types or to a single differentiated cell type, depending on the developmental pathway and on the environment in which the cells develop and differentiate.
[0088] The term "stem cell" as used herein, refers to an undifferentiated cell which is capable of proliferation and giving rise to more progenitor cells having the ability to generate a large number of mother cells that can in turn give rise to differentiated, or differentiable daughter cells. The daughter cells themselves can be induced to proliferate and produce progeny that subsequently differentiate into one or more mature cell types, while also retaining one or more cells with parental developmental potential. The term "stem cell" refers to a subset of progenitors that have the capacity or potential, under particular circumstances, to differentiate to a more specialized or differentiated phenotype, and which retains the capacity, under certain circumstances, to proliferate without substantially differentiating. In one embodiment, the term stem cell refers generally to a naturally occurring mother cell whose descendants (progeny) specialize, often in different directions, by differentiation, e.g., by acquiring completely individual characters, as occurs in progressive diversification of embryonic cells and tissues. Cellular differentiation is a process typically occurring through many cell divisions. A differentiated cell may derive from a multipotent cell which itself is derived from a multipotent cell, and so on. While each of these multipotent cells may be considered stem cells, the range of cell types each can give rise to may vary considerably. Some differentiated cells also have the capacity to give rise to cells of greater developmental potential. Such capacity may be natural or may be induced artificially upon treatment with various factors. In many biological instances, stem cells are also "multipotent" because they can produce progeny of more than one distinct cell type, but this is not required for "stem-ness." Self-renewal is the other classical part of the stem cell definition, and it is essential as used in this document. In theory, self-renewal can occur by either of two major mechanisms. Stem cells may divide asymmetrically, with one daughter retaining the stem state and the other daughter expressing some distinct other specific function and phenotype. Alternatively, some of the stem cells in a population can divide symmetrically into two stems, thus maintaining some stem cells in the population as a whole, while other cells in the population give rise to differentiated progeny only.
[0089] The term "embryonic stem cell" is used to refer to the pluripotent stem cells of the inner cell mass of the embryonic blastocyst (see U.S. Pat. Nos. 5,843,780, 6,200,806, which are incorporated herein by reference). Such cells can similarly be obtained from the inner cell mass of blastocysts derived from somatic cell nuclear transfer (see, for example, U.S. Pat. Nos. 5,945,577, 5,994,619, 6,235,970, which are incorporated herein by reference). The distinguishing characteristics of an embryonic stem cell define an embryonic stem cell phenotype. Accordingly, a cell has the phenotype of an embryonic stem cell if it possesses one or more of the unique characteristics of an embryonic stem cell such that that cell can be distinguished from other cells. Exemplary distinguishing embryonic stem cell characteristics include, without limitation, gene expression profile, proliferative capacity, differentiation capacity, karyotype, responsiveness to particular culture conditions, and the like.
[0090] The term "adult stem cell" or "ASC" is used to refer to any multipotent stem cell derived from non-embryonic tissue, including fetal, juvenile, and adult tissue. Stem cells have been isolated from a wide variety of adult tissues including blood, bone marrow, brain, olfactory epithelium, skin, pancreas, skeletal muscle, and cardiac muscle. Each of these stem cells can be characterized based on gene expression, factor responsiveness, and morphology in culture. As indicated above, stem cells have been found resident in virtually every tissue. Accordingly, the technology described herein appreciates that stem cell populations can be isolated from virtually any animal tissue. As used herein, the term "adult cell" refers to a cell found throughout the body after embryonic development.
[0091] As used herein, the terms "iPS cell" and "induced pluripotent stem cell" are used interchangeably and refers to a pluripotent cell artificially derived (e.g., induced by complete or partial reversal) from a differentiated somatic cell (i.e. from a non-pluripotent cell). A pluripotent cell can differentiate to cells of all three developmental germ layers.
[0092] The term "derived from" used in the context of a cell derived from another cell means that a cell has stemmed from (e.g. changed from or was produced by) a cell which is a different cell type. In some instances, for example, a cell derived from an iPS cell refers to a cell which has differentiated from an iPS cell. Alternatively, a cell can be converted from one cell type to a different cell type by a process referred to as transdifferention or direct reprogramming. Alternatively, in the terms of iPS cells, a cell (e.g. an iPS cell) can be derived from a differentiated cell by a process referred to in the art as dedifferentiation or reprogramming.
[0093] The term "pluripotent" as used herein refers to a cell that can give rise to any type of cell in the body except germ line cells. The term "pluripotency" or a "pluripotent state" as used herein refers to a cell with the ability to differentiate into all three embryonic germ layers: endoderm (gut tissue), mesoderm (including blood, muscle, and vessels), and ectoderm (such as skin and nerve), and typically has the potential to divide in vitro for a long period of time, e.g., greater than one year or more than 30 passages. Pluripotency is also evidenced by the expression of embryonic stem (ES) cell markers, although the preferred test for pluripotency is the demonstration of the capacity to differentiate into cells of all three germ layers, as detected using, for example, a nude mouse teratoma formation assay. iPS cells are pluripotent cells. Pluripotent cells undergo further differentiation into multipotent cells that are committed to give rise to cells that have a particular function. For example, multipotent cardiovascular stem cells give rise to the cells of the heart, including cardiomyocytes, as well as other cells involved in the vasculature of the heart.
[0094] The term "phenotype" refers to one or a number of total biological characteristics that define the cell or organism under a particular set of environmental conditions and factors, regardless of the actual genotype.
[0095] The term "lineages" as used herein refers to a term to describe cells with a common ancestry, for example cells that are derived from the same cardiovascular stem cell or other stem cell, or cells with a common developmental fate. By way of an example only, when referring to a cell that is of endoderm origin or is "endodermal linage," this means the cell was derived from an endodermal cell and can differentiate along the endodermal lineage restricted pathways, such as one or more developmental lineage pathways which give rise to definitive endoderm cells, which in turn can differentiate into liver cells, thymus, pancreas, lung and intestine.
[0096] In the context of cell ontogeny, the term "differentiated", or "differentiating" is a relative term. A "differentiated cell" is a cell that has progressed further down the developmental pathway than the cell it is being compared with. Thus, stem cells can differentiate to lineage-restricted precursor cells (such as a mesodermal stem cell), which in turn can differentiate into other types of precursor cells further down the pathway (such as an atrial precursor), and then to an end-stage differentiated cell, such as atrial cardiomyocytes or smooth muscle cells, which play a characteristic role in a certain tissue type, and may or may not retain the capacity to proliferate further. The term "differentiated cell" refers to any primary cell that is not, in its native form, pluripotent as that term is defined herein. The term a "differentiated cell" also encompasses cells that are partially differentiated, such as multipotent cells, or cells that are stable non-pluripotent partially reprogrammed cells. In some embodiments, a differentiated cell is a cell that is a stable intermediate cell, such as a non-pluripotent partially reprogrammed cell. It should be noted that placing many primary cells in culture can lead to some loss of fully differentiated characteristics. However, simply culturing such primary cells, e.g., after removal or isolateion from a tissue or organism does not render these cells non-differentated cells (e.g. undifferentiated cells) or pluripotent cells. The transition of a differentiated cell (including stable non-pluripotent partially reprogrammed cell intermediates) to pluripotency requires a reprogramming stimulus beyond the stimuli that lead to partial loss of differentiated character in culture.
[0097] The term "differentiation" as referred to herein refers to the process whereby a cell moves further down the developmental pathway and begins expressing markers and phenotypic characteristics known to be associated with a cell that are more specialized and closer to becoming terminally differentiated cells. The pathway along which cells progress from a less committed cell to a cell that is increasingly committed to a particular cell type, and eventually to a terminally differentiated cell is referred to as progressive differentiation or progressive commitment. Cell which are more specialized (e.g., have begun to progress along a path of progressive differentiation) but not yet terminally differentiated are referred to as partially differentiated. Differentiation is a developmental process whereby cells assume a more specialized phenotype, e.g., acquire one or more characteristics or functions distinct from other cell types. In some cases, the differentiated phenotype refers to a cell phenotype that is at the mature endpoint in some developmental pathway (a so called terminally differentiated cell). In many, but not all tissues, the process of differentiation is coupled with exit from the cell cycle. In these cases, the terminally differentiated cells lose or greatly restrict their capacity to proliferate. However, in the context of this specification, the terms "differentiation" or "differentiated" refer to cells that are more specialized in their fate or function than at one time in their development. For example in the context of this application, a differentiated cell includes a cardiomyocyte which has differentiated from cardiovascular progenitor cell, where such cardiovascular progenitor cell can in some instances be derived from the differentiation of an ES cell, or alternatively from the differentiation of an induced pluripotent stem (iPS) cell, or in some embodiments from a human ES cell line. A cell that is "differentiated" relative to a progenitor cell has one or more phenotypic differences relative to that progenitor cell and characteristic of a more mature or specialized cell type. Phenotypic differences include, but are not limited to morphologic differences and differences in gene expression and biological activity, including not only the presence or absence of an expressed marker, but also differences in the amount of a marker and differences in the co-expression patterns of a set of markers.
[0098] The term "contacting" or "contact" as used herein in connection with contacting a cell with an agent as described herein, includes subjecting the cell to a culture medium which comprises that agent.
[0099] The term "statistically significant" or "significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.
[0100] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about." The term "about" when used in connection with percentages can mean.+-.1%.
[0101] As used herein the term "comprising" or "comprises" is used in reference to compositions, methods, and respective component(s) thereof, that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.
[0102] The term "consisting of" refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.
[0103] As used herein the term "consisting essentially of" refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment.
[0104] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, "e.g." is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."
[0105] Definitions of common terms in cell biology and molecular biology can be found in "The Merck Manual of Diagnosis and Therapy", 19th Edition, published by Merck Research Laboratories, 2006 (ISBN 0-911910-19-0); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); Benjamin Lewin, Genes X, published by Jones & Bartlett Publishing, 2009 (ISBN-10: 0763766321); Kendrew et al. (eds.), Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8) and Current Protocols in Protein Sciences 2009, Wiley Intersciences, Coligan et al., eds.
[0106] Unless otherwise stated, the present invention was performed using standard procedures, as described, for example in Sambrook et al., Molecular Cloning: A Laboratory Manual (4 ed.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (1995); or Methods in Enzymology: Guide to Molecular Cloning Techniques Vol. 152, S. L. Berger and A. R. Kimmel Eds., Academic Press Inc., San Diego, USA (1987); Current Protocols in Protein Science (CPPS) (John E. Coligan, et. al., ed., John Wiley and Sons, Inc.), Current Protocols in Cell Biology (CPCB) (Juan S. Bonifacino et. al. ed., John Wiley and Sons, Inc.), and Culture of Animal Cells: A Manual of Basic Technique by R. Ian Freshney, Publisher: Wiley-Liss; 5th edition (2005), Animal Cell Culture Methods (Methods in Cell Biology, Vol. 57, Jennie P. Mather and David Barnes editors, Academic Press, 1st edition, 1998) which are all incorporated by reference herein in their entireties.
[0107] Other terms are defined herein within the description of the various aspects of the invention.
[0108] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.
[0109] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.
[0110] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.
[0111] The technology described herein is further illustrated by the following examples which in no way should be construed as being further limiting.
[0112] Some embodiments of the technology described herein can be defined according to any of the following numbered paragraphs:
1. A method of differentiating a stem cell, the method comprising:
[0113] i) contacting the stem cell with one or more ectopic differentiation factors; and
[0114] ii) inhibiting the cell cycle of the stem cell;
[0115] wherein steps i) and ii) occur within 15 days of each other. 2. The method of paragraph 1, wherein steps i) and ii) occur within 14 days of each other. 3. The method of paragraph 1, wherein steps i) and ii) occur within 13 days of each other. 4. The method of paragraph 1, wherein steps i) and ii) occur within 12 days of each other. 5. The method of paragraph 1, wherein steps i) and ii) occur within 11 days of each other. 6. The method of paragraph 1, wherein steps i) and ii) occur within 10 days of each other. 7. The method of paragraph 1, wherein steps i) and ii) occur within 9 days of each other. 8. The method of paragraph 1, wherein steps i) and ii) occur within 8 days of each other. 9. The method of paragraph 1, wherein steps i) and ii) occur within 7 days of each other. 10. The method of paragraph 1, wherein steps i) and ii) occur within 6 days of each other. 11. The method of paragraph 1, wherein steps i) and ii) occur within 5 days of each other. 12. The method of paragraph 1, wherein steps i) and ii) occur within 4 days of each other. 13. The method of paragraph 1, wherein steps i) and ii) occur within 3 days of each other. 14. The method of paragraph 1, wherein steps i) and ii) occur within 2 days of each other. 15. The method of paragraph 1, wherein steps i) and ii) occur within 24 hours of each other. 16. The method of paragraph 1, wherein steps i) and ii) occur simultaneously. 17. The method of any of paragraphs 1-16, wherein the differentiation factor is a terminal transcription factor. 18. The method of paragraph 17, wherein the terminal transcription factor is selected from Table 1. 19. The method of any of paragraphs 17-18, wherein the stem cell is to be differentiated to a skeletal muscle phenotype and is contacted with the terminal transcription factor MyoD. 20. The method of any of paragraphs 17-18, wherein the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with a terminal transcription factor selected from the group consisting of: Ngn2; Isl1; and Lhx3. 21. The method of any of paragraphs 17-18, wherein the stem cell is to be differentiated to a spinal motor neuron phenotype and is contacted with the terminal transcription factors Ngn2; Isl1; and Lhx3. 22. The method of any of paragraphs 17-18, wherein the stem cell is to be differentiated to a cardiomyocyte phenotype and is contacted with the terminal transcription factor Gata5. 23. The method of any of paragraphs 17-18, wherein the stem cell is to be differentiated to a hepatocyte or hepatoblast phenotype and is contacted with the terminal transcription factor Hnf4.alpha.. 24. The method of any of paragraphs 1-23, wherein the cell cycle is inhibited by one or more of the following:
[0116] reducing or removing growth factors; reducing serum levels; reducing serum levels below 5%; contacting the cell with a PI3K inhibitor; contacting the cell with an E2F family transcription factor inhibitor; contacting the cell with a Myc inhibitor; contacting the cell with a MAPK inhibitor; contacting the cell with a MEK1/2 inhibitor; contacting the cell with a CDK inhibitor; contacting the cell with an Id inhibitor; contacting the cell with a Rb agonist; contacting the cell with a Ink family agonist; contacting the cell with a Cip/Kip family agonist; and culturing the cell in a media lacking a factor selected from the group consisting of:
[0117] LIF; Bmp; Fgf; Activin; or TGF.beta.. 25. The method of paragraph 24, wherein the cell cycle is inhibited by reducing or removing growth factors. 26. The method of paragraph 24, wherein the cell cycle is inhibited by culturing the cell in a media lacking a factor selected from the group consisting of:
[0118] LIF; Bmp; Fgf; Activin; or TGF.beta.. 27. The method of paragraph 26, wherein the cell cycle is inhibited by culturing the cell in a media lacking LIF. 28. The method of paragraph 24, wherein the PI3K inhibitor is LY294002. 29. The method of paragraph 24, wherein the E2F transcription factor inhibitor is HLM006474. 30. The method of paragraph 24, wherein the Myc inhibitor is JQ1 or 10058-F4. 31. The method of paragraph 24, wherein the MAPK inhibitor is PD98059. 32. The method of paragraph 24, wherein the CDK inhibitor is a CDK4 or CDK2 inhibitor. 33. The method of paragraph 24, wherein the CDK inhibitor is p16, p15, p18, or p19. 34. The method of paragraph 24, wherein the CDK inhibitor is p21, p27, or p57. 35. The method of any of paragraphs 1-34, wherein the stem cell is an embryonic stem cell. 36. The method of any of paragraphs 1-35, wherein steps i) and ii) result in a population of cells comprising one or more terminally-differentiated cell types. 37. The method of any of paragraphs 1-35, wherein steps i) and ii) result in a population of cells comprising no more than 2 terminally-differentiated cell types. 38. The method of any of paragraphs 1-35, wherein steps i) and ii) result in a population of cells of which at least 50% are terminally-differentiated cells. 39. The method of any of paragraphs 1-35, wherein steps i) and ii) result in a population of cells of which at least 60% are terminally-differentiated cells. 40. The method of any of paragraphs 1-35, wherein steps i) and ii) result in a population of cells of which at least 70% are terminally-differentiated cells. 41. The method of any of paragraphs 1-35, wherein steps i) and ii) result in a population of cells of which at least 80% are terminally-differentiated cells.
Examples
Example 1: Molecular Ties Between the Cell Cycle and Differentiation in Embryonic Stem Cells
[0119] Attainment of the differentiated state during the final stages of somatic cell differentiation is closely tied to cell cycle progression. Much less is known about the role of the cell cycle at very early stages of embryonic development. It is demonstrated herein that molecular pathways involving the cell cycle can be engineered to strongly affect embryonic stem cell differentiation at early stages in vitro. Strategies based on perturbing these pathways can shorten the rate and simplify the lineage path of ES differentiation. These results make it likely that pathways involving cell proliferation intersect at various points with pathways that regulate cell lineages in embryos and demonstrate that this knowledge can be used profitably to guide the path and effectiveness of cell differentiation of pluripotent cells.
[0120] As cells differentiate during embryonic development, they progress through a stereotypical sequence of events, starting from highly potent embryonic precursors to germ layer intermediates, then to lineage-restricted progenitors, and finally, to terminally differentiated cell types. Any of these stages may consist of further states of differentiation and may be difficult to recognize. Most of our knowledge about the differentiation process comes from studies in the latter stages of differentiation (i.e. terminal model systems), where cells are one step away from their final fate and are usually restricted to differentiate to one type of cell. Less is known about what happens during early embryonic stages, where the differentiation process is just beginning and many alternative pathways of differentiation may still be available.
[0121] In terminal somatic cell culture models, inhibition of the cell cycle is almost always a requisite for differentiation. Forced inhibition of the cell cycle very often induces terminal differentiation and vice versa (1-3). The molecular pathways that couple the cell cycle to differentiation involve molecules of the G1/S transition including growth factors, downstream signaling pathways, Myc, the Rb/E2F pathway, and the CDK inhibitors (e.g. p21). The role of G1 length on embryonic stem cell self-renewal was investigated and it was found that in contrast to the terminal stages it did not accelerate the loss of pluripotency or facilitate differentiation (4). Described herein is the state of the cell cycle molecular network in the ES cell system and how the cell cycle may be re-coupled to differentiation to re-direct lineage pathways, e.g., for practical benefit.
[0122] Results
[0123] In terminally differentiated cells the cell cycle and differentiation are linked together through a molecular network rooted in the G1/S transition. A wiring diagram summarizing such a network is shown in FIG. 1A, with explanations and justifications provided in FIGS. 7A-7C, which was constructed from known or postulated relationships in normal somatic cycling cells, and interactions between the cell cycle machinery and terminal transcription factors, such as MyoD.
[0124] During the process of differentiation, the network changes. For cultured cells at the terminal stage of differentiation, this involves an exit from the cell cycle, activation of terminal transcription factors, and a shift towards insulin signaling away from other growth factors for survival and growth. These changes to the network are shown in FIG. 1B. At the other end of the differentiation process are embryonic stem cells, which have a number of unique features. They can be maintained in an undifferentiated state with the combination of Leukemia Inhibitory Factor (LIF) and high amounts of serum, or LIF and Bmp4, as shown in FIG. 1C. The actual differentiation process from ES cells to terminally differentiated cells spans at least three states in a defined order (ES to somatic cycling cells to terminal differentiation), but may pass through other intermediate stages of differentiation, expressing genes and behavior different from terminal cells and pluripotent stem cells; little is known concerning the cell cycle and their state of differentiation in these largely uncharacterized cell cycle states (FIG. 1D).
[0125] Guided Differentiation and Cell Cycle Manipulation of ES Cells.
[0126] To probe the effect of the cell cycle on differentiation an ES cell line was used that constitutively over-expressed the transcription factor MyoD driven off an EF1alpha promoter (5) activated by tamoxifen-induced Cre recombination. The use of this cell line facilitated the analysis by channeling differentiation away from a diverse collection of phenotypes into a more uniform population of cells expressing muscle genes, such as myosin heavy chain (MHC). The first cell cycle manipulation was growth factor or serum withdrawal. Using the cell line that continuously expressed MyoD, LIF was removed at what is referred to herein as zero time to initiate differentiation and serum was reduced at various times thereafter from the standard 15% serum to 2% with additional insulin (10 .mu.g/ml). As shown in FIG. 2A, in the continuous presence of 15% serum, MHC is completely suppressed, despite constitutive MyoD overexpression. When serum is reduced one day after MyoD induction, MHC begins to accumulate four days later. By day 12, 20-30 percent of cells express MHC and show characteristic morphology of mature skeletal muscle fibers including elongation, increase in volume, and significant multi-nucleation (FIG. 8). If serum removal is delayed relative to LIF removal, the cells still begin to express MHC with a 2 to 4 day delay after serum reduction. Thus serum reduction strongly potentiates terminal muscle differentiation in a very short time under the conditions studied.
[0127] From the cell cycle summary in FIG. 1A, MyoD activation and hence muscle differentiation from ES cells should be blocked by either the action of LIF, which activates Myc, or Bmp4, which promotes Id protein family expression. However any implication of growth factor effects through the manipulation of serum can be fraught with the inconsistencies and complexities of serum. To avoid these problems more defined conditions were examined with two types of basal insulin-containing media, N2B27 and DMEM plus 20% Knock-out Serum Replacement (KOSR), neither of which contains growth factors. Use of both media in ES cells led to activation of MyoD and terminal myogenesis similar to the 2% low serum media, with some improvement (FIG. 2B; assessed on Day 4). The N2B27 media produced approximately 38.5% MHC+nuclei while 20% KOSR produced approximately 19.6%. As expected when LIF or Bmp4 was added back to N2B27 differentiation was blocked (0%; FIG. 2B). These results confirm the expectation that the reduction of LIF and BMP in the setting of no other growth factors, produces highly effective conditions for ES differentiation.
[0128] The lineage from ES cells to terminal differentiation first involves the loss of pluripotency factors, followed by passage through intermediate cell types, identifiable by expression of specific transcription factors. It was found that the decline in Oct4 and Nanog mRNA levels induced by LIF removal was completely unaffected by serum reduction. This is similar to results showing that extension of G1 had no effect on Nanog levels (4).
[0129] By contrast, beyond the loss of pluripotency factors there is a dramatic effect of serum removal on the differentiation cascade toward muscle. From studies in embryos, there is a prescribed sequence of steps in setting up the myogenic lineage involving the specification of the mesoderm, the sub-specification of the myotome, and the steps leading to overt cell differentiation (6-7). When the mRNA levels of genes within this hierarchy were examined using the above protocol of serum reduction, it was found that Pax3, which is expressed in the dermomyotome, rose dramatically (to a peak of .about.50 fold) and very prematurely within 2 days of serum reduction. The pre-myogenic homeodomain factors Six1 (8) and Six4 (9), which are normally upstream of Pax3, are not affected or modestly suppressed, as was the case for the paired-box domain protein Pax7, which is expressed in the dermomyotome and somites during embryogenesis (10). There are small effects of serum reduction on the myogenic regulatory factor (MRF) genes, like Myf5, MRF4 and endogenous MyoD, but there is a massive (300 fold) upregulation of myogenin (MyoG), which plays a key role in very late-stage skeletal myogenesis during the period of days 3 to 7 (11). Other muscle lineage markers also respond rapidly to serum withdrawal in the presence of MyoD, indicating that the entire suite of terminal muscle lineage is induced very prematurely. Seven of these--desmin, skeletal muscle actin, troponin, myosin light chain, tropomyosin, the myoblast fusion regulator Dyrk1b (12), and titin--are shown in FIG. 9. The dramatic overexpression of Pax3 and MyoG depend on the over-expressed exogenous MyoD, as without the induction of MyoD, their expression is lower. These results document the extraordinarily rapid production of some downstream muscle differentiation factors and definitive muscle proteins in the setting of growth factor or serum withdrawal.
[0130] Promoting Differentiation by Perturbing Intracellular Pathways.
[0131] Based on suggestions from the pathway diagrams in FIGS. 1A-1D, a few critical components of cell cycle control were focused on and their effects on the two markers strongly perturbed by serum withdrawal, Pax3 and MyoG, were measured. Perturbations were made both under high and low serum conditions and were extended throughout the time course of differentiation. LY294002 is a potent broad inhibitor of phosphoinositide-3-kinases (PI3Ks), and when applied continuously to ES cells over 7 days induced a significant 2.7 fold increase in Pax3 mRNA expression (FIG. 4). This increase was observed both in high serum and low serum media. However, continuing treatment with LY294002 led to cell death and no expression of myogenin was observed (FIG. 4, bottom panels). A similar situation was observed with HLM006474, which broadly inhibits E2F family transcription factors in their interaction with DP proteins. Myc drives cell cycle progression and growth. Its activity can be inhibited by two compounds: JQ1, a newly-identified compound that specifically inhibits bromodomains but subsequently results in Myc downregulation, and 10058-F4, an inhibitor that blocks the dimerization of Myc-Max complexes. Both are indirect inhibitors of Myc activity; as yet there are no direct pharmacologic inhibitors of the Myc protein. The effects of JQ1 were similar to LY294002 and HLM00647: an increase in Pax3 early expression, but later suppression of MyoG expression. Out of all drugs the Myc-bromodomain inhibitor JQ1 had the largest effect in inducing Pax3, whereas the Myc-Max dimerization inhibitor 10058-F4 had suppressive effects on both Pax3 and MyoG.
[0132] The effects of inhibiting cyclin-dependent kinases (kinases that are more centrally involved in cell cycle control) and MAP kinase, which very often is involved in cell cycle regulation, were also examined Roscovitine is a broad CDK inhibitor that blocks a number of family members, including CDK1, CDK2, and CDK5. After continuous treatment throughout the 7 days of differentiation in the time course, roscovitine had no effect on Pax3 expression (FIG. 4). It also had little effect on the later expression of MyoG, either under high or low serum conditions. This lack of effect on Pax3 and MyoG was also observed for the more specific CDK4 inhibitor PD0332991. However, the MAPK inhibitor PD98059, which blocks MEK1/2, had no effect on Pax3 and induced MyoG only under low serum conditions (FIG. 4 bottom). The protein CDK inhibitor p21, which is much more specific than roscovitine, blocks CDK2 and prevents entry into S-phase. In ES cells p21 is expressed at low levels, but gradually increases during the course of ES cell differentiation (13). An mES cell line that constitutively overexpresses the p21 protein bicistronically with a mCherry tag (fused to the C-terminus with a 2A peptide) was developed. This line exhibits an elongated G1 and can be propagated in standard LIF+serum media. When induced to differentiate by the removal of LIF, this line upregulated MyoG under low serum media, but had no effect on Pax3, a behavior similar to the MAPK inhibitor. Thus, within the set of cell cycle inhibitors examined, stage-specific and condition-specific effects on gene expression were observed.
[0133] Induction of Unguided Differentiation.
[0134] Although forced expression of MyoD nicely served to focus differentiation into the skeletal muscle cell lineage, it was also desired to examine what happens in ES cells that are not guided in their differentiation path by MyoD. When LIF is removed in ES cells without MyoD, there is differentiation into a heterogeneous mixture of cell types. Under standard culture conditions of 15% serum, which promotes expansion, ES cells deprived of LIF normally differentiate first into general mesodermal, endodermal, and ectodermal tissues, and then later into a heterogeneous mixture of terminal cell types (7, 14). The effects of serum withdrawal on this system were examined. When high and low serum time courses in ES cells differentiating without exogenous MyoD were compared over a period of 7 days there was premature expression of genes that are normally associated with multiple cell lineages (FIG. 5). Low serum induced the expression of many lineage-specific factors. For example, an increase in the neural marker Delta (Dll1) was observed. The cardiac muscle factors Sox6, Smyd1, GATA4, GATA6 all increased, as well as the neural/muscle transcription factor Mef2c. For adipose genes, a very large increase in PPAR.gamma. expression (>400 fold) was detected. The early endoderm genes Sox17 and Nkx2.2 also were elevated in low serum compared to high serum. Similarly, increases in Runx2 (osteoblast differentiation), Mitf (melanocyte), and Sox9 (chondrocyte differentiation) were also observed. For hematopoietic factors, increases in the erythrocyte factor GATA1 (FIG. 5) and the progenitor factor GATA2 (FIG. 10) were observed. A full list of factors that were profiled and their time course data is available in FIG. 10.
[0135] The early upregulation of such a large number of somatic lineage factors indicates that growth factor/serum reduction is permissive for a wide variety of differentiated gene expression. Many of the upregulated factors have been reported to function in terminal differentiation. Perhaps most interesting is the failure to express many of the markers of the early lineages. As seen in the MyoD-guided system, only Pax3 and MyoG were significantly activated, but not other factors in the muscle lineage hierarchy. In the unguided system, in addition to the terminal factors that were upregulated, there were numerous intermediate lineage factors that were not (e.g. Pax6, C/EBP.alpha., C/EBP.beta., Pdx1, Cdx2, etc.)(FIG. 10 and Table 3).
[0136] Discussion
[0137] Our understanding of cell differentiation comes mainly from two different sources: studies of cell culture systems and studies of embryonic systems. Although the embryo remains the gold standard for the functional process of embryogenesis, there is today a strong incentive to understand alternative in vitro pathways that can be exploited for therapeutic purposes. Furthermore there is no reason why we should consider embryonic lineages as mechanistically the most informative. Embryos have to accomplish feats other than differentiation, such as morphogenesis and cell proliferation, and many intermediate behaviors of cells may reflect those roles.
[0138] Much ingenuity and decades of effort has resulted in the discovery of ways to manipulate cells isolated and cultured from various tissues so that they can differentiate into one or a very few cell types. It is now recognized that these processes take cells from an already determined state and drive them to a state of clear expression of specific markers, rather than starting from a very early precursor state. Such manipulations can drive presumptive myoblasts to muscle, neuroblasts to neurons, fibroblasts to adipocytes, etc. A very different source of cells are pluripotent ES cells of the mouse and now of human. These cells start at an earlier state and can be driven to differentiate either by re-creating some early embryonic state through embryoid bodies or by going through a series of steps in culture, thought to parallel the various intermediate states of differentiation found in the embryo itself. As work in stem cells and ES cells in particular exploded in the last few years there has been a serious effort to identify and recreate in culture the series of signals that drive the pluripotent state to the differentiated state. In the embryo, these include the addition and removal of factors like Wnts, Nodals, BMPs, EGFs, etc. There is both a practical side to this endeavor: to either generate differentiated cells that can generate replacement tissues and organs or to find ways to stimulate the body's regenerative potential to repair worn or diseased cells.
[0139] There has also been a long standing interest in understanding how the cell cycle could further the process of differentiation Inhibition of cell proliferation in G1 is almost always accompanied by cell differentiation. The work described herein was designed to determine whether this effect of cell cycle inhibition can be observed early in the differentiation process and whether the paths taken are the same as seen in the absence of cell cycle inhibition.
[0140] Described herein are cell cycle perturbations, starting with a reduction or removal of growth factors/serum, change the timing and the course of differentiation to muscle in a model that involves the continuous expression of MyoD. Notably none of the perturbations had an effect on exit from the ES cell state as reflected in the loss of Oct4 and Nanog. Surprisingly, this progression to the differentiated state seemed not to seem to follow the normal sequence of gene expressions seen in ES cells in culture or by embryonic lineages in the embryo. More than one path to differentiation was found, as described herein.
[0141] Described herein are heuristic descriptions of somatic cycling cells, terminally differentiating cells, and embryonic stem cells (FIGS. 1A-1D). Terminally differentiated cells typically maintain their size or grow slowly, stimulated commonly by the insulin pathway. In this cell cycle state the drivers of the cell cycle are inhibited and the expression of cell cycle inhibitors are stimulated, leading to the expression of terminally differentiated genes like MyoD, neurogenin, etc. The proliferative state that preceded terminal differentiation is reduced in the expression of CDK inhibitors and particularly in the activity of Rb. In this case MyoD activity is also reduced. Lastly, the pluripotent embryonic state has new extracellular players: LIF, serum growth factors, and BMP4. In this state, there is more complete suppression of Rb and MyoD through the activation of proliferative signals in the cell cycle and the downstream suppression of anti-proliferative factors such as CDK inhibitors.
[0142] The results described herein indicate that in the MyoD-guided system there are minimally 3 states and two transitions (FIG. 6, top box). The first stable state is pluripotency. When the cell cycle is suppressed there is a rapid transition to an intermediate somatic state, which correlates with an upregulation in Pax3. Manipulations that promote this transition also promote Pax3 upregulation. For example, this transition could be facilitated by growth factor/serum withdrawal, LY294002 (PI3K inhibition), HLM006474 (E2F inhibition), and JQ1 (Bromodomain/Myc inhibition). Subsequently there is a second transition to the terminally differentiating state, which correlates with upregulation of MyoG. Manipulations that promote this transition also promote MyoG. MyoG could be facilitated by PD98059 (MEK1/2 inhibitor), and p21 (CDK inhibitor) when combined with low serum, but not with roscovitine (broad CDK family inhibitor) or PD0332991 (CDK4 inhibitor).
[0143] Though this scheme is likely to be a simplification for any lineage and may differ in different lineages, it nevertheless helped to make sense of a number of observations. The removal of extracellular factors in the form of LIF and Bmp4, and the replacement of serum with insulin leads to activation of MyoD and full induction of terminal myogenesis. When applied early, this leads to a very direct form of ES-to-terminal differentiation, and Pax3 and MyoG upregulation is observed. PI3K inhibition is predicted to activate MyoD by removing the stimulus to Myc, but is also expected to be inhibitory on the last steps of terminal differentiation as it becomes necessary for metabolic cell growth of the final differentiated cell. Accordingly, LY294002 upregulated Pax3 but promoted poor survival, which could have suppressed MyoG expression. This suggests that the step of MyoG upregulation corresponds to what happens in the terminal phase in this model, which is consistent with what is known about myogenin's role from terminal models. From the heuristic description, it is also expected that Myc or E2F suppression would help activate MyoD. JQ1 and HLM006474 both induced Pax3, which is consistent with this prediction. However, it was also noticed that they suppressed MyoG expression.
[0144] The cell cycle schemes also correctly predict that some CDK inhibitors and the MAPK inhibitor would have little effect on Pax3 expression by themselves, but would facilitate MyoG expression. This is due to the fact that in ES cells Myc and Id proteins are highly expressed and can independently repress the expression of endogenous MyoD and other myogenic regulatory factors outside of CDK activity (FIG. 1C). As ES cells differentiate, they transition to the somatic cell cycling state and then to the terminally differentiated model (FIG. 1D). Throughout this transition Myc and Id activity decline until CDK activity is the predominant factor blocking differentiation. Hence at the early stage of Pax3 activation CDK inhibition is not expected to have a significant effect, whereas at the late stage of MyoG activation the expectation is that it will. Moreover, CDK4 activity is suppressed in ES cells, so additional inhibition of their activity by PD0332991 should reveal no effect on Pax3. MAPK (MEK1/2) activity is also suppressed in ES cells, but is upregulated during differentiation. Thus its inhibition should stimulate MyoG induction, but not Pax3 induction.
[0145] It is described herein that the CDK inhibitors and the MAPK inhibitor promote differentiation only under low serum conditions, as high levels of growth factor/serum conditions are expected to induce higher levels of Myc and Id expression. It is further described herein that different CDK inhibitors can have different effects. The p21 protein is highly effective at promoting MyoG expression, but not roscovitine or PD0332991. Without wishing to be bound by theory, this may have to do with the differing specificities of the kinase inhibitors used.
[0146] It is specifically contemplated herein that the methods described herein can permit the differentiation of other cell types, e.g., with other terminal factors in place of MyoD. Indeed, many terminal cell systems couple cell cycle inhibition with differentiation (1), and many potent transcription factors interact with cell cycle components in ways similar to MyoD, including Ngn2, Pdx1, Smad3, Mitf, Runx2, PU.1, Hnf4.alpha., and C/EBP.beta. (17-24). Expression of several genes associated with diverse differentiated cell types could be stimulated by cell cycle inhibition in a heterogeneous differentiation system where MyoD was not expressed (FIG. 5).
[0147] The forced silencing of proliferative pathways and the resulting rapid differentiation in vitro described herein is a useful strategy to generate terminal cell types as compared to trying to recapitulate embryonic differentiation pathways, which often takes weeks (FIG. 6, bottom box)(26-31).
[0148] Materials and Methods
[0149] ES culture and differentiation. The ES cells contain MyoD (and associated puromycin resistance marker) expressed from a EF1alpha promoter (5). MyoD could be expressed once a loxP segment inserted between the promoter and transgene was excised by a cre recombinase fused to the estrogen receptor. ES cells were cultured in LIF and standard conditions containing 15% FBS, non-essential amino acids, L-glutamine, penicillin/streptomycin, and beta-mercaptoethanol. To induce MyoD, cells were treated for 24 hrs with 1 .mu.M 4OHT (Sigma) in ES media. Reduced serum media consisted of DMEM and 2% horse serum (Invitrogen) plus 10 .mu.g/ml insulin (to maintain cell survival)(Sigma) with sodium pyruvate and penicillin/streptomycin. During differentiation, cells were treated with 1 .mu.g/ml puromycin continuously to select for cells which maintained MyoD expression. N2B27 components/supplements and Knock-out serum replacement were purchased from Invitrogen. LIF was used at a 1000 U/ml and Bmp4 at 10 ng/ml.
[0150] Drugs. The PI3K inhibitor LY294002, Roscovitine, the MEK1/2 inhibitor PD98059, and 10058-F4 were purchased from Sigma. The E2F inhibitor HLM006474 was purchased from Millipore. PD0332991 was purchased from SelleckChem. JQ1 was purchased from ApexBio.
[0151] Immunostaining. Myosin heavy chain expression was detected with use of the MF20 antibody (R&D systems). Cells were fixed in 4% PFA, permeabilized in 0.1% Triton-X, and co-stained with antibody and DAPI (Sigma).
[0152] RNA isolation and RT-PCR. RNA was isolated using RNAeasy plus kit (Qiagen). Reverse transcription was performed using iScript.TM. cDNA synthesis (Bio-rad). Real-time quantitative PCR was done on a CFX96.TM. PCR machine using SYBR green supermix (Bio-rad). A complete list of primers used is provided in the Supplementary Methods.
[0153] Microarray analysis. RNA time-course samples were hybridized to Illumina Ref8 BeadChip.TM. arrays. Data analysis was performed with GenomeStudio.TM. software and the help of the BCH IDDRC Molecular Genetics Core.
[0154] Cloning. The mouse p21 open reading frame was cloned into the pmCherry-N1.TM. plasmid (Clontech) with a self-cleaving P2A peptide and mCherry fused to its C-terminus. The plasmid was transfected into the MyoD-inducible ES cell line and selected by G418. The final line was derived from the picking of a single cell clone colony.
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[0200] Sakamuro D and Prendergast G C (1999) New Myc-interacting proteins: a second Myc network emerges. Oncogene 18:2942-2954.
TABLE-US-00002
[0200] TABLE 2 qRT-PCR Primer list. Primers are labelled (Gene name_)(F or R) depending on forward or reverse Primer Primer Sequence SEQ ID NO GAPDH_F GTGTTCCTACCCCCAATGTGT 01 GAPDH_R GTTGAAGTCGCAGGAGACAAC 02 NeuroD1_F ACAGACGCTCTGCAAAGGTTT 03 NeuroD1_R GGACTGGTAGGAGTAGGGATG 04 Pax6_F TACCAGTGTCTACCAGCCAAT 05 Pax6_R TGCACGAGTATGAGGAGGTCT 06 Dll1_F GCAGGACCTTCTTTCGCGTAT 07 Dll1_R AAGGGGAATCGGATGGGGTT 08 Pparg_F TTTTCCGAAGAACCATCCGATT 09 Pparg_R ATGGCATTGTGAGACATCCCC 010 Nkx2.2_F AAGCATTTCAAAACCGACGGA 011 Nkx2.2_R CCTCAAATCCACAGATGACCAGA 012 Ngn3_F CCAAGAGCGAGTTGGCACT 013 Ngn3_R CGGGCCATAGAAGCTGTGG 014 CEBPa_F GATAAGAACAGCAACGAGTACCG 015 CEBPa_R GTCACTGGTCAACTCCAACACC 016 CEBPb_F CATCGACTTCAGCCCCTACC 017 CEBPb_R GGCTCACGTAACCGTAGTCG 018 MeF2c_F TCTCCGCGTTCTTATCCCAC 019 MeF2c_R AGGAGTTGCTACGGAAACCAC 020 Pdx1_F CCCCAGTTTACAAGCTCGCT 021 Pdx1_R CTCGGTTCCATTCGGGAAAGG 022 Nestin_F CCCTGAAGTCGAGGAGCTG 023 Nestin_R CTGCTGCACCTCTAAGCGA 024 Sox6_F TCAACCTGCCAAACAAAAGC 025 Sox6_R GCTGGATCTGTTCTCGCATC 026 Smyd1_F TCCGAGGGTTTGTATCACGAG 027 Smyd1_R CCTCCTGGCATAATGTGAGGC 028 Runx2_F CCAAGGAACAAACCGTCAAA 029 Runx2_R AAGCGGGTCTGCAGAGTGTA 030 EBF_F AGATTCCAGGTCGTGGTGTCTA 031 EBF_R ACAGGGAGTAGCATGTTCCAGA 032 Tal1_F GGTCCTCACACCAAAGTAGTGC 033 Tal1_R CGGAGGATCTCATTCTTGCTTA 034 Gata4_F ATAATCTCCTTCACCCCAGCTC 035 Gata4_R GGGCAGGGCTTCTATGTCTAGT 036 Mrg1_F ATTTGTTGGCTGCATGATCTTT 037 Mrg1_R CGGTATGACTTTTCCTGATCCA 038 Mitf_F AGGCAGAAAAAGGACAATCACA 039 Mitf_R CTTCCGGATGTAGTCCACAGAG 040 Gata2_F AAGCGAAAACCAAACTGCATAA 041 Gata2_R CCAAGAACCACTCAAAGGACTG 042 Gata3_F TCCCATTTGTGAATAAGCCATT 043 Gata3_R TCCTTCATGCCTTTCTTACAGC 044 Runx1_F CTCCCAATAGCCCTTCTCACTT 045 Runx1_R AGCAAGAGAATGGCTGACTCAC 046 PU1_F ACAGATGCACGTCCTCGATACT 047 PU1_R CTTCTCCATCAGACACCTCCAG 048 Sox9_F TCTCCCCCTTTTCTTTGTTGTT 049 Sox9_R ACGCACACATCCACATACAGTC 050 Lbh_F CTTGCTTCCACTCTGCTCTGTT 051 Lbh_R ACGGCAAGACCAAGACAGATAA 052 Gata1_F CAGAATAGCCTTGACCTTGTGG 053 Gata1_R AGGAAAATGTCAGGCATAGCAA 054 Ikaros_F GTTTGTTGCCCAGTAAGACGAG 055 Ikaros_R GCTTTGGCTTCCAAGAAGTTTT 056 Gata6_F CCAAATCATGTGCTTCTTGTGA 057 Gata6_R TATTCTTGTTGAGACCCCAGGA 058 Oct4_F ATGGCATACTGTGGACCTC 059 Oct4_R AGCAGCTTGGCAAACTGTTC 060 Nanog_F CAGCAGATGCAAGAACTCTCC 061 Nanog_R GGATACTCCACTGGTGCTGAG 062 Brachyury_F CTCTAATGTCCTCCCTTGTTGCC 063 Brachyury_R TGCAGATTGTCTTTGGCTACTT 064 Sox17_F ACAACGCAGAGCTAAGCAAGAT 065 Sox17_R GTACTTGTAGTTGGGGTGGTCCT 066 Cdx2_F AAAAGACAAATACCGGGTGGTG 067 Cdx2_R TGATTTTCCTCTCCTTGGCTCT 068 Pax3_F CATCCGACCTGGTGCCATC 069 Pax3_R ATTTCCCAGCTAAACATGCCC 070 Pax7_F TGGGGTCTTCATCAACGGTC 071 Pax7_R ATCGGCACAGAATCTTGGAGA 072 Myf5_F CACCACCAACCCTAACCAGAG 073 Myf5_R AGGCTGTAATAGTTCTCCACCTG 074 MyoG_F GCAGGCTCAAGAAAGTGAATGA 075 MyoG_R TAGGCGCTCAATGTACTGGAT 076 MRF4_F AGAGGGCTCTCCTTTGTATCC 077 MRF4_R CTGCTTTCCGACGATCTGTGG 078 MyoD1endo_F CTGCAGCAGCAGAGGGCGCACCA 079 MyoD1endo_R GAAGAACGGCTTCGAAAGGACAGTTGG 080 Six1_F GAAAGGGAGAACACCGAAAACA 081 Six1_R GTGGCCCATATTGCTCTGGA 082 Six4_F ACCCCAGTACCGAGGATGAAT 083 Six4_R AACTCCAGACGAGCTTAGTGA 084
[0201] Table 3: List of factors affected by cell cycle inhibition during unguided differentiation and the cell type lineages in which they play a role. Lineages refer to differentiation systems in which the factors have been reported to be involved. The effect of low serum compared to high serum is listed as increased, decreased, or same/similar. Over the seven day time course, when the effect of low serum occurs is referred to as the stage. If the effect occurs within Days 1-3, the stage is referred to as early, or else mid (Days 3-4), or late (Days 5-7).
TABLE-US-00003 Gene Lineage Increase or Decrease Stage NeuroD1 Neural Increase Early Dll1 Neural Increase Mid Pax6 Neural Increase Mid Nestin Neural Decrease Mid/Late Sox6 Cardiac Increase Late Smyd1 Cardiac Increase Late Mef2c Cardiac Increase Late Gata4 Cardiac Increase Mid/Late Gata6 Cardiac Increase Mid/Late C/EBP.beta. Adipocyte Same N/A PPAR.gamma. Adipocyte Increase Late CEBP.alpha. Adipocyte Increase Late Sox17 Pancreatic Increase Late Nkx2.2 Pancreatic Increase Late Pdx1 Pancreatic Same N/A Ngn3 Pancreatic Decrease Mid/Late Runx2 Osteoblast Increase Late Cdx2 Placental Same N/A Cited2 Multiple Increase Late Mitf Melanocyte Increase Late Sox9 Chondrocyte Increase Mid/Late Lbh Chondrocyte Same N/A Runx1 Blood Increase Late Pu.1 Blood Decrease Early Gata2 Blood Increase Mid/Late Gata3 Blood Increase Late Tal1 Blood Decrease Late EBF Blood Altered N/A Gata1 Blood Increase Early to late Ikaros Blood Similar N/A
Example 2: The Generality of Direct Embryonic Stem Cell Programming
[0202] Described above herein is a principle for the direct programming of cell fates. Further described herein is a demonstration that this programming principle can be extended from skeletal muscle to spinal motor neurons, cardiomyocytes, and hepatoblast-like cells. The broad applicability of this principle to these cell types indicates a common differentiation structure is shared across multiple lineages, and indicates that cell cycle-associated processes serve a fundamental role in regulating the rate and path of embryonic differentiation.
[0203] The induction of cell fates during embryogenesis is orchestrated through the action of developmental signals, such as growth factors (1). Proper exposure to these signals leads to the normal patterning and growth of the embryo. It is described herein that the major point of this signaling, with respect to differentiation, is to align two properties within the cell: 1. its transcriptional state, which determines the lineage and cell type to be specified, and 2. its appropriate "cell cycle" state, which determines the rate of differentiation (2). Given the alignment of these two properties, it can be possible to induce cells to turn into any fate, even through transformations that do not occur naturally. This decomposition of the normal differentiation process helps us understand the critical elements required for cell fate changes and the roles they play, which cannot be understood by only studying normal embryonic differentiation. Moreover, it could improve our ability to alter cell fates for regenerative medicine
[0204] Described herein are methods relating to the combination of the appropriate transcriptional state with the appropriate "cell cycle" state to determine a specific cell fate. Neither of these two components is sufficient alone. However, when combined together, these two conditions lead to a rapid and direct conversion. This was first demonstrated in experiments where mouse embryonic stem (ES) cells are rapidly and effectively converted into skeletal muscle. Normally, a standard strategy of differentiating ES cells into skeletal muscle would require sequential treatment of growth factors to recapitulate intermediate embryonic progenitor stages, such as mesoderm (3). This need to reconstitute a series of intermediate stages can be avoided by engineering the ES cell to overexpress MyoD (the transcriptional component, which by itself does not trigger muscle differentiation) and simultaneously using methods of inhibiting the cell cycle (such as growth factor withdrawal)(2). Out of the usual myogenic regulatory hierarchy, which includes Six1, Six4, Pax3, Pax7, MyoG, Myf5, and Mrf4, only Pax3 and MyoG appear to be significantly upregulated in addition to the exogenous MyoD.
[0205] Setting the transcriptional state can be achieved by overexpressing an appropriate transcription factor. Setting the "cell cycle" state can be achieved by manipulating cell cycle pathways. The pathways that normally connect extracellular growth factors to the intracellular G1/S machinery and their nuclear effectors (e.g Myc, Rb) are highly involved (summarized in network models in ref 2). Withdrawing growth factors delivers a strong inhibitory signal, whereas inhibiting downstream pathways has effects that are differentiation stage-specific. The skeletal muscle system has been a model for cell differentiation, and initial studies were performed on this system.
[0206] Described herein is the demonstration that other lineages share a similar capacity to be directly programmed. MyoD was replaced with transcription factors for three additional cell types. The results indicate a much greater generality of the process of direct programming.
[0207] Results
[0208] Spinal Motor Neurons
[0209] To generate spinal motor neurons, a mouse ES cell line that overexpressed a combination of three transcription factor lineage specifiers (Ngn2, Isl1, Lhx3) was used. This combination was previously shown to specify spinal motor neuron identity (4). These iNIL cells, as they are also called, upon doxycycline stimulation express the three transcription factors from a single open reading frame coupled by 2A peptides. Growth factor withdrawal was used as the method of cell cycle manipulation in the experiments described in this Example.
[0210] As expected from the results on skeletal muscle myotubes, neurons rapidly formed from ES cells upon switching to different types of growth factor-free media. Four days after removing LIF and adding doxycycline (Day 0), ES cells that had been differentiated in growth factor-free (N2B27 or 20% Knockout Serum Replacement/KOSR) or growth factor-reduced media (2% horse serum/HS with insulin) expressed much higher levels of the terminal neuron differentiation marker beta-3 tubulin (Tubb3) than in high growth factor media (15% FBS), and displayed morphological characteristics of neurons, which was not seen in high serum (FIG. 11A and FIG. 14). Tubb3 expression was confirmed by immunostaining. When either of the ES cell growth factors LIF or Bmp4 were added back into growth factor-free media, there was a strong block on neuronal differentiation.
[0211] To see which genes are induced during this rapid differentiation process, the mRNA expression of neural lineage genes was profiled across the time course of differentiation (first 5 days). As before, LIF was removed, the media changed to N2B27, and doxycycline added at Day 0. Many neural genes were upregulated in the growth factor-free N2B27 media (FIG. 11B). These include Pax6, which had a sustained activation that increased during the five days of differentiation. Hb9 and NeuroD1 were also activated, as were endogenous Lhx3 and Lhx4. Other genes that were similarly activated include D111, Onecut1, Onecut2, Mef2c, and Pax3. Some of these genes were upregulated even at day one. In contrast, most of the activation of terminal genes occurred slightly later, around day 2-3. These include Tubb3, neuronal guidance molecule Slit2a, axon guidance receptors Robot and Robo2, receptor Dcc, and cholinergic receptor Chrnb2. Similar increases were not observed under the high serum condition.
[0212] Cardiomyocytes
[0213] Similar experiments were performed on an ES cell line that overexpressed the transcription factor Gata5. The Gata4/5/6 family of transcription factors have been shown to specify cardiomyocytes previously (5). The earliest terminal marker expression for cardiomyocytes in growth factor media could be detected by day 3 after LIF removal and dox addition. Similar to neurons, ES cells differentiated in growth factor-free or growth factor-reduced media displayed higher levels of genes involved with cardiomyocyte terminal differentiation, such as cardiac troponin (Tnnt2) by day 4, compared with high serum (FIG. 12A). The earliest spontaneously beating cardiomyocyte clusters could be observed at day 5, although this is a rare event. More commonly, beating clusters could be observed starting at day 8-9 (FIG. 15). This may reflect a requirement for aggregation.
[0214] Several cardiac lineage genes in N2B27 media were upregulated (FIG. 12B). These include the lineage specifiers Sox6, Smyd1, Isl1, and Mef2c, as well as Fabp3, Mef2a, Tbx20, c-kit, Srf, and the Gata5 related family members 4 and 6. Terminal differentiation genes were also upregulated with rapid kinetics, including natriuretic peptide A, cardiac troponin, smooth muscle actin (Acta2), Myosin light chains 2 and 7 (Myl2/7), alpha-actinin (Actn2), and the potassium channel Hcn4, all rose within 3-5 days.
[0215] Hepatoblast-Like Cells
[0216] One essential lineage specifying factor for hepatocytes is hepatic nuclear factor 4.alpha. (Hnf4.alpha.)(6). Switching of Hnf4.alpha.-overexpressing ES cells to growth factor-free or growth factor-reduced media led to the activation of a subset of hepatic genes. At day 0, LIF and doxycycline were removed and the media was either switched or kept to 15% FBS. By day 4, there were high levels of alphafetoprotein (AFP) that could be detected in the cells differentiated in the growth factor-free or growth factor-reduced media and less than 10% the level of AFP in cells in 15% FBS (FIG. 13A and FIG. 16). AFP expression could be confirmed by immunostaining. While this activation by growth factor withdrawal was similar to the pattern seen in previous cell types, there was an additional interesting point of variation compared to other lineages examined so far. The re-addition of Bmp4 did not reduce the amount of AFP expression, although the re-addition of LIF did, as usually observed. Hnf4.alpha.-overexpressing cells continued to divide for several days even after incubation in growth factor-free N2B27 media. The AFP expression and continuous division indicate that the cells have characteristics of hepatoblasts, rather than hepatocytes. Dexamethasone (a corticosteroid) often helps maintain hepatocyte survival in culture. However, it did not have any additional effect on AFP expression. Many hepatic genes upregulated, including acetylcholinesterase (AchE), endogenous Hnf4.alpha. (from days 5-7), Foxa2 (from days 2-5), Foxa1, Asgr1, and Prox1 (FIG. 13B). Albumin production was also detected, as was Sox17, Ppar.alpha., Cdh3, Tbx3, Krt18, Hhex, Lrh1, C/EBP.alpha., Hnf1a, and Hnf1b.
[0217] Discussion
[0218] The results presented herein from skeletal muscle, spinal motor neurons, cardiomyocytes, and hepatocytes show that the effects of perturbing the cell cycle after establishing the proper transcriptional state occurs in more than one cell lineage. For spinal motor neurons and cardiomyocytes, the differentiation appeared to be more complete, including both histological and molecular features. The hepatocytes were less complete, and resembled hepatoblast-like cells. However, in each case direct programming induced characteristic genes in each lineage.
[0219] The ability to directly program cell types suggests an underlying logic of how cell types are normally specified. In normal embryonic development, and in stem cell protocols that seek to mimic this process, proliferation and differentiation are usually simultaneously specified by growth factors. Sequential changes to the composition and concentration of these growth factors specify cell type identity and maintain an expanding embryo. These changes generate numerous intermediate cell types, until cell cycle exit drives cells into terminal differentiation. In contrast, removing growth factors at an early stage can shortcut cells into adopting late, terminal fates. In this sense, proliferative signals may serve as a general "rate-limiting step" in everyday differentiation. For practical applications, the direct programming process described herein provides an alternative to current strategies of embryonic stem cell differentiation, which seek to mimic the natural differentiation pathways.
[0220] Materials and Methods
[0221] ESC culture and cell lines. ESCs were cultured in standard media (DMEM with LIF+15% fetal bovine serum) on 0.1% gelatin-coated dishes. The Tet-Off Hnf4.alpha. line was cultured with 0.2 .mu.g/ml doxycycline.
[0222] ESC differentiation. Twenty-four hours before starting, ESCs are trypsinized and spread out as monolayer onto gelatin in standard ES media. At day 0 (ESCs), the media was switched from standard ES media to either N2B27 media (Invitrogen), 20% Knockout Serum Replacement (KOSR)(Invitrogen), 2% horse serum (HS)(Invitrogen)+10 .mu.g/ml insulin, or just 15% FBS without LIF. Doxycycline was also added at day 0 (3 .mu.g/ml) to induce expression or removed entirely for the Hnf4.alpha. line. Media was refreshed daily.
[0223] For the neurons, the ES cells were seeded onto plates pre-coated with a mix of poly-d-lysine (100 .mu.g/ml) and laminin (50 .mu.g/ml) instead of gelatin for adherence. 1000 U/ml of LIF or 10 ng/ml Bmp4 was added when needed. Dexamethasone (Sigma) was used at 0.1 .mu.M.
[0224] RNA isolation and qPCR. RNA was isolated using Qiagen Rnaeasy.TM. Plus Kit. Purified RNA was then reverse transcribed using Bio-rail's iSCRIPT.TM. cDNA synthesis kit. Quantitative PCR was performed using Bio-rad's SYBR.TM. green Supermix.
[0225] Immunostaining Antibodies for Tubb3 and AFP were provided respectively by Cell Signaling (D71G9), Sino Biological (clone 27). Cells were fixed in 4% PFA and permeabilized with 0.1% Triton.
REFERENCES
[0226] 1. Freeman M, and Gurdon J B (2002) Regulatory principles of developmental signaling. Annu. Rev. Cell. Dev. Biol. 18:515-39.
[0227] 2. Li V C, and Kirschner M W (2014) Molecular ties between the cell cycle and differentiation in embryonic stem cells. P.N.A.S. 111:9503-8.
[0228] 3. Salani S, Donadoni C, Rizzo F, Bresolin N, Comi G P, Corti S (2012) Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as an in vitro model and for therapy of muscular dystrophies. J Cell Mol Med. 16:1353-64.
[0229] 4. Mazzoni E O, et al. (2013) Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. Nat. Neurosci. 16:1219-27.
[0230] 5. Turbendian H K, et al. (2013) GATA factors efficiently direct cardiac fate from embryonic stem cells. Development 140:1639-44.
[0231] 6. DeLaForest A, Nagaoka M, Si-Tayeb K, Noto F K, Konopka G, Battle M A, Duncan S A (2011) HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 138:4143-53.
[0232] 7. Nishiyama A, et al. (2009) Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. Cell Stem Cell 5:420-33.
Sequence CWU
1
1
178121DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 1gtgttcctac ccccaatgtg t
21221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 2gttgaagtcg caggagacaa c
21321DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 3acagacgctc tgcaaaggtt t
21421DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 4ggactggtag gagtagggat g
21521DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
5taccagtgtc taccagccaa t
21621DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 6tgcacgagta tgaggaggtc t
21721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 7gcaggacctt ctttcgcgta t
21820DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 8aaggggaatc ggatggggtt
20922DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 9ttttccgaag aaccatccga tt
221021DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
10atggcattgt gagacatccc c
211121DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 11aagcatttca aaaccgacgg a
211223DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 12cctcaaatcc acagatgacc aga
231319DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 13ccaagagcga gttggcact
191419DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 14cgggccatag aagctgtgg
191523DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
15gataagaaca gcaacgagta ccg
231622DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 16gtcactggtc aactccaaca cc
221720DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 17catcgacttc agcccctacc
201820DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 18ggctcacgta accgtagtcg
201920DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 19tctccgcgtt cttatcccac
202021DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
20aggagttgct acggaaacca c
212120DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 21ccccagttta caagctcgct
202221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 22ctcggttcca ttcgggaaag g
212319DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 23ccctgaagtc gaggagctg
192419DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 24ctgctgcacc tctaagcga
192520DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
25tcaacctgcc aaacaaaagc
202620DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 26gctggatctg ttctcgcatc
202721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 27tccgagggtt tgtatcacga g
212821DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 28cctcctggca taatgtgagg c
212920DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 29ccaaggaaca aaccgtcaaa
203020DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
30aagcgggtct gcagagtgta
203122DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 31agattccagg tcgtggtgtc ta
223222DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 32acagggagta gcatgttcca ga
223322DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 33ggtcctcaca ccaaagtagt gc
223422DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 34cggaggatct cattcttgct ta
223522DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
35ataatctcct tcaccccagc tc
223622DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 36gggcagggct tctatgtcta gt
223722DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 37atttgttggc tgcatgatct tt
223822DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 38cggtatgact tttcctgatc ca
223922DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 39aggcagaaaa aggacaatca ca
224022DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
40cttccggatg tagtccacag ag
224122DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 41aagcgaaaac caaactgcat aa
224222DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 42ccaagaacca ctcaaaggac tg
224322DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 43tcccatttgt gaataagcca tt
224422DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 44tccttcatgc ctttcttaca gc
224522DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
45ctcccaatag cccttctcac tt
224622DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 46agcaagagaa tggctgactc ac
224722DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 47acagatgcac gtcctcgata ct
224822DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 48cttctccatc agacacctcc ag
224922DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 49tctccccctt ttctttgttg tt
225022DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
50acgcacacat ccacatacag tc
225122DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 51cttgcttcca ctctgctctg tt
225222DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 52acggcaagac caagacagat aa
225322DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 53cagaatagcc ttgaccttgt gg
225422DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 54aggaaaatgt caggcatagc aa
225522DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
55gtttgttgcc cagtaagacg ag
225622DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 56gctttggctt ccaagaagtt tt
225722DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 57ccaaatcatg tgcttcttgt ga
225822DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 58tattcttgtt gagaccccag ga
225919DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 59atggcatact gtggacctc
196020DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
60agcagcttgg caaactgttc
206121DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 61cagcagatgc aagaactctc c
216221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 62ggatactcca ctggtgctga g
216323DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 63ctctaatgtc ctcccttgtt gcc
236422DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 64tgcagattgt ctttggctac tt
226522DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
65acaacgcaga gctaagcaag at
226623DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 66gtacttgtag ttggggtggt cct
236722DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 67aaaagacaaa taccgggtgg tg
226822DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 68tgattttcct ctccttggct ct
226919DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 69catccgacct ggtgccatc
197021DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
70atttcccagc taaacatgcc c
217120DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 71tggggtcttc atcaacggtc
207221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 72atcggcacag aatcttggag a
217321DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 73caccaccaac cctaaccaga g
217423DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 74aggctgtaat agttctccac ctg
237522DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
75gcaggctcaa gaaagtgaat ga
227621DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 76taggcgctca atgtactgga t
217721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 77agagggctct cctttgtatc c
217821DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 78ctgctttccg acgatctgtg g
217923DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 79ctgcagcagc agagggcgca cca
238027DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
80gaagaacggc ttcgaaagga cagttgg
278122DNAArtificial SequenceDescription of Artificial Sequence Synthetic
primer 81gaaagggaga acaccgaaaa ca
228220DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 82gtggcccata ttgctctgga
208321DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 83accccagtac cgaggatgaa t
218421DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 84aactccagac gagcttagtg a
21852379DNAHomo sapiens
85gacccccgag ctgtgctgct cgcggccgcc accgccgggc cccggccgtc cctggctccc
60ctcctgcctc gagaagggca gggcttctca gaggcttggc gggaaaaaga acggagggag
120ggatcgcgct gagtataaaa gccggttttc ggggctttat ctaactcgct gtagtaattc
180cagcgagagg cagagggagc gagcgggcgg ccggctaggg tggaagagcc gggcgagcag
240agctgcgctg cgggcgtcct gggaagggag atccggagcg aatagggggc ttcgcctctg
300gcccagccct cccgctgatc ccccagccag cggtccgcaa cccttgccgc atccacgaaa
360ctttgcccat agcagcgggc gggcactttg cactggaact tacaacaccc gagcaaggac
420gcgactctcc cgacgcgggg aggctattct gcccatttgg ggacacttcc ccgccgctgc
480caggacccgc ttctctgaaa ggctctcctt gcagctgctt agacgctgga tttttttcgg
540gtagtggaaa accagcagcc tcccgcgacg atgcccctca acgttagctt caccaacagg
600aactatgacc tcgactacga ctcggtgcag ccgtatttct actgcgacga ggaggagaac
660ttctaccagc agcagcagca gagcgagctg cagcccccgg cgcccagcga ggatatctgg
720aagaaattcg agctgctgcc caccccgccc ctgtccccta gccgccgctc cgggctctgc
780tcgccctcct acgttgcggt cacacccttc tcccttcggg gagacaacga cggcggtggc
840gggagcttct ccacggccga ccagctggag atggtgaccg agctgctggg aggagacatg
900gtgaaccaga gtttcatctg cgacccggac gacgagacct tcatcaaaaa catcatcatc
960caggactgta tgtggagcgg cttctcggcc gccgccaagc tcgtctcaga gaagctggcc
1020tcctaccagg ctgcgcgcaa agacagcggc agcccgaacc ccgcccgcgg ccacagcgtc
1080tgctccacct ccagcttgta cctgcaggat ctgagcgccg ccgcctcaga gtgcatcgac
1140ccctcggtgg tcttccccta ccctctcaac gacagcagct cgcccaagtc ctgcgcctcg
1200caagactcca gcgccttctc tccgtcctcg gattctctgc tctcctcgac ggagtcctcc
1260ccgcagggca gccccgagcc cctggtgctc catgaggaga caccgcccac caccagcagc
1320gactctgagg aggaacaaga agatgaggaa gaaatcgatg ttgtttctgt ggaaaagagg
1380caggctcctg gcaaaaggtc agagtctgga tcaccttctg ctggaggcca cagcaaacct
1440cctcacagcc cactggtcct caagaggtgc cacgtctcca cacatcagca caactacgca
1500gcgcctccct ccactcggaa ggactatcct gctgccaaga gggtcaagtt ggacagtgtc
1560agagtcctga gacagatcag caacaaccga aaatgcacca gccccaggtc ctcggacacc
1620gaggagaatg tcaagaggcg aacacacaac gtcttggagc gccagaggag gaacgagcta
1680aaacggagct tttttgccct gcgtgaccag atcccggagt tggaaaacaa tgaaaaggcc
1740cccaaggtag ttatccttaa aaaagccaca gcatacatcc tgtccgtcca agcagaggag
1800caaaagctca tttctgaaga ggacttgttg cggaaacgac gagaacagtt gaaacacaaa
1860cttgaacagc tacggaactc ttgtgcgtaa ggaaaagtaa ggaaaacgat tccttctaac
1920agaaatgtcc tgagcaatca cctatgaact tgtttcaaat gcatgatcaa atgcaacctc
1980acaaccttgg ctgagtcttg agactgaaag atttagccat aatgtaaact gcctcaaatt
2040ggactttggg cataaaagaa cttttttatg cttaccatct tttttttttc tttaacagat
2100ttgtatttaa gaattgtttt taaaaaattt taagatttac acaatgtttc tctgtaaata
2160ttgccattaa atgtaaataa ctttaataaa acgtttatag cagttacaca gaatttcaat
2220cctagtatat agtacctagt attataggta ctataaaccc taattttttt tatttaagta
2280cattttgctt tttaaagttg atttttttct attgttttta gaaaaaataa aataactggc
2340aaatatatca ttgagccaaa tcttaaaaaa aaaaaaaaa
237986454PRTHomo sapiens 86Met Asp Phe Phe Arg Val Val Glu Asn Gln Gln
Pro Pro Ala Thr Met 1 5 10
15 Pro Leu Asn Val Ser Phe Thr Asn Arg Asn Tyr Asp Leu Asp Tyr Asp
20 25 30 Ser Val
Gln Pro Tyr Phe Tyr Cys Asp Glu Glu Glu Asn Phe Tyr Gln 35
40 45 Gln Gln Gln Gln Ser Glu Leu
Gln Pro Pro Ala Pro Ser Glu Asp Ile 50 55
60 Trp Lys Lys Phe Glu Leu Leu Pro Thr Pro Pro Leu
Ser Pro Ser Arg 65 70 75
80 Arg Ser Gly Leu Cys Ser Pro Ser Tyr Val Ala Val Thr Pro Phe Ser
85 90 95 Leu Arg Gly
Asp Asn Asp Gly Gly Gly Gly Ser Phe Ser Thr Ala Asp 100
105 110 Gln Leu Glu Met Val Thr Glu Leu
Leu Gly Gly Asp Met Val Asn Gln 115 120
125 Ser Phe Ile Cys Asp Pro Asp Asp Glu Thr Phe Ile Lys
Asn Ile Ile 130 135 140
Ile Gln Asp Cys Met Trp Ser Gly Phe Ser Ala Ala Ala Lys Leu Val 145
150 155 160 Ser Glu Lys Leu
Ala Ser Tyr Gln Ala Ala Arg Lys Asp Ser Gly Ser 165
170 175 Pro Asn Pro Ala Arg Gly His Ser Val
Cys Ser Thr Ser Ser Leu Tyr 180 185
190 Leu Gln Asp Leu Ser Ala Ala Ala Ser Glu Cys Ile Asp Pro
Ser Val 195 200 205
Val Phe Pro Tyr Pro Leu Asn Asp Ser Ser Ser Pro Lys Ser Cys Ala 210
215 220 Ser Gln Asp Ser Ser
Ala Phe Ser Pro Ser Ser Asp Ser Leu Leu Ser 225 230
235 240 Ser Thr Glu Ser Ser Pro Gln Gly Ser Pro
Glu Pro Leu Val Leu His 245 250
255 Glu Glu Thr Pro Pro Thr Thr Ser Ser Asp Ser Glu Glu Glu Gln
Glu 260 265 270 Asp
Glu Glu Glu Ile Asp Val Val Ser Val Glu Lys Arg Gln Ala Pro 275
280 285 Gly Lys Arg Ser Glu Ser
Gly Ser Pro Ser Ala Gly Gly His Ser Lys 290 295
300 Pro Pro His Ser Pro Leu Val Leu Lys Arg Cys
His Val Ser Thr His 305 310 315
320 Gln His Asn Tyr Ala Ala Pro Pro Ser Thr Arg Lys Asp Tyr Pro Ala
325 330 335 Ala Lys
Arg Val Lys Leu Asp Ser Val Arg Val Leu Arg Gln Ile Ser 340
345 350 Asn Asn Arg Lys Cys Thr Ser
Pro Arg Ser Ser Asp Thr Glu Glu Asn 355 360
365 Val Lys Arg Arg Thr His Asn Val Leu Glu Arg Gln
Arg Arg Asn Glu 370 375 380
Leu Lys Arg Ser Phe Phe Ala Leu Arg Asp Gln Ile Pro Glu Leu Glu 385
390 395 400 Asn Asn Glu
Lys Ala Pro Lys Val Val Ile Leu Lys Lys Ala Thr Ala 405
410 415 Tyr Ile Leu Ser Val Gln Ala Glu
Glu Gln Lys Leu Ile Ser Glu Glu 420 425
430 Asp Leu Leu Arg Lys Arg Arg Glu Gln Leu Lys His Lys
Leu Glu Gln 435 440 445
Leu Arg Asn Ser Cys Ala 450 871000DNAHomo sapiens
87actctcattc cacgttctta actgttccat tttccgtatc tgcttcgggc ttccacctca
60tttttttcgc tttgcccatt ctgtttcagc cagtcgccaa gaatcatgaa agtcgccagt
120ggcagcaccg ccaccgccgc cgcgggcccc agctgcgcgc tgaaggccgg caagacagcg
180agcggtgcgg gcgaggtggt gcgctgtctg tctgagcaga gcgtggccat ctcgcgctgc
240gccgggggcg ccggggcgcg cctgcctgcc ctgctggacg agcagcaggt aaacgtgctg
300ctctacgaca tgaacggctg ttactcacgc ctcaaggagc tggtgcccac cctgccccag
360aaccgcaagg tgagcaaggt ggagattctc cagcacgtca tcgactacat cagggacctt
420cagttggagc tgaactcgga atccgaagtt ggaacccccg ggggccgagg gctgccggtc
480cgggctccgc tcagcaccct caacggcgag atcagcgccc tgacggccga ggcggcatgc
540gttcctgcgg acgatcgcat cttgtgtcgc tgaagcgcct cccccaggga ccggcggacc
600ccagccatcc agggggcaag aggaattacg tgctctgtgg gtctccccca acgcgcctcg
660ccggatctga gggagaacaa gaccgatcgg cggccactgc gcccttaact gcatccagcc
720tggggctgag gctgaggcac tggcgaggag agggcgctcc tctctgcaca cctactagtc
780accagagact ttagggggtg ggattccact cgtgtgtttc tattttttga aaagcagaca
840ttttaaaaaa tggtcacgtt tggtgcttct cagatttctg aggaaattgc tttgtattgt
900atattacaat gatcaccgac tgaaaatatt gttttacaat agttctgtgg ggctgttttt
960ttgttattaa acaaataatt tagatggtgg taaaaaaaaa
100088155PRTHomo sapiens 88Met Lys Val Ala Ser Gly Ser Thr Ala Thr Ala
Ala Ala Gly Pro Ser 1 5 10
15 Cys Ala Leu Lys Ala Gly Lys Thr Ala Ser Gly Ala Gly Glu Val Val
20 25 30 Arg Cys
Leu Ser Glu Gln Ser Val Ala Ile Ser Arg Cys Ala Gly Gly 35
40 45 Ala Gly Ala Arg Leu Pro Ala
Leu Leu Asp Glu Gln Gln Val Asn Val 50 55
60 Leu Leu Tyr Asp Met Asn Gly Cys Tyr Ser Arg Leu
Lys Glu Leu Val 65 70 75
80 Pro Thr Leu Pro Gln Asn Arg Lys Val Ser Lys Val Glu Ile Leu Gln
85 90 95 His Val Ile
Asp Tyr Ile Arg Asp Leu Gln Leu Glu Leu Asn Ser Glu 100
105 110 Ser Glu Val Gly Thr Pro Gly Gly
Arg Gly Leu Pro Val Arg Ala Pro 115 120
125 Leu Ser Thr Leu Asn Gly Glu Ile Ser Ala Leu Thr Ala
Glu Ala Ala 130 135 140
Cys Val Pro Ala Asp Asp Arg Ile Leu Cys Arg 145 150
155 894772DNAHomo sapiens 89gctcagttgc cgggcggggg agggcgcgtc
cggtttttct caggggacgt tgaaattatt 60tttgtaacgg gagtcgggag aggacggggc
gtgccccgac gtgcgcgcgc gtcgtcctcc 120ccggcgctcc tccacagctc gctggctccc
gccgcggaaa ggcgtcatgc cgcccaaaac 180cccccgaaaa acggccgcca ccgccgccgc
tgccgccgcg gaacccccgg caccgccgcc 240gccgccccct cctgaggagg acccagagca
ggacagcggc ccggaggacc tgcctctcgt 300caggcttgag tttgaagaaa cagaagaacc
tgattttact gcattatgtc agaaattaaa 360gataccagat catgtcagag agagagcttg
gttaacttgg gagaaagttt catctgtgga 420tggagtattg ggaggttata ttcaaaagaa
aaaggaactg tggggaatct gtatctttat 480tgcagcagtt gacctagatg agatgtcgtt
cacttttact gagctacaga aaaacataga 540aatcagtgtc cataaattct ttaacttact
aaaagaaatt gataccagta ccaaagttga 600taatgctatg tcaagactgt tgaagaagta
tgatgtattg tttgcactct tcagcaaatt 660ggaaaggaca tgtgaactta tatatttgac
acaacccagc agttcgatat ctactgaaat 720aaattctgca ttggtgctaa aagtttcttg
gatcacattt ttattagcta aaggggaagt 780attacaaatg gaagatgatc tggtgatttc
atttcagtta atgctatgtg tccttgacta 840ttttattaaa ctctcacctc ccatgttgct
caaagaacca tataaaacag ctgttatacc 900cattaatggt tcacctcgaa cacccaggcg
aggtcagaac aggagtgcac ggatagcaaa 960acaactagaa aatgatacaa gaattattga
agttctctgt aaagaacatg aatgtaatat 1020agatgaggtg aaaaatgttt atttcaaaaa
ttttatacct tttatgaatt ctcttggact 1080tgtaacatct aatggacttc cagaggttga
aaatctttct aaacgatacg aagaaattta 1140tcttaaaaat aaagatctag atgcaagatt
atttttggat catgataaaa ctcttcagac 1200tgattctata gacagttttg aaacacagag
aacaccacga aaaagtaacc ttgatgaaga 1260ggtgaatgta attcctccac acactccagt
taggactgtt atgaacacta tccaacaatt 1320aatgatgatt ttaaattcag caagtgatca
accttcagaa aatctgattt cctattttaa 1380caactgcaca gtgaatccaa aagaaagtat
actgaaaaga gtgaaggata taggatacat 1440ctttaaagag aaatttgcta aagctgtggg
acagggttgt gtcgaaattg gatcacagcg 1500atacaaactt ggagttcgct tgtattaccg
agtaatggaa tccatgctta aatcagaaga 1560agaacgatta tccattcaaa attttagcaa
acttctgaat gacaacattt ttcatatgtc 1620tttattggcg tgcgctcttg aggttgtaat
ggccacatat agcagaagta catctcagaa 1680tcttgattct ggaacagatt tgtctttccc
atggattctg aatgtgctta atttaaaagc 1740ctttgatttt tacaaagtga tcgaaagttt
tatcaaagca gaaggcaact tgacaagaga 1800aatgataaaa catttagaac gatgtgaaca
tcgaatcatg gaatcccttg catggctctc 1860agattcacct ttatttgatc ttattaaaca
atcaaaggac cgagaaggac caactgatca 1920ccttgaatct gcttgtcctc ttaatcttcc
tctccagaat aatcacactg cagcagatat 1980gtatctttct cctgtaagat ctccaaagaa
aaaaggttca actacgcgtg taaattctac 2040tgcaaatgca gagacacaag caacctcagc
cttccagacc cagaagccat tgaaatctac 2100ctctctttca ctgttttata aaaaagtgta
tcggctagcc tatctccggc taaatacact 2160ttgtgaacgc cttctgtctg agcacccaga
attagaacat atcatctgga cccttttcca 2220gcacaccctg cagaatgagt atgaactcat
gagagacagg catttggacc aaattatgat 2280gtgttccatg tatggcatat gcaaagtgaa
gaatatagac cttaaattca aaatcattgt 2340aacagcatac aaggatcttc ctcatgctgt
tcaggagaca ttcaaacgtg ttttgatcaa 2400agaagaggag tatgattcta ttatagtatt
ctataactcg gtcttcatgc agagactgaa 2460aacaaatatt ttgcagtatg cttccaccag
gccccctacc ttgtcaccaa tacctcacat 2520tcctcgaagc ccttacaagt ttcctagttc
acccttacgg attcctggag ggaacatcta 2580tatttcaccc ctgaagagtc catataaaat
ttcagaaggt ctgccaacac caacaaaaat 2640gactccaaga tcaagaatct tagtatcaat
tggtgaatca ttcgggactt ctgagaagtt 2700ccagaaaata aatcagatgg tatgtaacag
cgaccgtgtg ctcaaaagaa gtgctgaagg 2760aagcaaccct cctaaaccac tgaaaaaact
acgctttgat attgaaggat cagatgaagc 2820agatggaagt aaacatctcc caggagagtc
caaatttcag cagaaactgg cagaaatgac 2880ttctactcga acacgaatgc aaaagcagaa
aatgaatgat agcatggata cctcaaacaa 2940ggaagagaaa tgaggatctc aggaccttgg
tggacactgt gtacacctct ggattcattg 3000tctctcacag atgtgactgt ataactttcc
caggttctgt ttatggccac atttaatatc 3060ttcagctctt tttgtggata taaaatgtgc
agatgcaatt gtttgggtga ttcctaagcc 3120acttgaaatg ttagtcattg ttatttatac
aagattgaaa atcttgtgta aatcctgcca 3180tttaaaaagt tgtagcagat tgtttcctct
tccaaagtaa aattgctgtg ctttatggat 3240agtaagaatg gccctagagt gggagtcctg
ataacccagg cctgtctgac tactttgcct 3300tcttttgtag catataggtg atgtttgctc
ttgtttttat taatttatat gtatattttt 3360ttaatttaac atgaacaccc ttagaaaatg
tgtcctatct atcttccaaa tgcaatttga 3420ttgactgccc attcaccaaa attatcctga
actcttctgc aaaaatggat attattagaa 3480attagaaaaa aattactaat tttacacatt
agattttatt ttactattgg aatctgatat 3540actgtgtgct tgttttataa aattttgctt
ttaattaaat aaaagctgga agcaaagtat 3600aaccatatga tactatcata ctactgaaac
agatttcata cctcagaatg taaaagaact 3660tactgattat tttcttcatc caacttatgt
ttttaaatga ggattattga tagtactctt 3720ggtttttata ccattcagat cactgaattt
ataaagtacc catctagtac ttgaaaaagt 3780aaagtgttct gccagatctt aggtatagag
gaccctaaca cagtatatcc caagtgcact 3840ttctaatgtt tctgggtcct gaagaattaa
gatacaaatt aattttactc cataaacaga 3900ctgttaatta taggagcctt aatttttttt
tcatagagat ttgtctaatt gcatctcaaa 3960attattctgc cctccttaat ttgggaaggt
ttgtgttttc tctggaatgg tacatgtctt 4020ccatgtatct tttgaactgg caattgtcta
tttatctttt atttttttaa gtcagtatgg 4080tctaacactg gcatgttcaa agccacatta
tttctagtcc aaaattacaa gtaatcaagg 4140gtcattatgg gttaggcatt aatgtttcta
tctgattttg tgcaaaagct tcaaattaaa 4200acagctgcat tagaaaaaga ggcgcttctc
ccctccccta cacctaaagg tgtatttaaa 4260ctatcttgtg tgattaactt atttagagat
gctgtaactt aaaatagggg atatttaagg 4320tagcttcagc tagcttttag gaaaatcact
ttgtctaact cagaattatt tttaaaaaga 4380aatctggtct tgttagaaaa caaaatttta
ttttgtgctc atttaagttt caaacttact 4440attttgacag ttattttgat aacaatgaca
ctagaaaact tgactccatt tcatcattgt 4500ttctgcatga atatcataca aatcagttag
tttttaggtc aagggcttac tatttctggg 4560tcttttgcta ctaagttcac attagaatta
gtgccagaat tttaggaact tcagagatcg 4620tgtattgaga tttcttaaat aatgcttcag
atattattgc tttattgctt ttttgtattg 4680gttaaaactg tacatttaaa attgctatgt
tactattttc tacaattaat agtttgtcta 4740ttttaaaata aattagttgt taagagtctt
aa 477290928PRTHomo sapiens 90Met Pro Pro
Lys Thr Pro Arg Lys Thr Ala Ala Thr Ala Ala Ala Ala 1 5
10 15 Ala Ala Glu Pro Pro Ala Pro Pro
Pro Pro Pro Pro Pro Glu Glu Asp 20 25
30 Pro Glu Gln Asp Ser Gly Pro Glu Asp Leu Pro Leu Val
Arg Leu Glu 35 40 45
Phe Glu Glu Thr Glu Glu Pro Asp Phe Thr Ala Leu Cys Gln Lys Leu 50
55 60 Lys Ile Pro Asp
His Val Arg Glu Arg Ala Trp Leu Thr Trp Glu Lys 65 70
75 80 Val Ser Ser Val Asp Gly Val Leu Gly
Gly Tyr Ile Gln Lys Lys Lys 85 90
95 Glu Leu Trp Gly Ile Cys Ile Phe Ile Ala Ala Val Asp Leu
Asp Glu 100 105 110
Met Ser Phe Thr Phe Thr Glu Leu Gln Lys Asn Ile Glu Ile Ser Val
115 120 125 His Lys Phe Phe
Asn Leu Leu Lys Glu Ile Asp Thr Ser Thr Lys Val 130
135 140 Asp Asn Ala Met Ser Arg Leu Leu
Lys Lys Tyr Asp Val Leu Phe Ala 145 150
155 160 Leu Phe Ser Lys Leu Glu Arg Thr Cys Glu Leu Ile
Tyr Leu Thr Gln 165 170
175 Pro Ser Ser Ser Ile Ser Thr Glu Ile Asn Ser Ala Leu Val Leu Lys
180 185 190 Val Ser Trp
Ile Thr Phe Leu Leu Ala Lys Gly Glu Val Leu Gln Met 195
200 205 Glu Asp Asp Leu Val Ile Ser Phe
Gln Leu Met Leu Cys Val Leu Asp 210 215
220 Tyr Phe Ile Lys Leu Ser Pro Pro Met Leu Leu Lys Glu
Pro Tyr Lys 225 230 235
240 Thr Ala Val Ile Pro Ile Asn Gly Ser Pro Arg Thr Pro Arg Arg Gly
245 250 255 Gln Asn Arg Ser
Ala Arg Ile Ala Lys Gln Leu Glu Asn Asp Thr Arg 260
265 270 Ile Ile Glu Val Leu Cys Lys Glu His
Glu Cys Asn Ile Asp Glu Val 275 280
285 Lys Asn Val Tyr Phe Lys Asn Phe Ile Pro Phe Met Asn Ser
Leu Gly 290 295 300
Leu Val Thr Ser Asn Gly Leu Pro Glu Val Glu Asn Leu Ser Lys Arg 305
310 315 320 Tyr Glu Glu Ile Tyr
Leu Lys Asn Lys Asp Leu Asp Ala Arg Leu Phe 325
330 335 Leu Asp His Asp Lys Thr Leu Gln Thr Asp
Ser Ile Asp Ser Phe Glu 340 345
350 Thr Gln Arg Thr Pro Arg Lys Ser Asn Leu Asp Glu Glu Val Asn
Val 355 360 365 Ile
Pro Pro His Thr Pro Val Arg Thr Val Met Asn Thr Ile Gln Gln 370
375 380 Leu Met Met Ile Leu Asn
Ser Ala Ser Asp Gln Pro Ser Glu Asn Leu 385 390
395 400 Ile Ser Tyr Phe Asn Asn Cys Thr Val Asn Pro
Lys Glu Ser Ile Leu 405 410
415 Lys Arg Val Lys Asp Ile Gly Tyr Ile Phe Lys Glu Lys Phe Ala Lys
420 425 430 Ala Val
Gly Gln Gly Cys Val Glu Ile Gly Ser Gln Arg Tyr Lys Leu 435
440 445 Gly Val Arg Leu Tyr Tyr Arg
Val Met Glu Ser Met Leu Lys Ser Glu 450 455
460 Glu Glu Arg Leu Ser Ile Gln Asn Phe Ser Lys Leu
Leu Asn Asp Asn 465 470 475
480 Ile Phe His Met Ser Leu Leu Ala Cys Ala Leu Glu Val Val Met Ala
485 490 495 Thr Tyr Ser
Arg Ser Thr Ser Gln Asn Leu Asp Ser Gly Thr Asp Leu 500
505 510 Ser Phe Pro Trp Ile Leu Asn Val
Leu Asn Leu Lys Ala Phe Asp Phe 515 520
525 Tyr Lys Val Ile Glu Ser Phe Ile Lys Ala Glu Gly Asn
Leu Thr Arg 530 535 540
Glu Met Ile Lys His Leu Glu Arg Cys Glu His Arg Ile Met Glu Ser 545
550 555 560 Leu Ala Trp Leu
Ser Asp Ser Pro Leu Phe Asp Leu Ile Lys Gln Ser 565
570 575 Lys Asp Arg Glu Gly Pro Thr Asp His
Leu Glu Ser Ala Cys Pro Leu 580 585
590 Asn Leu Pro Leu Gln Asn Asn His Thr Ala Ala Asp Met Tyr
Leu Ser 595 600 605
Pro Val Arg Ser Pro Lys Lys Lys Gly Ser Thr Thr Arg Val Asn Ser 610
615 620 Thr Ala Asn Ala Glu
Thr Gln Ala Thr Ser Ala Phe Gln Thr Gln Lys 625 630
635 640 Pro Leu Lys Ser Thr Ser Leu Ser Leu Phe
Tyr Lys Lys Val Tyr Arg 645 650
655 Leu Ala Tyr Leu Arg Leu Asn Thr Leu Cys Glu Arg Leu Leu Ser
Glu 660 665 670 His
Pro Glu Leu Glu His Ile Ile Trp Thr Leu Phe Gln His Thr Leu 675
680 685 Gln Asn Glu Tyr Glu Leu
Met Arg Asp Arg His Leu Asp Gln Ile Met 690 695
700 Met Cys Ser Met Tyr Gly Ile Cys Lys Val Lys
Asn Ile Asp Leu Lys 705 710 715
720 Phe Lys Ile Ile Val Thr Ala Tyr Lys Asp Leu Pro His Ala Val Gln
725 730 735 Glu Thr
Phe Lys Arg Val Leu Ile Lys Glu Glu Glu Tyr Asp Ser Ile 740
745 750 Ile Val Phe Tyr Asn Ser Val
Phe Met Gln Arg Leu Lys Thr Asn Ile 755 760
765 Leu Gln Tyr Ala Ser Thr Arg Pro Pro Thr Leu Ser
Pro Ile Pro His 770 775 780
Ile Pro Arg Ser Pro Tyr Lys Phe Pro Ser Ser Pro Leu Arg Ile Pro 785
790 795 800 Gly Gly Asn
Ile Tyr Ile Ser Pro Leu Lys Ser Pro Tyr Lys Ile Ser 805
810 815 Glu Gly Leu Pro Thr Pro Thr Lys
Met Thr Pro Arg Ser Arg Ile Leu 820 825
830 Val Ser Ile Gly Glu Ser Phe Gly Thr Ser Glu Lys Phe
Gln Lys Ile 835 840 845
Asn Gln Met Val Cys Asn Ser Asp Arg Val Leu Lys Arg Ser Ala Glu 850
855 860 Gly Ser Asn Pro
Pro Lys Pro Leu Lys Lys Leu Arg Phe Asp Ile Glu 865 870
875 880 Gly Ser Asp Glu Ala Asp Gly Ser Lys
His Leu Pro Gly Glu Ser Lys 885 890
895 Phe Gln Gln Lys Leu Ala Glu Met Thr Ser Thr Arg Thr Arg
Met Gln 900 905 910
Lys Gln Lys Met Asn Asp Ser Met Asp Thr Ser Asn Lys Glu Glu Lys
915 920 925 911267DNAHomo
sapiens 91cgagggctgc ttccggctgg tgcccccggg ggagacccaa cctggggcga
cttcaggggt 60gccacattcg ctaagtgctc ggagttaata gcacctcctc cgagcactcg
ctcacggcgt 120ccccttgcct ggaaagatac cgcggtccct ccagaggatt tgagggacag
ggtcggaggg 180ggctcttccg ccagcaccgg aggaagaaag aggaggggct ggctggtcac
cagagggtgg 240ggcggaccgc gtgcgctcgg cggctgcgga gagggggaga gcaggcagcg
ggcggcgggg 300agcagcatgg agccggcggc ggggagcagc atggagcctt cggctgactg
gctggccacg 360gccgcggccc ggggtcgggt agaggaggtg cgggcgctgc tggaggcggg
ggcgctgccc 420aacgcaccga atagttacgg tcggaggccg atccaggtca tgatgatggg
cagcgcccga 480gtggcggagc tgctgctgct ccacggcgcg gagcccaact gcgccgaccc
cgccactctc 540acccgacccg tgcacgacgc tgcccgggag ggcttcctgg acacgctggt
ggtgctgcac 600cgggccgggg cgcggctgga cgtgcgcgat gcctggggcc gtctgcccgt
ggacctggct 660gaggagctgg gccatcgcga tgtcgcacgg tacctgcgcg cggctgcggg
gggcaccaga 720ggcagtaacc atgcccgcat agatgccgcg gaaggtccct cagacatccc
cgattgaaag 780aaccagagag gctctgagaa acctcgggaa acttagatca tcagtcaccg
aaggtcctac 840agggccacaa ctgcccccgc cacaacccac cccgctttcg tagttttcat
ttagaaaata 900gagcttttaa aaatgtcctg ccttttaacg tagatatatg ccttccccca
ctaccgtaaa 960tgtccattta tatcattttt tatatattct tataaaaatg taaaaaagaa
aaacaccgct 1020tctgcctttt cactgtgttg gagttttctg gagtgagcac tcacgcccta
agcgcacatt 1080catgtgggca tttcttgcga gcctcgcagc ctccggaagc tgtcgacttc
atgacaagca 1140ttttgtgaac tagggaagct caggggggtt actggcttct cttgagtcac
actgctagca 1200aatggcagaa ccaaagctca aataaaaata aaataatttt cattcattca
ctcaaaaaaa 1260aaaaaaa
126792156PRTHomo sapiens 92Met Glu Pro Ala Ala Gly Ser Ser Met
Glu Pro Ser Ala Asp Trp Leu 1 5 10
15 Ala Thr Ala Ala Ala Arg Gly Arg Val Glu Glu Val Arg Ala
Leu Leu 20 25 30
Glu Ala Gly Ala Leu Pro Asn Ala Pro Asn Ser Tyr Gly Arg Arg Pro
35 40 45 Ile Gln Val Met
Met Met Gly Ser Ala Arg Val Ala Glu Leu Leu Leu 50
55 60 Leu His Gly Ala Glu Pro Asn Cys
Ala Asp Pro Ala Thr Leu Thr Arg 65 70
75 80 Pro Val His Asp Ala Ala Arg Glu Gly Phe Leu Asp
Thr Leu Val Val 85 90
95 Leu His Arg Ala Gly Ala Arg Leu Asp Val Arg Asp Ala Trp Gly Arg
100 105 110 Leu Pro Val
Asp Leu Ala Glu Glu Leu Gly His Arg Asp Val Ala Arg 115
120 125 Tyr Leu Arg Ala Ala Ala Gly Gly
Thr Arg Gly Ser Asn His Ala Arg 130 135
140 Ile Asp Ala Ala Glu Gly Pro Ser Asp Ile Pro Asp 145
150 155 933878DNAHomo sapiens
93ggctccccac tctgccagag cgaggcgggg cagtgaggac tccgcgacgc gtccgcaccc
60tgcggccaga gcggctttga gctcggctgc gtccgcgcta ggcgcttttt cccagaagca
120atccaggcgc gcccgctggt tcttgagcgc caggaaaagc ccggagctaa cgaccggccg
180ctcggccact gcacggggcc ccaagccgca gaaggacgac gggagggtaa tgaagctgag
240cccaggtctc ctaggaagga gagagtgcgc cggagcagcg tgggaaagaa gggaagagtg
300tcgttaagtt tacggccaac ggtggattat ccgggccgct gcgcgtctgg gggctgcgga
360atgcgcgagg agaacaaggg catgcccagt gggggcggca gcgatgaggg tctggccagc
420gccgcggcgc ggggactagt ggagaaggtg cgacagctcc tggaagccgg cgcggatccc
480aacggagtca accgtttcgg gaggcgcgcg atccaggtca tgatgatggg cagcgcccgc
540gtggcggagc tgctgctgct ccacggcgcg gagcccaact gcgcagaccc tgccactctc
600acccgaccgg tgcatgatgc tgcccgggag ggcttcctgg acacgctggt ggtgctgcac
660cgggccgggg cgcggctgga cgtgcgcgat gcctggggtc gtctgcccgt ggacttggcc
720gaggagcggg gccaccgcga cgttgcaggg tacctgcgca cagccacggg ggactgacgc
780caggttcccc agccgcccac aacgacttta ttttcttacc caatttccca cccccaccca
840cctaattcga tgaaggctgc caacggggag cggcggaaag cctgtaagcc tgcaagcctg
900tctgagactc acaggaagga ggagccgacc gggaataacc ttccatacat ttttttcttt
960gtcttatctg gccctcgaca ctcaccatga agcgaaacac agagaagcgg atttccaggg
1020atatttagga gtgtgtgaca ttccaggggt cgtttgcttt tcagggtttt ctgagggaaa
1080gtgcatatga aatccttgac tggacctggt ggctacgaat cttccgatgg atgaatctcc
1140cactccagcg ctgagtggga gaaggcagtg attagcactt gggtgacggc agtcgatgcg
1200ttcactccaa tgtctgctga ggagttatgg tgaacccaca acttaggccc tagcggcaga
1260aaggaaaacc tgaagactga ggacaaagtg gaggagggcc gaggtgggct tcagtaagtc
1320cccggcggcg ctttagtttg agcgcatggc aagtcacatg cgtaaacgac actctctgga
1380agccctggag accctcgccc aactccacca gatagcagag gggtaagaga ggatgtgcaa
1440gcgacgacag atgctaaaat ccctggatca cgacgctgca gagcaccttt gcacaggatg
1500ctggcctttg ctcttactac actgaggaga gattcccgcg ggttccgcag gcagactaca
1560caggatgagg tggtggagtg gagtgagagc aattgtaacg gttaactgta acgttttctt
1620tcacacacac acacacacac acacacacac atgctaggat gcggaaatcc ccttatgact
1680tgctactttt tgattttgtg atattttgta ctttttagtt gttcagcaac tgtcttattt
1740aatggggaga ttttaagtaa cataactagt ggctctcagt taaaatgtga ggaagaacta
1800cagctcttaa atgtagcaat ggcactgttg caaactcagt gcaaacgcct agattgcttt
1860cttcttaacc tatttatttc tttgttaaat ttttctgatt gtttccttta tagagtgtct
1920cagggtgcag aggtcagact aagaaatatt ccaaatgtct tttagaagat agatgcactt
1980atgcagtaaa ttatcttggg atagttccca aaagattgct gaaaaagtag attgagtata
2040aaaacttgaa aatatatgat ggctcgtggg atgtcctact atcactgaac aaactaaagg
2100tgcactgctt tgggatttaa tttccagggt tgcttgatca ttatatcatt ggaacaactg
2160atacttcact actttaataa agaattaaca gagattgaac tccaagaggt gggtaatttg
2220gtttaaaaat acatgttcat gggtttacca ctaactcctg agaaatgtta aaggttcaca
2280ggggttccct tctctcaatg tttgtaataa ttgctcataa gcaataccag caattcataa
2340aaactgctta cttatgccat agaaaattaa acacaaagtg tatacatgta ttatgcttct
2400aaatgctcat tctaccagat acacatttaa aagagaaaaa aggaacagaa acaagtcatt
2460tgagagtgga gacttataag aaggagtaca tttgagttga atacacaaat ctttacttct
2520ctaccaattc ctattcccaa aatgaacata ttactgggga aagttagttg agaatcagag
2580catatgttat tggggaaagg atatgtttat tgacacataa tctgtaccag gtatgcatta
2640aaatatattt gttaatttaa tatttaaacc tgagagatag gtattgtttc ccagatgagg
2700acaatgaggc aaagaaatat caagtaactt gccaaaggtt acaagatatt cattccatgg
2760atgcacaaag aagtgcatct agttccacag ctgattatgg ttgtcttgct tttcttccca
2820ttgcaccagc ttgtcctcca aaatcatgaa tgatacacat gaagataact ttttttaaaa
2880aaaagcagaa atacacaatg atctcccttg taagctccta aggtggcttt tctttctcta
2940acttctagta aatataaacg gtttgtttga aaactatttt aaaatgtcaa caatatggag
3000aataaccccc cccaacacac ctataaaaac ccaaattttt ggaacaaaga taatggaacc
3060tccattttca aactgaagca cagggacaga aaatatattt ctagttatca cttaagcact
3120caatcattag aggctacaag aataatattt ttaaagttac agtattttac aattattaga
3180aaacattcta tataaaagaa gtcagttgat actttaaaat ctcccatttg gtttataaaa
3240tcccttaatt tgacctctat atcttaaatt ccaagatgtt taaatttgct agttgcatta
3300tactgggtca tgaaaaatta tcccttgaaa tagatatgaa acatgttact tcatttctgg
3360tttaaataac ttgtggaatc tttcctaatg acaacctgat attaagggaa actaaagaaa
3420atgttattgt ggatcccaca gtactatatt acactgtttt ttttgtttgt tttgttagtt
3480ttttttattt aaagcaaacc tcaaacatta ttgggtatca attaccacct ggttgtattg
3540aaatagtaac ttatcaatgc catgtaaaaa ttaattccat tttcgaagcc acctggcaga
3600caggtttagc tgtttcatca gcagcctaat atatactgtt aaatttgtta aggatttcac
3660tttgaaggat acatgcaaaa catatagtta ctattttcat gagtcctgct tctagctcca
3720ttgtggaata cagaaaatta aatatacctg ttaagttcgt atctaaacct aagacattac
3780caaggtttgt acaaattcta ctacctgaca tttattccaa gaagatctgg aaagttaaat
3840aaatttataa atttaataac aaaaaaaaaa aaaaaaaa
387894138PRTHomo sapiens 94Met Arg Glu Glu Asn Lys Gly Met Pro Ser Gly
Gly Gly Ser Asp Glu 1 5 10
15 Gly Leu Ala Ser Ala Ala Ala Arg Gly Leu Val Glu Lys Val Arg Gln
20 25 30 Leu Leu
Glu Ala Gly Ala Asp Pro Asn Gly Val Asn Arg Phe Gly Arg 35
40 45 Arg Ala Ile Gln Val Met Met
Met Gly Ser Ala Arg Val Ala Glu Leu 50 55
60 Leu Leu Leu His Gly Ala Glu Pro Asn Cys Ala Asp
Pro Ala Thr Leu 65 70 75
80 Thr Arg Pro Val His Asp Ala Ala Arg Glu Gly Phe Leu Asp Thr Leu
85 90 95 Val Val Leu
His Arg Ala Gly Ala Arg Leu Asp Val Arg Asp Ala Trp 100
105 110 Gly Arg Leu Pro Val Asp Leu Ala
Glu Glu Arg Gly His Arg Asp Val 115 120
125 Ala Gly Tyr Leu Arg Thr Ala Thr Gly Asp 130
135 952104DNAHomo sapiens 95ctctgccgag cctccttaaa
actctgccgt taaaatgggg gcgggttttt caactcaaaa 60agcgctcaat ttttttcttt
tcaaaaaaag ctgatgaggt cggaaaaaag ggagaagaaa 120ccggcaccct ctctgagagg
caacagaagc agcaattgtt tcagcgaaaa aagcagcaag 180ggagggagtg aaggaaaaaa
gcaaaaaagg gggcgacacg caagtgcctg taggggtgaa 240aggagcaggg accggcgatc
taggggggga tcagctacaa aagaaactgt cactgggagc 300ggtgcggcca aggaggaagc
agtgctgcca ggctctgctc cagggcacag ctggctggcg 360gctgccctgt ccgcagcaaa
ggggcacagg ccggggaccg cgagaggtgg caaagtggca 420ccgggcgccg aggctgctga
gcgctcgccg agacggcgac cggactggct gccccggaac 480tgcggcgact ctccctactc
agaacttggc ctacgtttcc caggactctc cccatctcca 540gaggccccca caaaaccggg
aaaggaagga aaggacagcg gcggcagcag ctcaatgagt 600gcctacagca gaaagcctga
acgagctcgg tcgtaggcgg gaagttcccg ggggggctgc 660ccagtgcagc cgcaatgctg
ccgcgagctg ccccagcagt ccgggctccg tagacgcttt 720ccgcatcact ctccttcctc
gggctgccgg gagtcccggg acctggcggg gccggcatga 780cgggcttctc gggggcccgc
cgcacgcccg gcagcctccg gagacgcgcg ccgagcccgg 840ctcccacggc ctctgaggct
cggcggggct gcggctgcct ggcgggcggg ctccggagct 900ttcctgagcg gcattagccc
acggcttggc ccggacgcga ccaaaggctc ttctggagaa 960gcccagagca ctgggcaatc
gttacgacct gtaacttgag ggccaccgaa ctgctactcc 1020cgttcgcctt tggcgatcat
cttttaaccc tccggagcac gtcagcatcc agccaccgcg 1080gcgctctccc agcagcggag
gacccaggac tatcccttcg gcgagacgga tggaaaccga 1140gccccctgga ggacctgccc
ctgcagttct gcctcacacg gctcaagtca ccaccgtgaa 1200caagggaccc taaagaatgg
ccgagccttg ggggaacgag ttggcgtccg cagctgccag 1260gggggaccta gagcaactta
ctagtttgtt gcaaaataat gtaaacgtca atgcacaaaa 1320tggatttgga aggactgcgc
tgcaggttat gaaacttgga aatcccgaga ttgccaggag 1380actgctactt agaggtgcta
atcccgattt gaaagaccga actggtttcg ctgtcattca 1440tgatgcggcc agagcaggtt
tcctggacac tttacagact ttgctggagt ttcaagctga 1500tgttaacatc gaggataatg
aagggaacct gcccttgcac ttggctgcca aagaaggcca 1560cctccgggtg gtggagttcc
tggtgaagca cacggccagc aatgtggggc atcggaacca 1620taagggggac accgcctgtg
atttggccag gctctatggg aggaatgagg ttgttagcct 1680gatgcaggca aacggggctg
ggggagccac aaatcttcaa taaacgtggg gagggctccc 1740ccacgttgcc tctactttat
caattaactg agtagctctc ctgactttta atgtcatttg 1800ttaaaataca gttctgtcat
atgttaagca gctaaatttt ctgaaactgc ataagtgaaa 1860atcttacaac aggcttatga
atatatttaa gcaacatctt tttaacctgc aaaatctgtt 1920ctaacatgta attgcagata
actttgactt tcttctgaat attttatctt tccttggctt 1980ttcccttgct tccccttttg
ccaatctcaa cacccaagtt gaagactttg tttttaaaat 2040ggtttgtcct gatgcttttg
tctaattaaa acactttcaa aacaggaaaa aaaaaaaaaa 2100aaaa
210496168PRTHomo sapiens
96Met Ala Glu Pro Trp Gly Asn Glu Leu Ala Ser Ala Ala Ala Arg Gly 1
5 10 15 Asp Leu Glu Gln
Leu Thr Ser Leu Leu Gln Asn Asn Val Asn Val Asn 20
25 30 Ala Gln Asn Gly Phe Gly Arg Thr Ala
Leu Gln Val Met Lys Leu Gly 35 40
45 Asn Pro Glu Ile Ala Arg Arg Leu Leu Leu Arg Gly Ala Asn
Pro Asp 50 55 60
Leu Lys Asp Arg Thr Gly Phe Ala Val Ile His Asp Ala Ala Arg Ala 65
70 75 80 Gly Phe Leu Asp Thr
Leu Gln Thr Leu Leu Glu Phe Gln Ala Asp Val 85
90 95 Asn Ile Glu Asp Asn Glu Gly Asn Leu Pro
Leu His Leu Ala Ala Lys 100 105
110 Glu Gly His Leu Arg Val Val Glu Phe Leu Val Lys His Thr Ala
Ser 115 120 125 Asn
Val Gly His Arg Asn His Lys Gly Asp Thr Ala Cys Asp Leu Ala 130
135 140 Arg Leu Tyr Gly Arg Asn
Glu Val Val Ser Leu Met Gln Ala Asn Gly 145 150
155 160 Ala Gly Gly Ala Thr Asn Leu Gln
165 971416DNAHomo sapiens 97ggagggaggg tgagttaggg
ggagacccgg cccccaaggg gcgggcgccg ggcagggccc 60cgcgggcggc cgagggttgg
gcccggctcc cagcccctcg ccgtcctccg gctgacaggg 120ggaggagccc gccgggaggg
ccggggtctc gggctgggga gccgggacgg gagagcagcg 180cagccgggtg caccgcggcc
gcgccccggg agggctgttc gggccagcgc ccgccggctg 240ctccgcgctg acagcgccgg
gctggggcgg ggcggggggc tttgcaggcc gccagtgtcg 300acatgctgct ggaggaggtt
cgcgccggcg accggctgag tggggcggcg gcccggggcg 360acgtgcagga ggtgcgccgc
cttctgcacc gcgagctggt gcatcccgac gccctcaacc 420gcttcggcaa gacggcgctg
caggtcatga tgtttggcag caccgccatc gccctggagc 480tgctgaagca aggtgccagc
cccaatgtcc aggacacctc cggtaccagt ccagtccatg 540acgcagcccg cactggattc
ctggacaccc tgaaggtcct agtggagcac ggggctgatg 600tcaacgtgcc tgatggcacc
ggggcacttc caatccatct ggcagttcaa gagggtcaca 660ctgctgtggt cagctttctg
gcagctgaat ctgatctcca tcgcagggac gccaggggtc 720tcacaccctt ggagctggca
ctgcagagag gggctcagga cctcgtggac atcctgcagg 780gccacatggt ggccccgctg
tgatctgggg tcaccctctc cagcaagaga accccgtggg 840gttatgtatc agaagagagg
ggaagaaaca ctttctcttc ttgtttctcc tgcccactgc 900tgcagtaggg gaggagcaca
gtttgtggct tataggtgtt ggttttgggg gtgtgagtgt 960ttgggggacg tttctcattt
gtttttctca ctccttttgg tgtgttggac agagaagggc 1020tcctgcaggc cacagccacc
taaacggttc agtttcttct gcgcctcagg ctgctggggc 1080ctcagacgag acccaagggc
agagcattta agagtgaagt catgacctcc agggagccta 1140gaagctggtg gccttggccg
gctgtgctca gagacctgaa gtgtgcacgt tgcttcaggc 1200atggggggtg gggggagcgt
cccaaatcaa taagaaggta gaatgagtta tgagttattc 1260atattctgtt ggaagcttgt
tttccagtct cttgtacagc gttttaaaag aaatggattc 1320tatttattat gctttattgg
aaaaaatgtt gtaataattt aatgttttta cccattaaat 1380taagacttgt gcatgatcaa
aaaaaaaaaa aaaaaa 141698166PRTHomo sapiens
98Met Leu Leu Glu Glu Val Arg Ala Gly Asp Arg Leu Ser Gly Ala Ala 1
5 10 15 Ala Arg Gly Asp
Val Gln Glu Val Arg Arg Leu Leu His Arg Glu Leu 20
25 30 Val His Pro Asp Ala Leu Asn Arg Phe
Gly Lys Thr Ala Leu Gln Val 35 40
45 Met Met Phe Gly Ser Thr Ala Ile Ala Leu Glu Leu Leu Lys
Gln Gly 50 55 60
Ala Ser Pro Asn Val Gln Asp Thr Ser Gly Thr Ser Pro Val His Asp 65
70 75 80 Ala Ala Arg Thr Gly
Phe Leu Asp Thr Leu Lys Val Leu Val Glu His 85
90 95 Gly Ala Asp Val Asn Val Pro Asp Gly Thr
Gly Ala Leu Pro Ile His 100 105
110 Leu Ala Val Gln Glu Gly His Thr Ala Val Val Ser Phe Leu Ala
Ala 115 120 125 Glu
Ser Asp Leu His Arg Arg Asp Ala Arg Gly Leu Thr Pro Leu Glu 130
135 140 Leu Ala Leu Gln Arg Gly
Ala Gln Asp Leu Val Asp Ile Leu Gln Gly 145 150
155 160 His Met Val Ala Pro Leu 165
992535DNAHomo sapiens 99ttaaggccgc gctcgccagc ctcggcgggg cggctcccgc
cgccgcaacc aatggatctc 60ctcctctgtt taaatagact cgccgtgtca atcattttct
tcttcgtcag cctcccttcc 120accgccatat tgggccacta aaaaaagggg gctcgtcttt
tcggggtgtt tttctccccc 180tcccctgtcc ccgcttgctc acggctctgc gactccgacg
ccggcaaggt ttggagagcg 240gctgggttcg cgggacccgc gggcttgcac ccgcccagac
tcggacgggc tttgccaccc 300tctccgcttg cctggtcccc tctcctctcc gccctcccgc
tcgccagtcc atttgatcag 360cggagactcg gcggccgggc cggggcttcc ccgcagcccc
tgcgcgctcc tagagctcgg 420gccgtggctc gtcggggtct gtgtcttttg gctccgaggg
cagtcgctgg gcttccgaga 480ggggttcggg ctgcgtaggg gcgctttgtt ttgttcggtt
ttgttttttt gagagtgcga 540gagaggcggt cgtgcagacc cgggagaaag atgtcaaacg
tgcgagtgtc taacgggagc 600cctagcctgg agcggatgga cgccaggcag gcggagcacc
ccaagccctc ggcctgcagg 660aacctcttcg gcccggtgga ccacgaagag ttaacccggg
acttggagaa gcactgcaga 720gacatggaag aggcgagcca gcgcaagtgg aatttcgatt
ttcagaatca caaaccccta 780gagggcaagt acgagtggca agaggtggag aagggcagct
tgcccgagtt ctactacaga 840cccccgcggc cccccaaagg tgcctgcaag gtgccggcgc
aggagagcca ggatgtcagc 900gggagccgcc cggcggcgcc tttaattggg gctccggcta
actctgagga cacgcatttg 960gtggacccaa agactgatcc gtcggacagc cagacggggt
tagcggagca atgcgcagga 1020ataaggaagc gacctgcaac cgacgattct tctactcaaa
acaaaagagc caacagaaca 1080gaagaaaatg tttcagacgg ttccccaaat gccggttctg
tggagcagac gcccaagaag 1140cctggcctca gaagacgtca aacgtaaaca gctcgaatta
agaatatgtt tccttgttta 1200tcagatacat cactgcttga tgaagcaagg aagatataca
tgaaaatttt aaaaatacat 1260atcgctgact tcatggaatg gacatcctgt ataagcactg
aaaaacaaca acacaataac 1320actaaaattt taggcactct taaatgatct gcctctaaaa
gcgttggatg tagcattatg 1380caattaggtt tttccttatt tgcttcattg tactacctgt
gtatatagtt tttacctttt 1440atgtagcaca taaactttgg ggaagggagg gcagggtggg
gctgaggaac tgacgtggag 1500cggggtatga agagcttgct ttgatttaca gcaagtagat
aaatatttga cttgcatgaa 1560gagaagcaat tttggggaag ggtttgaatt gttttcttta
aagatgtaat gtccctttca 1620gagacagctg atacttcatt taaaaaaatc acaaaaattt
gaacactggc taaagataat 1680tgctatttat ttttacaaga agtttattct catttgggag
atctggtgat ctcccaagct 1740atctaaagtt tgttagatag ctgcatgtgg cttttttaaa
aaagcaacag aaacctatcc 1800tcactgccct ccccagtctc tcttaaagtt ggaatttacc
agttaattac tcagcagaat 1860ggtgatcact ccaggtagtt tggggcaaaa atccgaggtg
cttgggagtt ttgaatgtta 1920agaattgacc atctgctttt attaaatttg ttgacaaaat
tttctcattt tcttttcact 1980tcgggctgtg taaacacagt caaaataatt ctaaatccct
cgatattttt aaagatctgt 2040aagtaacttc acattaaaaa atgaaatatt ttttaattta
aagcttactc tgtccattta 2100tccacaggaa agtgttattt ttcaaggaag gttcatgtag
agaaaagcac acttgtagga 2160taagtgaaat ggatactaca tctttaaaca gtatttcatt
gcctgtgtat ggaaaaacca 2220tttgaagtgt acctgtgtac ataactctgt aaaaacactg
aaaaattata ctaacttatt 2280tatgttaaaa gatttttttt aatctagaca atatacaagc
caaagtggca tgttttgtgc 2340atttgtaaat gctgtgttgg gtagaatagg ttttcccctc
ttttgttaaa taatatggct 2400atgcttaaaa ggttgcatac tgagccaagt ataatttttt
gtaatgtgtg aaaaagatgc 2460caattattgt tacacattaa gtaatcaata aagaaaactt
ccatagctat tcattgagtc 2520aaaaaaaaaa aaaaa
2535100198PRTHomo sapiens 100Met Ser Asn Val Arg
Val Ser Asn Gly Ser Pro Ser Leu Glu Arg Met 1 5
10 15 Asp Ala Arg Gln Ala Glu His Pro Lys Pro
Ser Ala Cys Arg Asn Leu 20 25
30 Phe Gly Pro Val Asp His Glu Glu Leu Thr Arg Asp Leu Glu Lys
His 35 40 45 Cys
Arg Asp Met Glu Glu Ala Ser Gln Arg Lys Trp Asn Phe Asp Phe 50
55 60 Gln Asn His Lys Pro Leu
Glu Gly Lys Tyr Glu Trp Gln Glu Val Glu 65 70
75 80 Lys Gly Ser Leu Pro Glu Phe Tyr Tyr Arg Pro
Pro Arg Pro Pro Lys 85 90
95 Gly Ala Cys Lys Val Pro Ala Gln Glu Ser Gln Asp Val Ser Gly Ser
100 105 110 Arg Pro
Ala Ala Pro Leu Ile Gly Ala Pro Ala Asn Ser Glu Asp Thr 115
120 125 His Leu Val Asp Pro Lys Thr
Asp Pro Ser Asp Ser Gln Thr Gly Leu 130 135
140 Ala Glu Gln Cys Ala Gly Ile Arg Lys Arg Pro Ala
Thr Asp Asp Ser 145 150 155
160 Ser Thr Gln Asn Lys Arg Ala Asn Arg Thr Glu Glu Asn Val Ser Asp
165 170 175 Gly Ser Pro
Asn Ala Gly Ser Val Glu Gln Thr Pro Lys Lys Pro Gly 180
185 190 Leu Arg Arg Arg Gln Thr
195 1011943DNAHomo sapiens 101agtgcgctgt gctcgagggg
tgccggccag gcctgagcga gcgagctagc cagcaggcat 60cgagggggcg cggctgccgt
ccggacgaga caggcgaacc cgacgcagaa gagtccacca 120ccggacagcc aggtagccgc
cgcgtccctc gcacacgcag agtcgggcgg cgcggggtct 180cccttgcgcc cggcctccgc
cctctcctcc tctcctttcc ccttcttctc gctgtcctct 240cctctctcgc tgcccgcgtt
tgcgcagccc cgggccatgt ccgacgcgtc cctccgcagc 300acatccacga tggagcgtct
tgtcgcccgt gggaccttcc cagtactagt gcgcaccagc 360gcctgccgca gcctcttcgg
gccggtggac cacgaggagc tgagccgcga gctgcaggcc 420cgcctggccg agctgaacgc
cgaggaccag aaccgctggg attacgactt ccagcaggac 480atgccgctgc ggggccctgg
acgcctgcag tggaccgaag tggacagcga ctcggtgccc 540gcgttctacc gcgagacggt
gcaggtgggg cgctgccgcc tgctgctggc gccgcggccc 600gtcgcggtcg cggtggctgt
cagcccgccc ctcgagccgg ccgctgagtc cctcgacggc 660ctcgaggagg cgccggagca
gctgcctagt gtcccggtcc cggccccggc gtccaccccg 720cccccagtcc cggtcctggc
tccagccccg gccccggctc cggctccggt cgcggctccg 780gtcgcggctc cggtcgcggt
cgcggtcctg gccccggccc cggccccggc tccggctccg 840gctccggccc cggctccagt
cgcggccccg gccccagccc cggccccggc cccggccccg 900gcccccgccc cggccccggc
cccggacgcg gcgcctcaag agagcgccga gcagggcgcg 960aaccaggggc agcgcggcca
ggagcctctc gctgaccagc tgcactcggg gatttcggga 1020cgtcccgcgg ccggcaccgc
ggccgccagc gccaacggcg cggcgatcaa gaagctgtcc 1080gggcctctga tctccgattt
cttcgccaag cgcaagagat cagcgcctga gaagtcgtcg 1140ggcgatgtcc ccgcgccgtg
tccctctcca agcgccgccc ctggcgtggg ctcggtggag 1200cagaccccgc gcaagaggct
gcggtgagcc aatttagagc ccaaagagcc ccgagggaac 1260ctgccggggc agcggacgtt
ggaagggcgc tgggcctcgg ctgggaccgt tcatgtagca 1320gcaaccggcg gcggctgccg
cagagcagcg ttcggttttg tttttaaatt ttgaaaactg 1380tgcaatgtat taataacgtc
tttttatatc taaatgtatt ctgcacgaga aggtacactg 1440gtcccaaggt gtaaagcttt
aagagtcatt tatataaaat gtttaatctc tgctgaaact 1500cagtgcaaaa aaaagaaaaa
agaaaaaaaa aaggaaaaaa taaaaaaacc atgtatattt 1560gtacaaaaag tttttaaagt
tatactaact tatattttct atttatgtcc aggcgtggac 1620cgctctgcca cgcactagct
cggttattgg ttatgccaaa ggcactctcc atctcccaca 1680tctggttatt gacaagtgta
actttatttt catcgcggac tctggggaag ggggtcactc 1740acaagctgta gctgccatac
atgcccatct agcttgcagt ctcttcgcgc tttcgctgtc 1800tctcttatta tgactgtgtt
tatctgaaac ttgaagacaa gtctgttaaa atggttcctg 1860agccgtctgt accactgccc
cggcccctcg tccgccgggt tctaaataaa gaggccgaaa 1920aatgctgcaa aaaaaaaaaa
aaa 1943102316PRTHomo sapiens
102Met Ser Asp Ala Ser Leu Arg Ser Thr Ser Thr Met Glu Arg Leu Val 1
5 10 15 Ala Arg Gly Thr
Phe Pro Val Leu Val Arg Thr Ser Ala Cys Arg Ser 20
25 30 Leu Phe Gly Pro Val Asp His Glu Glu
Leu Ser Arg Glu Leu Gln Ala 35 40
45 Arg Leu Ala Glu Leu Asn Ala Glu Asp Gln Asn Arg Trp Asp
Tyr Asp 50 55 60
Phe Gln Gln Asp Met Pro Leu Arg Gly Pro Gly Arg Leu Gln Trp Thr 65
70 75 80 Glu Val Asp Ser Asp
Ser Val Pro Ala Phe Tyr Arg Glu Thr Val Gln 85
90 95 Val Gly Arg Cys Arg Leu Leu Leu Ala Pro
Arg Pro Val Ala Val Ala 100 105
110 Val Ala Val Ser Pro Pro Leu Glu Pro Ala Ala Glu Ser Leu Asp
Gly 115 120 125 Leu
Glu Glu Ala Pro Glu Gln Leu Pro Ser Val Pro Val Pro Ala Pro 130
135 140 Ala Ser Thr Pro Pro Pro
Val Pro Val Leu Ala Pro Ala Pro Ala Pro 145 150
155 160 Ala Pro Ala Pro Val Ala Ala Pro Val Ala Ala
Pro Val Ala Val Ala 165 170
175 Val Leu Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro
180 185 190 Ala Pro
Val Ala Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro Ala Pro 195
200 205 Ala Pro Ala Pro Ala Pro Ala
Pro Asp Ala Ala Pro Gln Glu Ser Ala 210 215
220 Glu Gln Gly Ala Asn Gln Gly Gln Arg Gly Gln Glu
Pro Leu Ala Asp 225 230 235
240 Gln Leu His Ser Gly Ile Ser Gly Arg Pro Ala Ala Gly Thr Ala Ala
245 250 255 Ala Ser Ala
Asn Gly Ala Ala Ile Lys Lys Leu Ser Gly Pro Leu Ile 260
265 270 Ser Asp Phe Phe Ala Lys Arg Lys
Arg Ser Ala Pro Glu Lys Ser Ser 275 280
285 Gly Asp Val Pro Ala Pro Cys Pro Ser Pro Ser Ala Ala
Pro Gly Val 290 295 300
Gly Ser Val Glu Gln Thr Pro Arg Lys Arg Leu Arg 305 310
315 1032175DNAHomo sapiens 103gttgtatatc agggccgcgc
tgagctgcgc cagctgaggt gtgagcagct gccgaagtca 60gttccttgtg gagccggagc
tgggcgcgga ttcgccgagg caccgaggca ctcagaggag 120gcgccatgtc agaaccggct
ggggatgtcc gtcagaaccc atgcggcagc aaggcctgcc 180gccgcctctt cggcccagtg
gacagcgagc agctgagccg cgactgtgat gcgctaatgg 240cgggctgcat ccaggaggcc
cgtgagcgat ggaacttcga ctttgtcacc gagacaccac 300tggagggtga cttcgcctgg
gagcgtgtgc ggggccttgg cctgcccaag ctctaccttc 360ccacggggcc ccggcgaggc
cgggatgagt tgggaggagg caggcggcct ggcacctcac 420ctgctctgct gcaggggaca
gcagaggaag accatgtgga cctgtcactg tcttgtaccc 480ttgtgcctcg ctcaggggag
caggctgaag ggtccccagg tggacctgga gactctcagg 540gtcgaaaacg gcggcagacc
agcatgacag atttctacca ctccaaacgc cggctgatct 600tctccaagag gaagccctaa
tccgcccaca ggaagcctgc agtcctggaa gcgcgagggc 660ctcaaaggcc cgctctacat
cttctgcctt agtctcagtt tgtgtgtctt aattattatt 720tgtgttttaa tttaaacacc
tcctcatgta cataccctgg ccgccccctg ccccccagcc 780tctggcatta gaattattta
aacaaaaact aggcggttga atgagaggtt cctaagagtg 840ctgggcattt ttattttatg
aaatactatt taaagcctcc tcatcccgtg ttctcctttt 900cctctctccc ggaggttggg
tgggccggct tcatgccagc tacttcctcc tccccacttg 960tccgctgggt ggtaccctct
ggaggggtgt ggctccttcc catcgctgtc acaggcggtt 1020atgaaattca ccccctttcc
tggacactca gacctgaatt ctttttcatt tgagaagtaa 1080acagatggca ctttgaaggg
gcctcaccga gtgggggcat catcaaaaac tttggagtcc 1140cctcacctcc tctaaggttg
ggcagggtga ccctgaagtg agcacagcct agggctgagc 1200tggggacctg gtaccctcct
ggctcttgat acccccctct gtcttgtgaa ggcaggggga 1260aggtggggtc ctggagcaga
ccaccccgcc tgccctcatg gcccctctga cctgcactgg 1320ggagcccgtc tcagtgttga
gccttttccc tctttggctc ccctgtacct tttgaggagc 1380cccagctacc cttcttctcc
agctgggctc tgcaattccc ctctgctgct gtccctcccc 1440cttgtccttt cccttcagta
ccctctcagc tccaggtggc tctgaggtgc ctgtcccacc 1500cccaccccca gctcaatgga
ctggaagggg aagggacaca caagaagaag ggcaccctag 1560ttctacctca ggcagctcaa
gcagcgaccg ccccctcctc tagctgtggg ggtgagggtc 1620ccatgtggtg gcacaggccc
ccttgagtgg ggttatctct gtgttagggg tatatgatgg 1680gggagtagat ctttctagga
gggagacact ggcccctcaa atcgtccagc gaccttcctc 1740atccacccca tccctcccca
gttcattgca ctttgattag cagcggaaca aggagtcaga 1800cattttaaga tggtggcagt
agaggctatg gacagggcat gccacgtggg ctcatatggg 1860gctgggagta gttgtctttc
ctggcactaa cgttgagccc ctggaggcac tgaagtgctt 1920agtgtacttg gagtattggg
gtctgacccc aaacaccttc cagctcctgt aacatactgg 1980cctggactgt tttctctcgg
ctccccatgt gtcctggttc ccgtttctcc acctagactg 2040taaacctctc gagggcaggg
accacaccct gtactgttct gtgtctttca cagctcctcc 2100cacaatgctg aatatacagc
aggtgctcaa taaatgattc ttagtgactt tacttgtaaa 2160aaaaaaaaaa aaaaa
2175104164PRTHomo sapiens
104Met Ser Glu Pro Ala Gly Asp Val Arg Gln Asn Pro Cys Gly Ser Lys 1
5 10 15 Ala Cys Arg Arg
Leu Phe Gly Pro Val Asp Ser Glu Gln Leu Ser Arg 20
25 30 Asp Cys Asp Ala Leu Met Ala Gly Cys
Ile Gln Glu Ala Arg Glu Arg 35 40
45 Trp Asn Phe Asp Phe Val Thr Glu Thr Pro Leu Glu Gly Asp
Phe Ala 50 55 60
Trp Glu Arg Val Arg Gly Leu Gly Leu Pro Lys Leu Tyr Leu Pro Thr 65
70 75 80 Gly Pro Arg Arg Gly
Arg Asp Glu Leu Gly Gly Gly Arg Arg Pro Gly 85
90 95 Thr Ser Pro Ala Leu Leu Gln Gly Thr Ala
Glu Glu Asp His Val Asp 100 105
110 Leu Ser Leu Ser Cys Thr Leu Val Pro Arg Ser Gly Glu Gln Ala
Glu 115 120 125 Gly
Ser Pro Gly Gly Pro Gly Asp Ser Gln Gly Arg Lys Arg Arg Gln 130
135 140 Thr Ser Met Thr Asp Phe
Tyr His Ser Lys Arg Arg Leu Ile Phe Ser 145 150
155 160 Lys Arg Lys Pro 1053808DNAHomo sapiens
105cttcctggac tggggatccc ggctaaatat agctgtttct gtcttacaac acaggctcca
60gtatataaat caggcaaatt ccccatttga gcatgaacct ctgaaaactg ccggcatctg
120aggtttcctc caaggccctc tgaagtgcag cccataatga aggtcttggc ggcagtacac
180agcccagggg gagccgttcc ccaacaacct ggacaagcta tgtggcccca acgtgacgga
240cttcccgccc ttccacgcca acggcacgga gaaggccaag ctggtggagc tgtaccgcat
300agtcgtgtac cttggcacct ccctgggcaa catcacccgg gaccagaaga tcctcaaccc
360cagtgccctc agcctccaca gcaagctcaa cgccaccgcc gacatcctgc gaggcctcct
420tagcaacgtg ctgtgccgcc tgtgcagcaa gtaccacgtg ggccatgtgg acgtgaccta
480cggccctgac acctcgggta aggatgtctt ccagaagaag aagctgggct gtcaactcct
540ggggaagtat aagcagatca tcgccgtgtt ggcccaggcc ttctagcagg aggtcttgaa
600gtgtgctgtg aaccgaggga tctcaggagt tgggtccaga tgtgggggcc tgtccaaggg
660tggctggggc ccagggcatc gctaaaccca aatgggggct gctggcagac cccgagggtg
720cctggccagt ccactccact ctgggctggg ctgtgatgaa gctgagcaga gtggaaactt
780ccatagggag ggagctagaa gaaggtgccc cttcctctgg gagattgtgg actggggagc
840gtgggctgga cttctgcctc tacttgtccc tttggcccct tgctcacttt gtgcagtgaa
900caaactacac aagtcatcta caagagccct gaccacaggg tgagacagca gggcccaggg
960gagtggacca gcccccagca aattatcacc atctgtgcct ttgctgcccc ttaggttggg
1020acttaggtgg gccagagggg ctaggatccc aaaggactcc ttgtccccta gaagtttgat
1080gagtggaaga tagagagggg cctctgggat ggaaggctgt cttcttttga ggatgatcag
1140agaacttggg cataggaaca atctggcaga agtttccaga aggaggtcac ttggcattca
1200ggctcttggg gaggcagaga agccaccttc aggcctggga aggaagacac tgggaggagg
1260agaggcctgg aaagctttgg taggttcttc gttctcttcc ccgtgatctt ccctgcagcc
1320tgggatggcc agggtctgat ggctggacct gcagcagggg tttgtggagg tgggtagggc
1380aggggcaggt tgctaagtca ggtgcagagg ttctgaggga cccaggctct tcctctgggt
1440aaaggtctgt aagaaggggc tggggtagct cagagtagca gctcacatct gaggccctgg
1500gaggccttgt gaggtcacac agaggtactt gagggggact ggaggccgtc tctggtcccc
1560agggcaaggg aacagcagaa cttagggtca gggtctcagg gaaccctgag ctccaagcgt
1620gctgtgcgtc tgacctggca tgatttctat ttattatgat atcctattta tattaactta
1680ttggtgcttt cagtggccaa gttaattccc ctttccctgg tccctactca acaaaatatg
1740atgatggctc ccgacacaag cgccagggcc agggcttagc agggcctggt ctggaagtcg
1800acaatgttac aagtggaata agccttacgg gtgaagctca gagaagggtc ggatctgaga
1860gaatggggag gcctgagtgg gagtgggggg ccttgctcca ccccccccca tcccctactg
1920tgacttgctt tagggtgtca gggtccaggc tgcaggggct gggccaattt gtggagaggc
1980cgggtgcctt tctgtcttga ttccaggggg ctggttcaca ctgttcttgg gcgccccagc
2040attgtgttgt gaggcgcact gttcctggca gatattgtgc cccctggagc agtgggcaag
2100acagtccttg tggcccaccc tgtccttgtt tctgtgtccc catgctgcct ctgaaatagc
2160gccctggaac aaccctgccc ctgcacccag catgctccga cacagcaggg aagctcctcc
2220tgtggcccgg acacccatag acggtgcggg gggcctggct gggccagacc ccaggaaggt
2280ggggtagact ggggggatca gctgcccatt gctcccaaga ggaggagagg gaggctgcag
2340atgcctggga ctcagaccag gaagctgtgg gccctcctgc tccaccccca tcccactccc
2400acccatgtct gggctcccag gcagggaacc cgatctcttc ctttgtgctg gggccaggcg
2460agtggagaaa cgccctccag tctgagagca ggggagggaa ggaggcagca gagttggggc
2520agctgctcag agcagtgttc tggcttcttc tcaaaccctg agcgggctgc cggcctccaa
2580gttcctccga caagatgatg gtactaatta tggtactttt cactcacttt gcacctttcc
2640ctgtcgctct ctaagcactt tacctggatg gcgcgtgggc agtgtgcagg caggtcctga
2700ggcctggggt tggggtggag ggtgcggccc ggagttgtcc atctgtccat cccaacagca
2760agacgaggat gtggctgttg agatgtgggc cacactcacc cttgtccagg atgcagggac
2820tgccttctcc ttcctgcttc atccggctta gcttggggct ggctgcattc ccccaggatg
2880ggcttcgaga aagacaaact tgtctggaaa ccagagttgc tgattccacc cggggggccc
2940ggctgactcg cccatcacct catctccctg tggacttggg agctctgtgc caggcccacc
3000ttgcggccct ggctctgagt cgctctccca cccagcctgg acttggcccc atgggaccca
3060tcctcagtgc tccctccaga tcccgtccgg cagcttggcg tccaccctgc acagcatcac
3120tgaatcacag agcctttgcg tgaaacagct ctgccaggcc gggagctggg tttctcttcc
3180ctttttatct gctggtgtgg accacacctg ggcctggccg gaggaagaga gagtttacca
3240agagagatgt ctccgggccc ttatttatta tttaaacatt tttttaaaaa gcactgctag
3300tttacttgtc tctcctcccc atcgtcccca tcgtcctcct tgtccctgac ttggggcact
3360tccaccctga cccagccagt ccagctctgc cttgccggct ctccagagta gacatagtgt
3420gtggggttgg agctctggca cccggggagg tagcatttcc ctgcagatgg tacagatgtt
3480cctgccttag agtcatctct agttccccac ctcaatcccg gcatccagcc ttcagtcccg
3540cccacgtgct agctccgtgg gcccaccgtg cggccttaga ggtttccctc cttcctttcc
3600actgaaaagc acatggcctt gggtgacaaa ttcctctttg atgaatgtac cctgtgggga
3660tgtttcatac tgacagatta tttttattta ttcaatgtca tatttaaaat atttattttt
3720tataccaaat gaatactttt ttttttaaga aaaaaaagag aaatgaataa agaatctact
3780cttggctggc aaaaaaaaaa aaaaaaaa
380810688PRTHomo sapiens 106Met Lys Val Leu Ala Ala Val His Ser Pro Gly
Gly Ala Val Pro Gln 1 5 10
15 Gln Pro Gly Gln Ala Met Trp Pro Gln Arg Asp Gly Leu Pro Ala Leu
20 25 30 Pro Arg
Gln Arg His Gly Glu Gly Gln Ala Gly Gly Ala Val Pro His 35
40 45 Ser Arg Val Pro Trp His Leu
Pro Gly Gln His His Pro Gly Pro Glu 50 55
60 Asp Pro Gln Pro Gln Cys Pro Gln Pro Pro Gln Gln
Ala Gln Arg His 65 70 75
80 Arg Arg His Pro Ala Arg Pro Pro 85
1072747DNAHomo sapiens 107gtcggaggga gggagggagg gagagaaaga aagagagaaa
aagaaggaaa gggagaggga 60gacggctgga gcccgaggac gagcgcggag ccgcggaccg
agcggggggc gggagacagg 120aaggagggag gcgagcagag ggaaggggaa gaggtcgggg
agcgagggcg ggagcggtcg 180cggtcgcgat cgagcaagca agcgggcgag aggacgccct
cccctggcct ccagtgcgcc 240gcttccctcg ccgccgcccc gccagcatgc ccggcgtggc
ccgcctgccg ctgctgctcg 300ggctgctgct gctcccgcgt cccggccggc cgctggactt
ggccgactac acctatgacc 360tggcggagga ggacgactcg gagcccctca actacaaaga
cccctgcaag gcggctgcct 420ttcttgggga cattgccctg gacgaagagg acctgagggc
cttccaggta cagcaggctg 480tggatctcag acggcacaca gctcgtaagt cctccatcaa
agctgcagtt ccaggaaaca 540cttctacccc cagctgccag agcaccaacg ggcagcctca
gaggggagcc tgtgggagat 600ggagaggtag atcccgtagc cggcgggcgg cgacgtcccg
accagagcgt gtgtggcccg 660atggggtcat cccctttgtc attgggggaa acttcactgg
tagccagagg gcagtcttcc 720ggcaggccat gaggcactgg gagaagcaca cctgtgtcac
cttcctggag cgcactgacg 780aggacagcta tattgtgttc acctatcgac cttgcgggtg
ctgctcctac gtgggtcgcc 840gcggcggggg cccccaggcc atctccatcg gcaagaactg
tgacaagttc ggcattgtgg 900tccacgagct gggccacgtc gtcggcttct ggcacgaaca
cactcggcca gaccgggacc 960gccacgtttc catcgttcgt gagaacatcc agccagggca
ggagtataac ttcctgaaga 1020tggagcctca ggaggtggag tccctggggg agacctatga
cttcgacagc atcatgcatt 1080acgctcggaa cacattctcc aggggcatct tcctggatac
cattgtcccc aagtatgagg 1140tgaacggggt gaaacctccc attggccaaa ggacacggct
cagcaagggg gacattgccc 1200aagcccgcaa gctttacaag tgcccagcct gtggagagac
cctgcaagac agcacaggca 1260acttctcctc ccctgaatac cccaatggct actctgctca
catgcactgc gtgtggcgca 1320tctctgtcac acccggggag aagatcatcc tgaacttcac
gtccctggac ctgtaccgca 1380gccgcctgtg ctggtacgac tatgtggagg tccgagatgg
cttctggagg aaggcgcccc 1440tccgaggccg cttctgcggg tccaaactcc ctgagcctat
cgtctccact gacagccgcc 1500tctgggttga attccgcagc agcagcaatt gggttggaaa
gggcttcttt gcagtctacg 1560aagccatctg cgggggtgat gtgaaaaagg actatggcca
cattcaatcg cccaactacc 1620cagacgatta ccggcccagc aaagtctgca tctggcggat
ccaggtgtct gagggcttcc 1680acgtgggcct cacattccag tcctttgaga ttgagcgcca
cgacagctgt gcctacgact 1740atctggaggt gcgcgacggg cacagtgaga gcagcaccct
catcgggcgc tactgtggct 1800atgagaagcc tgatgacatc aagagcacgt ccagccgcct
ctggctcaag ttcgtctctg 1860acgggtccat taacaaagcg ggctttgccg tcaacttttt
caaagaggtg gacgagtgct 1920ctcggcccaa ccgcgggggc tgtgagcagc ggtgcctcaa
caccctgggc agctacaagt 1980gcagctgtga ccccgggtac gagctggccc cagacaagcg
ccgctgtgag gctgcttgtg 2040gcggattcct caccaagctc aacggctcca tcaccagccc
gggctggccc aaggagtacc 2100cccccaacaa gaactgcatc tggcagctgg tggcccccac
ccagtaccgc atctccctgc 2160agtttgactt ctttgagaca gagggcaatg atgtgtgcaa
gtacgacttc gtggaggtgc 2220gcagtggact cacagctgac tccaagctgc atggcaagtt
ctgtggttct gagaagcccg 2280aggtcatcac ctcccagtac aacaacatgc gcgtggagtt
caagtccgac aacaccgtgt 2340ccaaaaaggg cttcaaggcc cacttcttct cagaaaagag
gccagctctg cagccccctc 2400ggggacgccc ccaccagctc aaattccgag tgcagaaaag
aaaccggacc ccccagtgag 2460gcctgccagg cctcccggac cccttgttac tcaggaacct
caccttggac ggaatgggat 2520gggggcttcg gtgcccacca accccccacc tccactctgc
cattccggcc cacctccctc 2580tggccggaca gaactggtgc tctcttctcc ccactgtgcc
cgtccgcgga ccggggaccc 2640ttccccgtgc cctaccccct cccattttga tggtgtctgt
gacatttcct gttgtgaagt 2700aaaagaggga cccctgcgtc ctgctccttt ctcttgcaga
aaaaaaa 2747108730PRTHomo sapiens 108Met Pro Gly Val Ala
Arg Leu Pro Leu Leu Leu Gly Leu Leu Leu Leu 1 5
10 15 Pro Arg Pro Gly Arg Pro Leu Asp Leu Ala
Asp Tyr Thr Tyr Asp Leu 20 25
30 Ala Glu Glu Asp Asp Ser Glu Pro Leu Asn Tyr Lys Asp Pro Cys
Lys 35 40 45 Ala
Ala Ala Phe Leu Gly Asp Ile Ala Leu Asp Glu Glu Asp Leu Arg 50
55 60 Ala Phe Gln Val Gln Gln
Ala Val Asp Leu Arg Arg His Thr Ala Arg 65 70
75 80 Lys Ser Ser Ile Lys Ala Ala Val Pro Gly Asn
Thr Ser Thr Pro Ser 85 90
95 Cys Gln Ser Thr Asn Gly Gln Pro Gln Arg Gly Ala Cys Gly Arg Trp
100 105 110 Arg Gly
Arg Ser Arg Ser Arg Arg Ala Ala Thr Ser Arg Pro Glu Arg 115
120 125 Val Trp Pro Asp Gly Val Ile
Pro Phe Val Ile Gly Gly Asn Phe Thr 130 135
140 Gly Ser Gln Arg Ala Val Phe Arg Gln Ala Met Arg
His Trp Glu Lys 145 150 155
160 His Thr Cys Val Thr Phe Leu Glu Arg Thr Asp Glu Asp Ser Tyr Ile
165 170 175 Val Phe Thr
Tyr Arg Pro Cys Gly Cys Cys Ser Tyr Val Gly Arg Arg 180
185 190 Gly Gly Gly Pro Gln Ala Ile Ser
Ile Gly Lys Asn Cys Asp Lys Phe 195 200
205 Gly Ile Val Val His Glu Leu Gly His Val Val Gly Phe
Trp His Glu 210 215 220
His Thr Arg Pro Asp Arg Asp Arg His Val Ser Ile Val Arg Glu Asn 225
230 235 240 Ile Gln Pro Gly
Gln Glu Tyr Asn Phe Leu Lys Met Glu Pro Gln Glu 245
250 255 Val Glu Ser Leu Gly Glu Thr Tyr Asp
Phe Asp Ser Ile Met His Tyr 260 265
270 Ala Arg Asn Thr Phe Ser Arg Gly Ile Phe Leu Asp Thr Ile
Val Pro 275 280 285
Lys Tyr Glu Val Asn Gly Val Lys Pro Pro Ile Gly Gln Arg Thr Arg 290
295 300 Leu Ser Lys Gly Asp
Ile Ala Gln Ala Arg Lys Leu Tyr Lys Cys Pro 305 310
315 320 Ala Cys Gly Glu Thr Leu Gln Asp Ser Thr
Gly Asn Phe Ser Ser Pro 325 330
335 Glu Tyr Pro Asn Gly Tyr Ser Ala His Met His Cys Val Trp Arg
Ile 340 345 350 Ser
Val Thr Pro Gly Glu Lys Ile Ile Leu Asn Phe Thr Ser Leu Asp 355
360 365 Leu Tyr Arg Ser Arg Leu
Cys Trp Tyr Asp Tyr Val Glu Val Arg Asp 370 375
380 Gly Phe Trp Arg Lys Ala Pro Leu Arg Gly Arg
Phe Cys Gly Ser Lys 385 390 395
400 Leu Pro Glu Pro Ile Val Ser Thr Asp Ser Arg Leu Trp Val Glu Phe
405 410 415 Arg Ser
Ser Ser Asn Trp Val Gly Lys Gly Phe Phe Ala Val Tyr Glu 420
425 430 Ala Ile Cys Gly Gly Asp Val
Lys Lys Asp Tyr Gly His Ile Gln Ser 435 440
445 Pro Asn Tyr Pro Asp Asp Tyr Arg Pro Ser Lys Val
Cys Ile Trp Arg 450 455 460
Ile Gln Val Ser Glu Gly Phe His Val Gly Leu Thr Phe Gln Ser Phe 465
470 475 480 Glu Ile Glu
Arg His Asp Ser Cys Ala Tyr Asp Tyr Leu Glu Val Arg 485
490 495 Asp Gly His Ser Glu Ser Ser Thr
Leu Ile Gly Arg Tyr Cys Gly Tyr 500 505
510 Glu Lys Pro Asp Asp Ile Lys Ser Thr Ser Ser Arg Leu
Trp Leu Lys 515 520 525
Phe Val Ser Asp Gly Ser Ile Asn Lys Ala Gly Phe Ala Val Asn Phe 530
535 540 Phe Lys Glu Val
Asp Glu Cys Ser Arg Pro Asn Arg Gly Gly Cys Glu 545 550
555 560 Gln Arg Cys Leu Asn Thr Leu Gly Ser
Tyr Lys Cys Ser Cys Asp Pro 565 570
575 Gly Tyr Glu Leu Ala Pro Asp Lys Arg Arg Cys Glu Ala Ala
Cys Gly 580 585 590
Gly Phe Leu Thr Lys Leu Asn Gly Ser Ile Thr Ser Pro Gly Trp Pro
595 600 605 Lys Glu Tyr Pro
Pro Asn Lys Asn Cys Ile Trp Gln Leu Val Ala Pro 610
615 620 Thr Gln Tyr Arg Ile Ser Leu Gln
Phe Asp Phe Phe Glu Thr Glu Gly 625 630
635 640 Asn Asp Val Cys Lys Tyr Asp Phe Val Glu Val Arg
Ser Gly Leu Thr 645 650
655 Ala Asp Ser Lys Leu His Gly Lys Phe Cys Gly Ser Glu Lys Pro Glu
660 665 670 Val Ile Thr
Ser Gln Tyr Asn Asn Met Arg Val Glu Phe Lys Ser Asp 675
680 685 Asn Thr Val Ser Lys Lys Gly Phe
Lys Ala His Phe Phe Ser Glu Lys 690 695
700 Arg Pro Ala Leu Gln Pro Pro Arg Gly Arg Pro His Gln
Leu Lys Phe 705 710 715
720 Arg Val Gln Lys Arg Asn Arg Thr Pro Gln 725
730 1093150DNAHomo sapiens 109ccacaaaggg cacttggccc cagggctagg
agagcgaggg gagagcacag ccacccgcct 60cggcggcccg ggactcggct cgactcgccg
gagaatgcgc ccgaggacga cggggcgcca 120gagccgcggt gctttcaact ggcgagcgcg
aatgggggtg cactggagta aggcagagtg 180atgcgggggg gcaactcgcc tggcaccgag
atcgccgccg tgcccttccc tggacccggc 240gtcgcccagg atggctgccc cgagccatgg
gccgcggcgg agctagcgcg gagcgcccga 300ccctcgaccc ccgagtcccg gagccggccc
cgcgcggggc cacgcgtccc tcgggcgctg 360gttcctaagg aggacgacag caccagcttc
tcctttctcc cttcccttcc ctgccccgca 420ctcctccccc tgctcgctgt tgttgtgtgt
cagcacttgg ctggggactt cttgaacttg 480cagggagaat aacttgcgca ccccactttg
cgccggtgcc tttgccccag cggagcctgc 540ttcgccatct ccgagcccca ccgcccctcc
actcctcggc cttgcccgac actgagacgc 600tgttcccagc gtgaaaagag agactgcgcg
gccggcaccc gggagaagga ggaggcaaag 660aaaaggaacg gacattcggt ccttgcgcca
ggtcctttga ccagagtttt tccatgtgga 720cgctctttca atggacgtgt ccccgcgtgc
ttcttagacg gactgcggtc tcctaaaggt 780cgaccatggt ggccgggacc cgctgtcttc
tagcgttgct gcttccccag gtcctcctgg 840gcggcgcggc tggcctcgtt ccggagctgg
gccgcaggaa gttcgcggcg gcgtcgtcgg 900gccgcccctc atcccagccc tctgacgagg
tcctgagcga gttcgagttg cggctgctca 960gcatgttcgg cctgaaacag agacccaccc
ccagcaggga cgccgtggtg cccccctaca 1020tgctagacct gtatcgcagg cactcaggtc
agccgggctc acccgcccca gaccaccggt 1080tggagagggc agccagccga gccaacactg
tgcgcagctt ccaccatgaa gaatctttgg 1140aagaactacc agaaacgagt gggaaaacaa
cccggagatt cttctttaat ttaagttcta 1200tccccacgga ggagtttatc acctcagcag
agcttcaggt tttccgagaa cagatgcaag 1260atgctttagg aaacaatagc agtttccatc
accgaattaa tatttatgaa atcataaaac 1320ctgcaacagc caactcgaaa ttccccgtga
ccagactttt ggacaccagg ttggtgaatc 1380agaatgcaag caggtgggaa agttttgatg
tcacccccgc tgtgatgcgg tggactgcac 1440agggacacgc caaccatgga ttcgtggtgg
aagtggccca cttggaggag aaacaaggtg 1500tctccaagag acatgttagg ataagcaggt
ctttgcacca agatgaacac agctggtcac 1560agataaggcc attgctagta acttttggcc
atgatggaaa agggcatcct ctccacaaaa 1620gagaaaaacg tcaagccaaa cacaaacagc
ggaaacgcct taagtccagc tgtaagagac 1680accctttgta cgtggacttc agtgacgtgg
ggtggaatga ctggattgtg gctcccccgg 1740ggtatcacgc cttttactgc cacggagaat
gcccttttcc tctggctgat catctgaact 1800ccactaatca tgccattgtt cagacgttgg
tcaactctgt taactctaag attcctaagg 1860catgctgtgt cccgacagaa ctcagtgcta
tctcgatgct gtaccttgac gagaatgaaa 1920aggttgtatt aaagaactat caggacatgg
ttgtggaggg ttgtgggtgt cgctagtaca 1980gcaaaattaa atacataaat atatatatat
atatatattt tagaaaaaag aaaaaaacaa 2040acaaacaaaa aaaccccacc ccagttgaca
ctttaatatt tcccaatgaa gactttattt 2100atggaatgga atggaaaaaa aaacagctat
tttgaaaata tatttatatc tacgaaaaga 2160agttgggaaa acaaatattt taatcagaga
attattcctt aaagatttaa aatgtattta 2220gttgtacatt ttatatgggt tcaaccccag
cacatgaagt ataatggtca gatttatttt 2280gtatttattt actattataa ccacttttta
ggaaaaaaat agctaatttg tatttatatg 2340taatcaaaag aagtatcggg tttgtacata
attttccaaa aattgtagtt gttttcagtt 2400gtgtgtattt aagatgaaaa gtctacatgg
aaggttactc tggcaaagtg cttagcacgt 2460ttgctttttt gcagtgctac tgttgagttc
acaagttcaa gtccagaaaa aaaaagtgga 2520taatccactc tgctgacttt caagattatt
atattattca attctcagga atgttgcaga 2580gtgattgtcc aatccatgag aatttacatc
cttattaggt ggaatatttg gataagaacc 2640agacattgct gatctattat agaaactctc
ctcctgcccc ttaatttaca gaaagaataa 2700agcaggatcc atagaaataa ttaggaaaac
gatgaacctg caggaaagtg aatgatggtt 2760tgttgttctt ctttcctaaa ttagtgatcc
cttcaaaggg gctgatctgg ccaaagtatt 2820caataaaacg taagatttct tcattattga
tattgtggtc atatatattt aaaattgata 2880tctcgtggcc ctcatcaagg gttggaaatt
tatttgtgtt ttacctttac ctcatctgag 2940agctctttat tctccaaaga acccagtttt
ctaacttttt gcccaacacg cagcaaaatt 3000atgcacatcg tgttttctgc ccaccctctg
ttctctgacc tatcagcttg cttttctttc 3060caaggttgtg tgtttgaaca catttctcca
aatgttaaac ctatttcaga taataaatat 3120caaatctctg gcatttcatt ctataaagtc
3150110396PRTHomo sapiens 110Met Val Ala
Gly Thr Arg Cys Leu Leu Ala Leu Leu Leu Pro Gln Val 1 5
10 15 Leu Leu Gly Gly Ala Ala Gly Leu
Val Pro Glu Leu Gly Arg Arg Lys 20 25
30 Phe Ala Ala Ala Ser Ser Gly Arg Pro Ser Ser Gln Pro
Ser Asp Glu 35 40 45
Val Leu Ser Glu Phe Glu Leu Arg Leu Leu Ser Met Phe Gly Leu Lys 50
55 60 Gln Arg Pro Thr
Pro Ser Arg Asp Ala Val Val Pro Pro Tyr Met Leu 65 70
75 80 Asp Leu Tyr Arg Arg His Ser Gly Gln
Pro Gly Ser Pro Ala Pro Asp 85 90
95 His Arg Leu Glu Arg Ala Ala Ser Arg Ala Asn Thr Val Arg
Ser Phe 100 105 110
His His Glu Glu Ser Leu Glu Glu Leu Pro Glu Thr Ser Gly Lys Thr
115 120 125 Thr Arg Arg Phe
Phe Phe Asn Leu Ser Ser Ile Pro Thr Glu Glu Phe 130
135 140 Ile Thr Ser Ala Glu Leu Gln Val
Phe Arg Glu Gln Met Gln Asp Ala 145 150
155 160 Leu Gly Asn Asn Ser Ser Phe His His Arg Ile Asn
Ile Tyr Glu Ile 165 170
175 Ile Lys Pro Ala Thr Ala Asn Ser Lys Phe Pro Val Thr Arg Leu Leu
180 185 190 Asp Thr Arg
Leu Val Asn Gln Asn Ala Ser Arg Trp Glu Ser Phe Asp 195
200 205 Val Thr Pro Ala Val Met Arg Trp
Thr Ala Gln Gly His Ala Asn His 210 215
220 Gly Phe Val Val Glu Val Ala His Leu Glu Glu Lys Gln
Gly Val Ser 225 230 235
240 Lys Arg His Val Arg Ile Ser Arg Ser Leu His Gln Asp Glu His Ser
245 250 255 Trp Ser Gln Ile
Arg Pro Leu Leu Val Thr Phe Gly His Asp Gly Lys 260
265 270 Gly His Pro Leu His Lys Arg Glu Lys
Arg Gln Ala Lys His Lys Gln 275 280
285 Arg Lys Arg Leu Lys Ser Ser Cys Lys Arg His Pro Leu Tyr
Val Asp 290 295 300
Phe Ser Asp Val Gly Trp Asn Asp Trp Ile Val Ala Pro Pro Gly Tyr 305
310 315 320 His Ala Phe Tyr Cys
His Gly Glu Cys Pro Phe Pro Leu Ala Asp His 325
330 335 Leu Asn Ser Thr Asn His Ala Ile Val Gln
Thr Leu Val Asn Ser Val 340 345
350 Asn Ser Lys Ile Pro Lys Ala Cys Cys Val Pro Thr Glu Leu Ser
Ala 355 360 365 Ile
Ser Met Leu Tyr Leu Asp Glu Asn Glu Lys Val Val Leu Lys Asn 370
375 380 Tyr Gln Asp Met Val Val
Glu Gly Cys Gly Cys Arg 385 390 395
1115734DNAHomo sapiens 111agatcttgaa aacacccggg ccacacacgc cgcgacctac
agctctttct cagcgttgga 60gtggagacgg cgcccgcagc gccctgcgcg ggtgaggtcc
gcgcagctgc tggggaagag 120cccacctgtc aggctgcgct gggtcagcgc agcaagtggg
gctggccgct atctcgctgc 180acccggccgc gtcccgggct ccgtgcgccc tcgccccagc
tggtttggag ttcaaccctc 240ggctccgccg ccggctcctt gcgccttcgg agtgtcccgc
agcgacgccg ggagccgacg 300cgccgcgcgg gtacctagcc atggctgggg cgagcaggct
gctctttctg tggctgggct 360gcttctgcgt gagcctggcg cagggagaga gaccgaagcc
acctttcccg gagctccgca 420aagctgtgcc aggtgaccgc acggcaggtg gtggcccgga
ctccgagctg cagccgcaag 480acaaggtctc tgaacacatg ctgcggctct atgacaggta
cagcacggtc caggcggccc 540ggacaccggg ctccctggag ggaggctcgc agccctggcg
ccctcggctc ctgcgcgaag 600gcaacacggt tcgcagcttt cgggcggcag cagcagaaac
tcttgaaaga aaaggactgt 660atatcttcaa tctgacatcg ctaaccaagt ctgaaaacat
tttgtctgcc acactgtatt 720tctgtattgg agagctagga aacatcagcc tgagttgtcc
agtgtctgga ggatgctccc 780atcatgctca gaggaaacac attcagattg atctttctgc
atggaccctc aaattcagca 840gaaaccaaag tcaactcctt ggccatctgt cagtggatat
ggccaaatct catcgagata 900ttatgtcctg gctgtctaaa gatatcactc aactcttgag
gaaggccaaa gaaaatgaag 960agttcctcat aggatttaac attacgtcca agggacgcca
gctgccaaag aggaggttac 1020cttttccaga gccttatatc ttggtatatg ccaatgatgc
cgccatttct gagccagaaa 1080gtgtggtatc aagcttacag ggacaccgga attttcccac
tggaactgtt cccaaatggg 1140atagccacat cagagctgcc ctttccattg agcggaggaa
gaagcgctct actggggtct 1200tgctgcctct gcagaacaac gagcttcctg gggcagaata
ccagtataaa aaggatgagg 1260tgtgggagga gagaaagcct tacaagaccc ttcaggctca
ggcccctgaa aagagtaaga 1320ataaaaagaa acagagaaag gggcctcatc ggaagagcca
gacgctccaa tttgatgagc 1380agaccctgaa aaaggcaagg agaaagcagt ggattgaacc
tcggaattgc gccaggagat 1440acctcaaggt agactttgca gatattggct ggagtgaatg
gattatctcc cccaagtcct 1500ttgatgccta ttattgctct ggagcatgcc agttccccat
gccaaagtct ttgaagccat 1560caaatcatgc taccatccag agtatagtga gagctgtggg
ggtcgttcct gggattcctg 1620agccttgctg tgtaccagaa aagatgtcct cactcagtat
tttattcttt gatgaaaata 1680agaatgtagt gcttaaagta taccctaaca tgacagtaga
gtcttgcgct tgcagataac 1740ctggcaaaga actcatttga atgcttaatt caatcattag
tttattttta tggacttctt 1800cctgtttttt tttttttttt ttttgcactg ccaatgcatt
ttgtttcaaa agattatttc 1860tatagtcaga ggggaatgag caaatagact gaagattgcc
accaaggaaa agaactgtat 1920ttgtttctga atgtaactta aagcaagatt tttagtaaat
atggacatct atttctcttt 1980ttgtaatcaa acacaacaac ttatcaaact gtttttagaa
ctgttagaga acacactggt 2040ttatttttgt aatgttcttt gaaaacagaa tggagaagca
gcaatagctt gtcatttatc 2100tcatttaatg actaatggga aatagagaac aatttcgcgt
tttgaattag gcttattgcc 2160ttagaatcct gagaaagtgc taaataatca actctgatgt
ttttcttaag ttcttgagac 2220tcttgtttat ccttgttttt cctccacaag tcattgtcta
agtgtaatgg aaagtttatg 2280ctgagcgtta gtgtgtatgt atgtgcgtac atgcgccagg
tgcctgtgcc ctctgtagga 2340tggtttgctt aatatggttt tataattcag tttacacagg
attctttatt ttttttaatt 2400ttgtattttg gcaaacacca ttcagttata agaactttgc
caaatatgat agaataattc 2460aagagcatat acagagagtt accacttgac ccagctattt
aattgcaaat acagttgttt 2520tcatttcatt tcctaccaga aaaaggaatc agaaacctag
tttttgaaaa cacaagtgta 2580attcctcttt tgtacttctt tttcacaaat gcttttattt
attctaaatt gaatttaaaa 2640atccttccta aagccattaa ctctttaatt ctcctgatat
gcctttactt cctatgaagt 2700tattggtaga tgttgaggcc caaaaactgg tagaatattg
aagatcttct taaatgacca 2760atttaaccat aaccaaatat tgaatatcat tcttcagtca
catctaagtc aggcactttt 2820tcacatagat cagggctttt ggctcagtca cgaaatctac
aagttagcaa agcttacaaa 2880acattattcg tcaggtatgg gaatcaaata tagacacttg
tttgtctttg ctttccattt 2940ctatgtgtca catacatata tgtgtcctct tataacttta
gtcttcaaaa ttatttcaat 3000atccttcttc tcactatatt tatttgtgtg atggaaatgc
tttcaggccg tagatcattg 3060ttggtgttaa tctgtggtta atcctcattt tagttccgtc
ttatctgata cttagaaata 3120tctcagccat tttggaggct gtgcagtatc agaagacgtg
gagtttgttc tgtctctgcc 3180tgtagctaat tatggtggtt cagtcattta ataaatatgt
tttgagcatc tattttgtga 3240aaggcactgt gttacctgtg tgtctttagt gtcctcactg
gtaaaatgaa gaggctggcc 3300atgagctgga agggttaagt ttataattcc agctatttca
cacccgtctt ccttgaagga 3360atgatagtga tagatataaa aacactgtaa gtccctcttt
taataaacta aatgaaagaa 3420catcctatac ttcgctgttt gtaaattagt atggcattcg
ctttggttta agtggtattt 3480tattgcaaac ccattaaaag aataactcat gaaaagaagc
tctttgacac cttggggtac 3540acaaatgttg gtgtgggtgt gtgttaattc tgtgagtgag
acacaccagt tctaaaaaaa 3600atgagtgaag ttctggtgcc tgagttacca tgctttcttc
tagttcttac agtagcataa 3660aattaaagat tcaaagtgag atggaggata aaattacttt
ttaatacatg ttctcaaaca 3720tttgaaaata aaagtatatg atagaagggg gccagagtgt
ggccaccatc ctgatcgtac 3780tgtttttcaa taaagaaaac tttttcattg gtagatttgg
tgaaattcta aatttaggtt 3840tttttctaga gctgtatcaa ccaaaacttc tggcaattcc
cagtatcact tcttagcctt 3900cttatatcca aatgcctgtt tattaccttt cttaatttga
atcaatgcct agttattaca 3960gattgcaccc cacaatggcc aaaaacccac tacataataa
aatttacagg tactaactag 4020ttaagattat attttaagta gcaattgata taaaattaca
acacaatgaa agaacttggg 4080taatctctta gcaatggaaa taggttttaa ccagcagttt
ttctgggtgc tttgtaacta 4140tcattttact aatgaattga ggatgtatta tggtttaaat
tggaagagtt ttattcccaa 4200agaataaagc aagattatct ttcagtagta gagattgaag
taaatgtatt aatattttaa 4260ttaatacaga tttactaaga gtagttagaa aatttagtaa
gtgcctgttt tacaaattgt 4320taggtactag tttctgtata attcctacac agaagcttta
gaaatctcct gatattaaat 4380tattaaattg gcattcatga aaagagaagc tacaattata
aactccattt gctaaatcat 4440gcataatact ctctctctct cttcccccac aagtaatctc
tctaccccat gcagtgtgca 4500cacacacaca cacacagtca gttactgaaa aaaataattc
tttttctttt tttttttaaa 4560tggagtttca ctcttgtcgc ccaggctgga gtgcagtggc
gtgatctcgg cccactgcaa 4620cctccacctc ccaggttcaa gcagttctcc tgcctcagcc
tcctgagtag ctgggattac 4680aggtgtccgc caccatgcct ggctaatttt tttatttgat
aaaaagaatt ctttttctca 4740ataactgttc tcttgaattc aaattaaggg actgccaaag
tcaattagaa tattttaaaa 4800atactttgtt gtaacctgtg taaataatat acaatttaca
ggatttggga ttgtagaact 4860taaactggaa gactggattc ctcagatctc aggactataa
cattccagat aaatttttac 4920attccctttg ctgtatatta actgatgatc atttatatgt
taagattttt taccttaata 4980tttctgaata aaactcttat tgcccattta atattttcat
aggcaatcaa atgtgagtaa 5040tactgctaag agtctgattt attaaaaata tttgtataat
tcattcagtt tagtttttca 5100gtttagtctt tctgctttca cttttctctg tgctaacaag
taactaatgt ctgggcattg 5160acttcttatt gaatcaaagt tgggttaggc atagctatgc
acacctgatg tgtaagatta 5220aagaagagat taaataagaa atcttgggta agttggactt
ttctgtatag ctcttttttc 5280ctctgagttg tattttaatg tagtttataa gtgataaaat
gatccttgtt ttctaaaagc 5340cagtccttcc cttcagcttt ccacagtttc tgtaaatgtt
taatacttgt acagtcaatg 5400gcaattttaa atatatatat atatataata tatgtatatg
gaaaaggttc aaagatgctt 5460ttaatttatt taatgactat tgccttccta taataataat
tttcatcctt aattatgata 5520atacttttag caagaaaaat tcctttttac tacagttttt
agatgcaaaa tgcagtttgg 5580ttctttagtc aaatccactt agagggtata ttgcagtgaa
actgtgaagg atacttcact 5640accaatgtat aagctttgtt gaatttgtat cattttcttt
cagtaatgaa aagctattca 5700ttatacagta tggaaataaa aattgcttca ttga
5734112472PRTHomo sapiens 112Met Ala Gly Ala Ser
Arg Leu Leu Phe Leu Trp Leu Gly Cys Phe Cys 1 5
10 15 Val Ser Leu Ala Gln Gly Glu Arg Pro Lys
Pro Pro Phe Pro Glu Leu 20 25
30 Arg Lys Ala Val Pro Gly Asp Arg Thr Ala Gly Gly Gly Pro Asp
Ser 35 40 45 Glu
Leu Gln Pro Gln Asp Lys Val Ser Glu His Met Leu Arg Leu Tyr 50
55 60 Asp Arg Tyr Ser Thr Val
Gln Ala Ala Arg Thr Pro Gly Ser Leu Glu 65 70
75 80 Gly Gly Ser Gln Pro Trp Arg Pro Arg Leu Leu
Arg Glu Gly Asn Thr 85 90
95 Val Arg Ser Phe Arg Ala Ala Ala Ala Glu Thr Leu Glu Arg Lys Gly
100 105 110 Leu Tyr
Ile Phe Asn Leu Thr Ser Leu Thr Lys Ser Glu Asn Ile Leu 115
120 125 Ser Ala Thr Leu Tyr Phe Cys
Ile Gly Glu Leu Gly Asn Ile Ser Leu 130 135
140 Ser Cys Pro Val Ser Gly Gly Cys Ser His His Ala
Gln Arg Lys His 145 150 155
160 Ile Gln Ile Asp Leu Ser Ala Trp Thr Leu Lys Phe Ser Arg Asn Gln
165 170 175 Ser Gln Leu
Leu Gly His Leu Ser Val Asp Met Ala Lys Ser His Arg 180
185 190 Asp Ile Met Ser Trp Leu Ser Lys
Asp Ile Thr Gln Leu Leu Arg Lys 195 200
205 Ala Lys Glu Asn Glu Glu Phe Leu Ile Gly Phe Asn Ile
Thr Ser Lys 210 215 220
Gly Arg Gln Leu Pro Lys Arg Arg Leu Pro Phe Pro Glu Pro Tyr Ile 225
230 235 240 Leu Val Tyr Ala
Asn Asp Ala Ala Ile Ser Glu Pro Glu Ser Val Val 245
250 255 Ser Ser Leu Gln Gly His Arg Asn Phe
Pro Thr Gly Thr Val Pro Lys 260 265
270 Trp Asp Ser His Ile Arg Ala Ala Leu Ser Ile Glu Arg Arg
Lys Lys 275 280 285
Arg Ser Thr Gly Val Leu Leu Pro Leu Gln Asn Asn Glu Leu Pro Gly 290
295 300 Ala Glu Tyr Gln Tyr
Lys Lys Asp Glu Val Trp Glu Glu Arg Lys Pro 305 310
315 320 Tyr Lys Thr Leu Gln Ala Gln Ala Pro Glu
Lys Ser Lys Asn Lys Lys 325 330
335 Lys Gln Arg Lys Gly Pro His Arg Lys Ser Gln Thr Leu Gln Phe
Asp 340 345 350 Glu
Gln Thr Leu Lys Lys Ala Arg Arg Lys Gln Trp Ile Glu Pro Arg 355
360 365 Asn Cys Ala Arg Arg Tyr
Leu Lys Val Asp Phe Ala Asp Ile Gly Trp 370 375
380 Ser Glu Trp Ile Ile Ser Pro Lys Ser Phe Asp
Ala Tyr Tyr Cys Ser 385 390 395
400 Gly Ala Cys Gln Phe Pro Met Pro Lys Ser Leu Lys Pro Ser Asn His
405 410 415 Ala Thr
Ile Gln Ser Ile Val Arg Ala Val Gly Val Val Pro Gly Ile 420
425 430 Pro Glu Pro Cys Cys Val Pro
Glu Lys Met Ser Ser Leu Ser Ile Leu 435 440
445 Phe Phe Asp Glu Asn Lys Asn Val Val Leu Lys Val
Tyr Pro Asn Met 450 455 460
Thr Val Glu Ser Cys Ala Cys Arg 465 470
1131957DNAHomo sapiens 113aagaggagga aggaagatgc gagaaggcag aggaggaggg
agggagggaa ggagcgcgga 60gcccggcccg gaagctaggt gagtgtggca tccgagctga
gggacgcgag cctgagacgc 120cgctgctgct ccggctgagt atctagcttg tctccccgat
gggattcccg tccaagctat 180ctcgagcctg cagcgccaca gtccccggcc ctcgcccagg
ttcactgcaa ccgttcagag 240gtccccagga gctgctgctg gcgagcccgc tactgcaggg
acctatggag ccattccgta 300gtgccatccc gagcaacgca ctgctgcagc ttccctgagc
ctttccagca agtttgttca 360agattggctg tcaagaatca tggactgtta ttatatgcct
tgttttctgt caagacacca 420tgattcctgg taaccgaatg ctgatggtcg ttttattatg
ccaagtcctg ctaggaggcg 480cgagccatgc tagtttgata cctgagacgg ggaagaaaaa
agtcgccgag attcagggcc 540acgcgggagg acgccgctca gggcagagcc atgagctcct
gcgggacttc gaggcgacac 600ttctgcagat gtttgggctg cgccgccgcc cgcagcctag
caagagtgcc gtcattccgg 660actacatgcg ggatctttac cggcttcagt ctggggagga
ggaggaagag cagatccaca 720gcactggtct tgagtatcct gagcgcccgg ccagccgggc
caacaccgtg aggagcttcc 780accacgaaga acatctggag aacatcccag ggaccagtga
aaactctgct tttcgtttcc 840tctttaacct cagcagcatc cctgagaacg aggtgatctc
ctctgcagag cttcggctct 900tccgggagca ggtggaccag ggccctgatt gggaaagggg
cttccaccgt ataaacattt 960atgaggttat gaagccccca gcagaagtgg tgcctgggca
cctcatcaca cgactactgg 1020acacgagact ggtccaccac aatgtgacac ggtgggaaac
ttttgatgtg agccctgcgg 1080tccttcgctg gacccgggag aagcagccaa actatgggct
agccattgag gtgactcacc 1140tccatcagac tcggacccac cagggccagc atgtcaggat
tagccgatcg ttacctcaag 1200ggagtgggaa ttgggcccag ctccggcccc tcctggtcac
ctttggccat gatggccggg 1260gccatgcctt gacccgacgc cggagggcca agcgtagccc
taagcatcac tcacagcggg 1320ccaggaagaa gaataagaac tgccggcgcc actcgctcta
tgtggacttc agcgatgtgg 1380gctggaatga ctggattgtg gccccaccag gctaccaggc
cttctactgc catggggact 1440gcccctttcc actggctgac cacctcaact caaccaacca
tgccattgtg cagaccctgg 1500tcaattctgt caattccagt atccccaaag cctgttgtgt
gcccactgaa ctgagtgcca 1560tctccatgct gtacctggat gagtatgata aggtggtact
gaaaaattat caggagatgg 1620tagtagaggg atgtgggtgc cgctgagatc aggcagtcct
tgaggataga cagatataca 1680caccacacac acacaccaca tacaccacac acacacgttc
ccatccactc acccacacac 1740tacacagact gcttccttat agctggactt ttatttaaaa
aaaaaaaaaa aaaaggaaaa 1800aatccctaaa cattcacctt gaccttattt atgactttac
gtgcaaatgt tttgaccata 1860ttgatcatat attttgacaa aatatattta taactacgta
ttaaaagaaa aaaataaaat 1920gagtcattat tttaaaggta aaaaaaaaaa aaaaaaa
1957114408PRTHomo sapiens 114Met Ile Pro Gly Asn
Arg Met Leu Met Val Val Leu Leu Cys Gln Val 1 5
10 15 Leu Leu Gly Gly Ala Ser His Ala Ser Leu
Ile Pro Glu Thr Gly Lys 20 25
30 Lys Lys Val Ala Glu Ile Gln Gly His Ala Gly Gly Arg Arg Ser
Gly 35 40 45 Gln
Ser His Glu Leu Leu Arg Asp Phe Glu Ala Thr Leu Leu Gln Met 50
55 60 Phe Gly Leu Arg Arg Arg
Pro Gln Pro Ser Lys Ser Ala Val Ile Pro 65 70
75 80 Asp Tyr Met Arg Asp Leu Tyr Arg Leu Gln Ser
Gly Glu Glu Glu Glu 85 90
95 Glu Gln Ile His Ser Thr Gly Leu Glu Tyr Pro Glu Arg Pro Ala Ser
100 105 110 Arg Ala
Asn Thr Val Arg Ser Phe His His Glu Glu His Leu Glu Asn 115
120 125 Ile Pro Gly Thr Ser Glu Asn
Ser Ala Phe Arg Phe Leu Phe Asn Leu 130 135
140 Ser Ser Ile Pro Glu Asn Glu Val Ile Ser Ser Ala
Glu Leu Arg Leu 145 150 155
160 Phe Arg Glu Gln Val Asp Gln Gly Pro Asp Trp Glu Arg Gly Phe His
165 170 175 Arg Ile Asn
Ile Tyr Glu Val Met Lys Pro Pro Ala Glu Val Val Pro 180
185 190 Gly His Leu Ile Thr Arg Leu Leu
Asp Thr Arg Leu Val His His Asn 195 200
205 Val Thr Arg Trp Glu Thr Phe Asp Val Ser Pro Ala Val
Leu Arg Trp 210 215 220
Thr Arg Glu Lys Gln Pro Asn Tyr Gly Leu Ala Ile Glu Val Thr His 225
230 235 240 Leu His Gln Thr
Arg Thr His Gln Gly Gln His Val Arg Ile Ser Arg 245
250 255 Ser Leu Pro Gln Gly Ser Gly Asn Trp
Ala Gln Leu Arg Pro Leu Leu 260 265
270 Val Thr Phe Gly His Asp Gly Arg Gly His Ala Leu Thr Arg
Arg Arg 275 280 285
Arg Ala Lys Arg Ser Pro Lys His His Ser Gln Arg Ala Arg Lys Lys 290
295 300 Asn Lys Asn Cys Arg
Arg His Ser Leu Tyr Val Asp Phe Ser Asp Val 305 310
315 320 Gly Trp Asn Asp Trp Ile Val Ala Pro Pro
Gly Tyr Gln Ala Phe Tyr 325 330
335 Cys His Gly Asp Cys Pro Phe Pro Leu Ala Asp His Leu Asn Ser
Thr 340 345 350 Asn
His Ala Ile Val Gln Thr Leu Val Asn Ser Val Asn Ser Ser Ile 355
360 365 Pro Lys Ala Cys Cys Val
Pro Thr Glu Leu Ser Ala Ile Ser Met Leu 370 375
380 Tyr Leu Asp Glu Tyr Asp Lys Val Val Leu Lys
Asn Tyr Gln Glu Met 385 390 395
400 Val Val Glu Gly Cys Gly Cys Arg 405
1152207DNAHomo sapiens 115ctcttgaaga gggctggtat atttgtgcct gctggaggtg
gaattaacag taagaaggag 60aaagggattg aatggactta caggaaggat ttcaagtaaa
ttcagggaaa cacatttact 120tgaatagtac aacctagagt attattttac actaagacga
cacaaaagat gttaaagtta 180tcaccaagct gccggacaga tatatattcc aacaccaagg
tgcagatcag catagatctg 240tgattcagaa atcaggattt gttttggaaa gagctcaagg
gttgagaaga actcaaaagc 300aagtgaagat tactttggga actacagttt atcagaagat
caacttttgc taattcaaat 360accaaaggcc tgattatcat aaattcatat aggaatgcat
aggtcatctg atcaaataat 420attagccgtc ttctgctaca tcaatgcagc aaaaactctt
aacaactgtg gataattgga 480aatctgagtt tcagctttct tagaaataac tactcttgac
atattccaaa atatttaaaa 540taggacagga aaatcggtga ggatgttgtg ctcagaaatg
tcactgtcat gaaaaatagg 600taaatttgtt ttttcagcta ctgggaaact gtacctccta
gaaccttagg tttttttttt 660ttttaagagg acaagaagga ctaaaaatat caacttttgc
ttttggacaa aaatgcatct 720gactgtattt ttacttaagg gtattgtggg tttcctctgg
agctgctggg ttctagtggg 780ttatgcaaaa ggaggtttgg gagacaatca tgttcactcc
agttttattt atagaagact 840acggaaccac gaaagacggg aaatacaaag ggaaattctc
tctatcttgg gtttgcctca 900cagacccaga ccattttcac ctggaaaaca agcgtcctct
gcacctctct ttatgctgga 960tctctacaat gccatgacca atgaagaaaa tcctgaagag
tcggagtact cagtaagggc 1020atccttggca gaagagacca gaggggcaag aaagggatac
ccagcctctc ccaatgggta 1080tcctcgtcgc atacagttat ctcggacgac tcctctgacc
acccagagtc ctcctctagc 1140cagcctccat gataccaact ttctgaatga tgctgacatg
gtcatgagct ttgtcaactt 1200agttgaaaga gacaaggatt tttctcacca gcgaaggcat
tacaaagaat ttcgatttga 1260tcttacccaa attcctcatg gagaggcagt gacagcagct
gaattccgga tatacaagga 1320ccggagcaac aaccgatttg aaaatgaaac aattaagatt
agcatatatc aaatcatcaa 1380ggaatacaca aatagggatg cagatctgtt cttgttagac
acaagaaagg cccaagcttt 1440agatgtgggt tggcttgtct ttgatatcac tgtgaccagc
aatcattggg tgattaatcc 1500ccagaataat ttgggcttac agctctgtgc agaaacaggg
gatggacgca gtatcaacgt 1560aaaatctgct ggtcttgtgg gaagacaggg acctcagtca
aaacaaccat tcatggtggc 1620cttcttcaag gcgagtgagg tacttcttcg atccgtgaga
gcagccaaca aacgaaaaaa 1680tcaaaaccgc aataaatcca gctctcatca ggactcctcc
agaatgtcca gtgttggaga 1740ttataacaca agtgagcaaa aacaagcctg taagaagcac
gaactctatg tgagcttccg 1800ggatctggga tggcaggact ggattatagc accagaagga
tacgctgcat tttattgtga 1860tggagaatgt tcttttccac ttaacgccca tatgaatgcc
accaaccacg ctatagttca 1920gactctggtt catctgatgt ttcctgacca cgtaccaaag
ccttgttgtg ctccaaccaa 1980attaaatgcc atctctgttc tgtactttga tgacagctcc
aatgtcattt tgaaaaaata 2040tagaaatatg gtagtacgct catgtggctg ccactaatat
taaataatat tgataataac 2100aaaaagatct gtattaaggt ttatggctgc aataaaaagc
atactttcag acaaacgggg 2160aatttcctaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa
aaaaaaa 2207116454PRTHomo sapiens 116Met His Leu Thr Val
Phe Leu Leu Lys Gly Ile Val Gly Phe Leu Trp 1 5
10 15 Ser Cys Trp Val Leu Val Gly Tyr Ala Lys
Gly Gly Leu Gly Asp Asn 20 25
30 His Val His Ser Ser Phe Ile Tyr Arg Arg Leu Arg Asn His Glu
Arg 35 40 45 Arg
Glu Ile Gln Arg Glu Ile Leu Ser Ile Leu Gly Leu Pro His Arg 50
55 60 Pro Arg Pro Phe Ser Pro
Gly Lys Gln Ala Ser Ser Ala Pro Leu Phe 65 70
75 80 Met Leu Asp Leu Tyr Asn Ala Met Thr Asn Glu
Glu Asn Pro Glu Glu 85 90
95 Ser Glu Tyr Ser Val Arg Ala Ser Leu Ala Glu Glu Thr Arg Gly Ala
100 105 110 Arg Lys
Gly Tyr Pro Ala Ser Pro Asn Gly Tyr Pro Arg Arg Ile Gln 115
120 125 Leu Ser Arg Thr Thr Pro Leu
Thr Thr Gln Ser Pro Pro Leu Ala Ser 130 135
140 Leu His Asp Thr Asn Phe Leu Asn Asp Ala Asp Met
Val Met Ser Phe 145 150 155
160 Val Asn Leu Val Glu Arg Asp Lys Asp Phe Ser His Gln Arg Arg His
165 170 175 Tyr Lys Glu
Phe Arg Phe Asp Leu Thr Gln Ile Pro His Gly Glu Ala 180
185 190 Val Thr Ala Ala Glu Phe Arg Ile
Tyr Lys Asp Arg Ser Asn Asn Arg 195 200
205 Phe Glu Asn Glu Thr Ile Lys Ile Ser Ile Tyr Gln Ile
Ile Lys Glu 210 215 220
Tyr Thr Asn Arg Asp Ala Asp Leu Phe Leu Leu Asp Thr Arg Lys Ala 225
230 235 240 Gln Ala Leu Asp
Val Gly Trp Leu Val Phe Asp Ile Thr Val Thr Ser 245
250 255 Asn His Trp Val Ile Asn Pro Gln Asn
Asn Leu Gly Leu Gln Leu Cys 260 265
270 Ala Glu Thr Gly Asp Gly Arg Ser Ile Asn Val Lys Ser Ala
Gly Leu 275 280 285
Val Gly Arg Gln Gly Pro Gln Ser Lys Gln Pro Phe Met Val Ala Phe 290
295 300 Phe Lys Ala Ser Glu
Val Leu Leu Arg Ser Val Arg Ala Ala Asn Lys 305 310
315 320 Arg Lys Asn Gln Asn Arg Asn Lys Ser Ser
Ser His Gln Asp Ser Ser 325 330
335 Arg Met Ser Ser Val Gly Asp Tyr Asn Thr Ser Glu Gln Lys Gln
Ala 340 345 350 Cys
Lys Lys His Glu Leu Tyr Val Ser Phe Arg Asp Leu Gly Trp Gln 355
360 365 Asp Trp Ile Ile Ala Pro
Glu Gly Tyr Ala Ala Phe Tyr Cys Asp Gly 370 375
380 Glu Cys Ser Phe Pro Leu Asn Ala His Met Asn
Ala Thr Asn His Ala 385 390 395
400 Ile Val Gln Thr Leu Val His Leu Met Phe Pro Asp His Val Pro Lys
405 410 415 Pro Cys
Cys Ala Pro Thr Lys Leu Asn Ala Ile Ser Val Leu Tyr Phe 420
425 430 Asp Asp Ser Ser Asn Val Ile
Leu Lys Lys Tyr Arg Asn Met Val Val 435 440
445 Arg Ser Cys Gly Cys His 450
1173105DNAHomo sapiens 117caactggggg cgccccggac gaccatgaga gataaggact
gagggccagg aaggggaagc 60gagcccgccg agaggtggcg gggactgctc acgccaaggg
ccacagcggc cgcgctccgg 120cctcgctccg ccgctccacg cctcgcggga tccgcggggg
cagcccggcc gggcggggat 180gccggggctg gggcggaggg cgcagtggct gtgctggtgg
tgggggctgc tgtgcagctg 240ctgcgggccc ccgccgctgc ggccgccctt gcccgctgcc
gcggccgccg ccgccggggg 300gcagctgctg ggggacggcg ggagccccgg ccgcacggag
cagccgccgc cgtcgccgca 360gtcctcctcg ggcttcctgt accggcggct caagacgcag
gagaagcggg agatgcagaa 420ggagatcttg tcggtgctgg ggctcccgca ccggccccgg
cccctgcacg gcctccaaca 480gccgcagccc ccggcgctcc ggcagcagga ggagcagcag
cagcagcagc agctgcctcg 540cggagagccc cctcccgggc gactgaagtc cgcgcccctc
ttcatgctgg atctgtacaa 600cgccctgtcc gccgacaacg acgaggacgg ggcgtcggag
ggggagaggc agcagtcctg 660gccccacgaa gcagccagct cgtcccagcg tcggcagccg
cccccgggcg ccgcgcaccc 720gctcaaccgc aagagccttc tggcccccgg atctggcagc
ggcggcgcgt ccccactgac 780cagcgcgcag gacagcgcct tcctcaacga cgcggacatg
gtcatgagct ttgtgaacct 840ggtggagtac gacaaggagt tctcccctcg tcagcgacac
cacaaagagt tcaagttcaa 900cttatcccag attcctgagg gtgaggtggt gacggctgca
gaattccgca tctacaagga 960ctgtgttatg gggagtttta aaaaccaaac ttttcttatc
agcatttatc aagtcttaca 1020ggagcatcag cacagagact ctgacctgtt tttgttggac
acccgtgtag tatgggcctc 1080agaagaaggc tggctggaat ttgacatcac ggccactagc
aatctgtggg ttgtgactcc 1140acagcataac atggggcttc agctgagcgt ggtgacaagg
gatggagtcc acgtccaccc 1200ccgagccgca ggcctggtgg gcagagacgg cccttacgac
aagcagccct tcatggtggc 1260tttcttcaaa gtgagtgagg tgcacgtgcg caccaccagg
tcagcctcca gccggcgccg 1320acaacagagt cgtaatcgct ctacccagtc ccaggacgtg
gcgcgggtct ccagtgcttc 1380agattacaac agcagtgaat tgaaaacagc ctgcaggaag
catgagctgt atgtgagttt 1440ccaagacctg ggatggcagg actggatcat tgcacccaag
ggctatgctg ccaattactg 1500tgatggagaa tgctccttcc cactcaacgc acacatgaat
gcaaccaacc acgcgattgt 1560gcagaccttg gttcacctta tgaaccccga gtatgtcccc
aaaccgtgct gtgcgccaac 1620taagctaaat gccatctcgg ttctttactt tgatgacaac
tccaatgtca ttctgaaaaa 1680atacaggaat atggttgtaa gagcttgtgg atgccactaa
ctcgaaacca gatgctgggg 1740acacacattc tgccttggat tcctagatta catctgcctt
aaaaaaacac ggaagcacag 1800ttggaggtgg gacgatgaga ctttgaaact atctcatgcc
agtgccttat tacccaggaa 1860gattttaaag gacctcatta ataatttgct cacttggtaa
atgacgtgag tagttgttgg 1920tctgtagcaa gctgagtttg gatgtctgta gcataaggtc
tggtaactgc agaaacataa 1980ccgtgaagct cttcctaccc tcctccccca aaaacccacc
aaaattagtt ttagctgtag 2040atcaagctat ttggggtgtt tgttagtaaa tagggaaaat
aatctcaaag gagttaaatg 2100tattcttggc taaaggatca gctggttcag tactgtctat
caaaggtaga ttttacagag 2160aacagaaatc ggggaagtgg ggggaacgcc tctgttcagt
tcattcccag aagtccacag 2220gacgcacagc ccaggccaca gccagggctc cacggggcgc
ccttgtctca gtcattgctg 2280ttgtatgttc gtgctggagt tttgttggtg tgaaaataca
cttatttcag ccaaaacata 2340ccatttctac acctcaatcc tccatttgct gtactctttg
ctagtaccaa aagtagactg 2400attacactga ggtgaggcta caaggggtgt gtaaccgtgt
aacacgtgaa ggcaatgctc 2460acctcttctt taccagaacg gttctttgac cagcacatta
acttctggac tgccggctct 2520agtacctttt cagtaaagtg gttctctgcc tttttactat
acagcatacc acgccacagg 2580gttagaacca acgaagaaaa taaaatgagg gtgcccagct
tataagaatg gtgttagggg 2640gatgagcatg ctgtttatga acggaaatca tgatttccct
tgtagaaagt gaggctcaga 2700ttaaatttta gaatattttc taaatgtctt tttcacaatc
atgtactggg aaggcaattt 2760catactaaac tgattaaata atacatttat aatctacaac
tgtttgcact tacagctttt 2820tttgtaaata taaactataa tttattgtct attttatatc
tgttttgctg taacattgaa 2880ggaaagacca gacttttaaa aaaaaagagt ttatttagaa
agtatcatag tgtaaacaaa 2940caaattgtac cactttgatt ttcttggaat acaagactcg
tgatgcaaag ctgaagttgt 3000gtgtacaaga ctcttgacag ttgtgcttct ctaggaggtt
gggttttttt aaaaaaagaa 3060ttatctgtga accatacgtg attaataaag atttccttta
aggca 3105118513PRTHomo sapiens 118Met Pro Gly Leu Gly
Arg Arg Ala Gln Trp Leu Cys Trp Trp Trp Gly 1 5
10 15 Leu Leu Cys Ser Cys Cys Gly Pro Pro Pro
Leu Arg Pro Pro Leu Pro 20 25
30 Ala Ala Ala Ala Ala Ala Ala Gly Gly Gln Leu Leu Gly Asp Gly
Gly 35 40 45 Ser
Pro Gly Arg Thr Glu Gln Pro Pro Pro Ser Pro Gln Ser Ser Ser 50
55 60 Gly Phe Leu Tyr Arg Arg
Leu Lys Thr Gln Glu Lys Arg Glu Met Gln 65 70
75 80 Lys Glu Ile Leu Ser Val Leu Gly Leu Pro His
Arg Pro Arg Pro Leu 85 90
95 His Gly Leu Gln Gln Pro Gln Pro Pro Ala Leu Arg Gln Gln Glu Glu
100 105 110 Gln Gln
Gln Gln Gln Gln Leu Pro Arg Gly Glu Pro Pro Pro Gly Arg 115
120 125 Leu Lys Ser Ala Pro Leu Phe
Met Leu Asp Leu Tyr Asn Ala Leu Ser 130 135
140 Ala Asp Asn Asp Glu Asp Gly Ala Ser Glu Gly Glu
Arg Gln Gln Ser 145 150 155
160 Trp Pro His Glu Ala Ala Ser Ser Ser Gln Arg Arg Gln Pro Pro Pro
165 170 175 Gly Ala Ala
His Pro Leu Asn Arg Lys Ser Leu Leu Ala Pro Gly Ser 180
185 190 Gly Ser Gly Gly Ala Ser Pro Leu
Thr Ser Ala Gln Asp Ser Ala Phe 195 200
205 Leu Asn Asp Ala Asp Met Val Met Ser Phe Val Asn Leu
Val Glu Tyr 210 215 220
Asp Lys Glu Phe Ser Pro Arg Gln Arg His His Lys Glu Phe Lys Phe 225
230 235 240 Asn Leu Ser Gln
Ile Pro Glu Gly Glu Val Val Thr Ala Ala Glu Phe 245
250 255 Arg Ile Tyr Lys Asp Cys Val Met Gly
Ser Phe Lys Asn Gln Thr Phe 260 265
270 Leu Ile Ser Ile Tyr Gln Val Leu Gln Glu His Gln His Arg
Asp Ser 275 280 285
Asp Leu Phe Leu Leu Asp Thr Arg Val Val Trp Ala Ser Glu Glu Gly 290
295 300 Trp Leu Glu Phe Asp
Ile Thr Ala Thr Ser Asn Leu Trp Val Val Thr 305 310
315 320 Pro Gln His Asn Met Gly Leu Gln Leu Ser
Val Val Thr Arg Asp Gly 325 330
335 Val His Val His Pro Arg Ala Ala Gly Leu Val Gly Arg Asp Gly
Pro 340 345 350 Tyr
Asp Lys Gln Pro Phe Met Val Ala Phe Phe Lys Val Ser Glu Val 355
360 365 His Val Arg Thr Thr Arg
Ser Ala Ser Ser Arg Arg Arg Gln Gln Ser 370 375
380 Arg Asn Arg Ser Thr Gln Ser Gln Asp Val Ala
Arg Val Ser Ser Ala 385 390 395
400 Ser Asp Tyr Asn Ser Ser Glu Leu Lys Thr Ala Cys Arg Lys His Glu
405 410 415 Leu Tyr
Val Ser Phe Gln Asp Leu Gly Trp Gln Asp Trp Ile Ile Ala 420
425 430 Pro Lys Gly Tyr Ala Ala Asn
Tyr Cys Asp Gly Glu Cys Ser Phe Pro 435 440
445 Leu Asn Ala His Met Asn Ala Thr Asn His Ala Ile
Val Gln Thr Leu 450 455 460
Val His Leu Met Asn Pro Glu Tyr Val Pro Lys Pro Cys Cys Ala Pro 465
470 475 480 Thr Lys Leu
Asn Ala Ile Ser Val Leu Tyr Phe Asp Asp Asn Ser Asn 485
490 495 Val Ile Leu Lys Lys Tyr Arg Asn
Met Val Val Arg Ala Cys Gly Cys 500 505
510 His 1194049DNAHomo sapiens 119agcgcgtacc actctggcgc
tcccgaggcg gcctcttgtg cgatccaggg cgcacaaggc 60tgggagagcg ccccggggcc
cctgctatcc gcgccggagg ttggaagagg gtgggttgcc 120gccgcccgag ggcgagagcg
ccagaggagc gggaagaagg agcgctcgcc cgcccgcctg 180cctcctcgct gcctccccgg
cgttggctct ctggactcct aggcttgctg gctgctcctc 240ccacccgcgc ccgcctcctc
actcgccttt tcgttcgccg gggctgcttt ccaagccctg 300cggtgcgccc gggcgagtgc
ggggcgaggg gcccggggcc agcaccgagc agggggcggg 360ggtccgggca gagcgcggcc
ggccggggag gggccatgtc tggcgcgggc gcagcggggc 420ccgtctgcag caagtgaccg
agcggcgcgg acggccgcct gccccctctg ccacctgggg 480cggtgcgggc ccggagcccg
gagcccgggt agcgcgtaga gccggcgcga tgcacgtgcg 540ctcactgcga gctgcggcgc
cgcacagctt cgtggcgctc tgggcacccc tgttcctgct 600gcgctccgcc ctggccgact
tcagcctgga caacgaggtg cactcgagct tcatccaccg 660gcgcctccgc agccaggagc
ggcgggagat gcagcgcgag atcctctcca ttttgggctt 720gccccaccgc ccgcgcccgc
acctccaggg caagcacaac tcggcaccca tgttcatgct 780ggacctgtac aacgccatgg
cggtggagga gggcggcggg cccggcggcc agggcttctc 840ctacccctac aaggccgtct
tcagtaccca gggcccccct ctggccagcc tgcaagatag 900ccatttcctc accgacgccg
acatggtcat gagcttcgtc aacctcgtgg aacatgacaa 960ggaattcttc cacccacgct
accaccatcg agagttccgg tttgatcttt ccaagatccc 1020agaaggggaa gctgtcacgg
cagccgaatt ccggatctac aaggactaca tccgggaacg 1080cttcgacaat gagacgttcc
ggatcagcgt ttatcaggtg ctccaggagc acttgggcag 1140ggaatcggat ctcttcctgc
tcgacagccg taccctctgg gcctcggagg agggctggct 1200ggtgtttgac atcacagcca
ccagcaacca ctgggtggtc aatccgcggc acaacctggg 1260cctgcagctc tcggtggaga
cgctggatgg gcagagcatc aaccccaagt tggcgggcct 1320gattgggcgg cacgggcccc
agaacaagca gcccttcatg gtggctttct tcaaggccac 1380ggaggtccac ttccgcagca
tccggtccac ggggagcaaa cagcgcagcc agaaccgctc 1440caagacgccc aagaaccagg
aagccctgcg gatggccaac gtggcagaga acagcagcag 1500cgaccagagg caggcctgta
agaagcacga gctgtatgtc agcttccgag acctgggctg 1560gcaggactgg atcatcgcgc
ctgaaggcta cgccgcctac tactgtgagg gggagtgtgc 1620cttccctctg aactcctaca
tgaacgccac caaccacgcc atcgtgcaga cgctggtcca 1680cttcatcaac ccggaaacgg
tgcccaagcc ctgctgtgcg cccacgcagc tcaatgccat 1740ctccgtcctc tacttcgatg
acagctccaa cgtcatcctg aagaaataca gaaacatggt 1800ggtccgggcc tgtggctgcc
actagctcct ccgagaattc agaccctttg gggccaagtt 1860tttctggatc ctccattgct
cgccttggcc aggaaccagc agaccaactg ccttttgtga 1920gaccttcccc tccctatccc
caactttaaa ggtgtgagag tattaggaaa catgagcagc 1980atatggcttt tgatcagttt
ttcagtggca gcatccaatg aacaagatcc tacaagctgt 2040gcaggcaaaa cctagcagga
aaaaaaaaca acgcataaag aaaaatggcc gggccaggtc 2100attggctggg aagtctcagc
catgcacgga ctcgtttcca gaggtaatta tgagcgccta 2160ccagccaggc cacccagccg
tgggaggaag ggggcgtggc aaggggtggg cacattggtg 2220tctgtgcgaa aggaaaattg
acccggaagt tcctgtaata aatgtcacaa taaaacgaat 2280gaatgaaaat ggttaggacg
ttacagatat attttcctaa acaatttatc cccatttctc 2340ggtttatcct gatgcgtaaa
cagaagctgt gtcaagtgga gggcggggag gtccctctcc 2400attccctaca gttttcatcc
tgaggcttgc agaggcccag tgtttaccga ggtttgccca 2460aatccaagat ctagtgggag
gggaaagagc aaatgtctgc tccgaggagg gcggtgtgtt 2520gatctttgga ggaaaaatat
gttctgttgt tcagctggat ttgccgtggc agaaatgaaa 2580ctaggtgtgt gaaatacccg
cagacatttg ggattggctt ttcacctcgc cccagtggta 2640gtaaatccat gtgaaattgc
agaggggaca aggacagcaa gtaggatgga acttgcaact 2700caaccctgtt gttaagaagc
accaatgggc cgggcacagt agctcccacc tgtaatccca 2760gcactttggg aggctgaggt
gggcggatca tttgaggtca ggagttcgag accagcctgg 2820ccaacatggt gaaaccccat
ctctactaaa aatacaaaaa ttagccgggc atggtggcac 2880gcacctgtaa tcccagctac
tctggaggct gaggcaggag aattgcttga accccagagg 2940tggaggttgc agtgagccaa
gatcgtccca ctgcactcca gcttgggtga caaaacaaga 3000ctccatctca aaagaaaaaa
aaaacagcac caatgaagcc tagttctcca cgggagtggg 3060gtgagcagga gcactgcaca
tcgccccagt ggaccctctg gtctttgtct gcagtggcat 3120tccaaggctg ggccctggca
agggcacccg tggctgtctc ttcatttgca gaccctgatc 3180agaagtctct gcaaacaaat
ttgctccttg aattaagggg gagatggcat aataggaggt 3240ctgatgggtg caggatgtgc
tggacttaca ttgcaaatag aagccttgtt gagggtgaca 3300tcctaaccaa gtgtcccgat
ttggaggtgg catttctgac gtggctcttg gtgtaagcct 3360gccttgcctt ggctggtgag
tcccataaat agtatgcact cagcctccgg ccacaaacac 3420aaggcctagg ggagggctag
actgtctgca aacgttttct gcatctgtaa agaaaacaag 3480gtgatcgaaa actgtggcca
tgtggaaccc ggtcttgtgg gggactgttt ctccatcttg 3540actcagacag ttcctggaaa
caccggggct ctgtttttat tttctttgat gtttttcttc 3600tttagtagct tgggctgcag
cctccactct ctagtcactg gggaggagta ttttttgtta 3660tgtttggttt catttgctgg
cagagctggg gctttttgtg tgatccctct tggtgtgagt 3720tttctgaccc aaccagcctc
tggttagcat catttgtaca tttaaacctg taaatagttg 3780ttacaaagca aagagattat
ttatttccat ccaaagctct tttgaacacc cccccccctt 3840taatccctcg ttcaggacga
tgagcttgct ttccttcaac ctgtttgttt tcttatttaa 3900gactatttat taatggttgg
accaatgtac tcacagctgt tgcgtcgagc agtccttagt 3960gaaaattctg tataaataga
caaaatgaaa agggtttgac cttgcaataa aaggagacgt 4020ttggttctgg caaaaaaaaa
aaaaaaaaa 4049120431PRTHomo sapiens
120Met His Val Arg Ser Leu Arg Ala Ala Ala Pro His Ser Phe Val Ala 1
5 10 15 Leu Trp Ala Pro
Leu Phe Leu Leu Arg Ser Ala Leu Ala Asp Phe Ser 20
25 30 Leu Asp Asn Glu Val His Ser Ser Phe
Ile His Arg Arg Leu Arg Ser 35 40
45 Gln Glu Arg Arg Glu Met Gln Arg Glu Ile Leu Ser Ile Leu
Gly Leu 50 55 60
Pro His Arg Pro Arg Pro His Leu Gln Gly Lys His Asn Ser Ala Pro 65
70 75 80 Met Phe Met Leu Asp
Leu Tyr Asn Ala Met Ala Val Glu Glu Gly Gly 85
90 95 Gly Pro Gly Gly Gln Gly Phe Ser Tyr Pro
Tyr Lys Ala Val Phe Ser 100 105
110 Thr Gln Gly Pro Pro Leu Ala Ser Leu Gln Asp Ser His Phe Leu
Thr 115 120 125 Asp
Ala Asp Met Val Met Ser Phe Val Asn Leu Val Glu His Asp Lys 130
135 140 Glu Phe Phe His Pro Arg
Tyr His His Arg Glu Phe Arg Phe Asp Leu 145 150
155 160 Ser Lys Ile Pro Glu Gly Glu Ala Val Thr Ala
Ala Glu Phe Arg Ile 165 170
175 Tyr Lys Asp Tyr Ile Arg Glu Arg Phe Asp Asn Glu Thr Phe Arg Ile
180 185 190 Ser Val
Tyr Gln Val Leu Gln Glu His Leu Gly Arg Glu Ser Asp Leu 195
200 205 Phe Leu Leu Asp Ser Arg Thr
Leu Trp Ala Ser Glu Glu Gly Trp Leu 210 215
220 Val Phe Asp Ile Thr Ala Thr Ser Asn His Trp Val
Val Asn Pro Arg 225 230 235
240 His Asn Leu Gly Leu Gln Leu Ser Val Glu Thr Leu Asp Gly Gln Ser
245 250 255 Ile Asn Pro
Lys Leu Ala Gly Leu Ile Gly Arg His Gly Pro Gln Asn 260
265 270 Lys Gln Pro Phe Met Val Ala Phe
Phe Lys Ala Thr Glu Val His Phe 275 280
285 Arg Ser Ile Arg Ser Thr Gly Ser Lys Gln Arg Ser Gln
Asn Arg Ser 290 295 300
Lys Thr Pro Lys Asn Gln Glu Ala Leu Arg Met Ala Asn Val Ala Glu 305
310 315 320 Asn Ser Ser Ser
Asp Gln Arg Gln Ala Cys Lys Lys His Glu Leu Tyr 325
330 335 Val Ser Phe Arg Asp Leu Gly Trp Gln
Asp Trp Ile Ile Ala Pro Glu 340 345
350 Gly Tyr Ala Ala Tyr Tyr Cys Glu Gly Glu Cys Ala Phe Pro
Leu Asn 355 360 365
Ser Tyr Met Asn Ala Thr Asn His Ala Ile Val Gln Thr Leu Val His 370
375 380 Phe Ile Asn Pro Glu
Thr Val Pro Lys Pro Cys Cys Ala Pro Thr Gln 385 390
395 400 Leu Asn Ala Ile Ser Val Leu Tyr Phe Asp
Asp Ser Ser Asn Val Ile 405 410
415 Leu Lys Lys Tyr Arg Asn Met Val Val Arg Ala Cys Gly Cys His
420 425 430
1215430DNAHomo sapiens 121aagctattga agctgacacc cacagagtta aactcagttg
ctgaagccac cagctccccc 60tcccagtcct tcttttcaga gtaggctggc agctgtccta
actgcctact aaagccaaat 120gcttgaggag agagagagag taaggagcca gccatgaatc
ctttccagaa aaatgagtcc 180aaggaaactc ttttttcacc tgtctccatt gaagaggtac
cacctcgacc acctagccct 240ccaaagaagc catctccgac aatctgtggc tccaactatc
cactgagcat tgccttcatt 300gtggtgaatg aattctgcga gcgcttttcc tattatggaa
tgaaagctgt gctgatcctg 360tatttcctgt atttcctgca ctggaatgaa gatacctcca
catctatata ccatgccttc 420agcagcctct gttattttac tcccatcctg ggagcagcca
ttgctgactc gtggttggga 480aaattcaaag tcctatcatt gatcggcctg agtctaatag
ctttggggac aggaggcatc 540aaaccctgtg tggcagcttt tggtggagac cagtttgaag
aaaaacatgc agaggaacgg 600actagatact tctcagtctt ctacctgtcc atcaatgcag
ggagcttgat ttctacattt 660atcacaccca tgctgagagg agatgtgcaa tgttttggag
aagactgcta tgcattggct 720tttggagttc caggactgct catggtaatt gcacttgttg
tgtttgcaat gggaagcaaa 780atatacaata aaccaccccc tgaaggaaac atagtggctc
aagttttcaa atgtatctgg 840tttgctattt ccaatcgttt caagaaccgt tctggagaca
ttccaaagcg acagcactgg 900ctagactggg cggctgagaa atatccaaag cagctcatta
tggatgtaaa ggcactgacc 960agggtactat tcctttatat cccattgccc atgttctggg
ctcttttgga tcagcagggt 1020tcacgatgga ctttgcaagc catcaggatg aataggaatt
tggggttttt tgtgcttcag 1080ccggaccaga tgcaggttct aaatcccctt ctggttctta
tcttcatccc gttgtttgac 1140tttgtcattt atcgtctggt ctccaagtgt ggaattaact
tctcatcact taggaaaatg 1200gctgttggta tgatcctagc atgcctggca tttgcagttg
cggcagctgt agagataaaa 1260ataaatgaaa tggccccagc ccagccaggt ccccaggagg
ttttcctaca agtcttgaat 1320ctggcagatg atgaggtgaa ggtgacagtg gtgggaaatg
aaaacaattc tctgttgata 1380gagtccatca aatcctttca gaaaacacca cactattcca
aactgcacct gaaaacaaaa 1440agccaggatt ttcacttcca cctgaaatat cacaatttgt
ctctctacac tgagcattct 1500gtgcaggaga agaactggta cagtcttgtc attcgtgaag
atgggaacag tatctccagc 1560atgatggtaa aggatacaga aagcagaaca accaatggga
tgacaaccgt gaggtttgtt 1620aacactttgc ataaagatgt caacatctcc ctgagtacag
atacctctct caatgttggt 1680gaagactatg gtgtgtctgc ttatagaact gtgcaaagag
gagaataccc tgcagtgcac 1740tgtagaacag aagataagaa cttttctctg aatttgggtc
ttctagactt tggtgcagca 1800tatctgtttg ttattactaa taacaccaat cagggtcttc
aggcctggaa gattgaagac 1860attccagcca acaaaatgtc cattgcgtgg cagctaccac
aatatgccct ggttacagct 1920ggggaggtca tgttctctgt cacaggtctt gagttttctt
attctcaggc tccctctagc 1980atgaaatctg tgctccaggc agcttggcta ttgacaattg
cagttgggaa tatcatcgtg 2040cttgttgtgg cacagttcag tggcctggta cagtgggccg
aattcatttt gttttcctgc 2100ctcctgctgg tgatctgcct gatcttctcc atcatgggct
actactatgt tcctgtaaag 2160acagaggata tgcggggtcc agcagataag cacattcctc
acatccaggg gaacatgatc 2220aaactagaga ccaagaagac aaaactctga tgactcccta
gattctgtcc tgaccccaat 2280tcctggccct gtcttgaagc attttttttc ttctactgga
ttagacaaga gagatagcag 2340catatcagag ctgatctcct ccacctttct ccaatgacag
aagttccagg actggttttc 2400cagtacatct ttaaacaagg ccccagagac tctatgtctg
cccgtccatc agtgaactca 2460ttaaaacttg tgcagtgttg ctggagctgg cctggtgtct
ccaaatgacc atgaaaatac 2520acacgtataa tggagatcat tctctgtggg tatgcaaagt
tatgggaatt cctttatagg 2580taactgccat ttaggactga tggccctaat ttttgaggtg
ctgatttaga ggcaaaattg 2640cagaataaca aagaaatggt atttcaagtt ttttttttta
taagcaatgt aattatgcta 2700ttcacagggg cctcaagaat tggtatgtat gatgtgatct
ggtccagcca gggcctggct 2760tgtcagctct ctaggtttga tatgacttta gtaaatttgt
caatatagat ggtaggaagc 2820agaatgccat tttattaaaa cacaggagaa gttatatctc
tctgattatg atagtatttt 2880atttacttat ccaaaccctc ctttctcagt atggatagat
catggaaacc agattagaga 2940tagtaagcat tagtaaacat tgttctggag aacaggaaca
ggtgtaagtt gtagaaatcc 3000tgaagagcca gtcattcttt tacagagtac attcttctta
gcctctatgg cgctggtcta 3060tgcccttcag tgaacagttg tataaacaat aattataatt
tgcaaccttg tcttgtcaac 3120cttgctgatc cagctttttc ttattattac accttgtctt
gcttattgca gcaaatattc 3180aataacaaca atgtttctat aagtccaact tcctttatta
atgtttccat ttagcctcaa 3240aaatatcaaa gtagttcctt tttgatgttg ttttcctgat
ttacttttcc cataagtttt 3300aaataccatt tctgccttga agcctagaaa ttttcttttt
attcaaaaaa agttacatta 3360atgctctagg tttgaggttc taaaatggaa atgtcaatag
aggagcatgg tcctatgtga 3420ggttcctatc aaaatttgtg ggagtaggga tggtagagca
tgagggtttt gtttgtgtat 3480gtgtatggtc atgaaaaaaa attgagaaac attacctcat
acacaatgaa tgaatcagag 3540gacagacacg ggaatggcac gactgtgcag tgtgttacta
ggaaaaaagt tcagaatcac 3600tgttctagag agcttcattt ccattggttt taaaacatta
ttctcatgta gaacagtgtt 3660gggtctcata ctgttaatgt taatacgtaa caatgttcat
gttaacaggc acctgttaat 3720attaacagat aatgttactg ttaacaggta agagaaattg
ctctaagtgc ccaaacttta 3780tatacttcag ttttaatgac aagcatttca gaaatataag
agcggcagcc agaccaacca 3840gtttttccag atatcttgat gtgaacctga ccctactcct
ttagaagaca gcctgttcat 3900ttttaaatag ctttaaccca aactgttcta tgaccattgt
ttcaagagac attaacacag 3960ttctgtaaat agaagtgtct atggacaaat aagtttggga
aatgtggcat actgtatcct 4020tttcttaaca tttgcatatt aaagactctg agatatcctg
cagtaaagac acaagatacc 4080ttgtttaaat taacatgtac gctgcagaac attggtttgg
aaaaaactgt tgagcagttc 4140ttccttgtaa gtgctgagct tcctctctga aacctcctac
cattgttttt tttcccctgt 4200agctaacaag aataagtata acagccggcc aggcacagtg
gctcatgcct gtaatcccag 4260cactttggga ggctgagaca ggtggatcac ctgaggtcag
gagttcgaga ccagcctggc 4320caacatggtg aaaccgtgtc tctactaaaa gtacaaaaat
tagccaggtg tgatggcagg 4380tgcctgtaat cccagctact cgggaggctg aagcagaaga
attgcttgaa cccgggaggc 4440agaggttgca atgagccgag atcacgccat cacactctag
cctgggggac aagagtgaga 4500cttcatctaa aaaaaaaaag aaaagaatat gtataccccc
tttttcatgt ggcagatgtt 4560tagctatttg gggagaactt tcatggctct tccctaatca
tcaagtattc aaggtaaaga 4620ttctcggttc ctgtaatggt tcctcaccag gcataatttg
tccttttacc atcctacttt 4680ctgtcttctg aaaaacattc tttatctgaa atacagcaat
taatattaag atatcttaat 4740atgaagtgcc tggagtcaaa tataacattc caaagtagtc
tgactggaag aactagcacc 4800tgcctttctt caaacaatgc acttctgtta atgcagtgta
aggtaacatg agttgttttt 4860ggaaactaca tcataatgtg ggcttacatt ctagcactta
tcacttaatg acagggatac 4920atttgaggaa tgcattgtta ggcaattttg tcattatgca
aacatcatag agtgtactta 4980cacaaaccta tggtatagcc tactacacat ctaagttata
tggtatagac tgtttctcca 5040gctatatggt gtagactgtt tctcctaggc tacaaacctg
cacagcatgt tactgtatta 5100aatgctgtag gcaattgtaa cacaatggta tttttatact
taaacatatc taaacataga 5160aacggtacaa aaaactttac acattatata gatgtatcaa
attattcata tgtgctctga 5220aaatgtctat atctgttatg tatcaatttt ttaaaaagtg
aatgacataa ttcatttgaa 5280aaaatgtgga cacacaaatt ggaaaagagg tataaatgca
gtattataat ctaatgggac 5340caccatcaca tatttggtct gtcattgact gaaactgcaa
tatagagttt ttcttaacat 5400ttgcatatta aagactctga ctatatatgg
5430122698PRTHomo sapiens 122Met Asn Pro Phe Gln
Lys Asn Glu Ser Lys Glu Thr Leu Phe Ser Pro 1 5
10 15 Val Ser Ile Glu Glu Val Pro Pro Arg Pro
Pro Ser Pro Pro Lys Lys 20 25
30 Pro Ser Pro Thr Ile Cys Gly Ser Asn Tyr Pro Leu Ser Ile Ala
Phe 35 40 45 Ile
Val Val Asn Glu Phe Cys Glu Arg Phe Ser Tyr Tyr Gly Met Lys 50
55 60 Ala Val Leu Ile Leu Tyr
Phe Leu Tyr Phe Leu His Trp Asn Glu Asp 65 70
75 80 Thr Ser Thr Ser Ile Tyr His Ala Phe Ser Ser
Leu Cys Tyr Phe Thr 85 90
95 Pro Ile Leu Gly Ala Ala Ile Ala Asp Ser Trp Leu Gly Lys Phe Lys
100 105 110 Val Leu
Ser Leu Ile Gly Leu Ser Leu Ile Ala Leu Gly Thr Gly Gly 115
120 125 Ile Lys Pro Cys Val Ala Ala
Phe Gly Gly Asp Gln Phe Glu Glu Lys 130 135
140 His Ala Glu Glu Arg Thr Arg Tyr Phe Ser Val Phe
Tyr Leu Ser Ile 145 150 155
160 Asn Ala Gly Ser Leu Ile Ser Thr Phe Ile Thr Pro Met Leu Arg Gly
165 170 175 Asp Val Gln
Cys Phe Gly Glu Asp Cys Tyr Ala Leu Ala Phe Gly Val 180
185 190 Pro Gly Leu Leu Met Val Ile Ala
Leu Val Val Phe Ala Met Gly Ser 195 200
205 Lys Ile Tyr Asn Lys Pro Pro Pro Glu Gly Asn Ile Val
Ala Gln Val 210 215 220
Phe Lys Cys Ile Trp Phe Ala Ile Ser Asn Arg Phe Lys Asn Arg Ser 225
230 235 240 Gly Asp Ile Pro
Lys Arg Gln His Trp Leu Asp Trp Ala Ala Glu Lys 245
250 255 Tyr Pro Lys Gln Leu Ile Met Asp Val
Lys Ala Leu Thr Arg Val Leu 260 265
270 Phe Leu Tyr Ile Pro Leu Pro Met Phe Trp Ala Leu Leu Asp
Gln Gln 275 280 285
Gly Ser Arg Trp Thr Leu Gln Ala Ile Arg Met Asn Arg Asn Leu Gly 290
295 300 Phe Phe Val Leu Gln
Pro Asp Gln Met Gln Val Leu Asn Pro Leu Leu 305 310
315 320 Val Leu Ile Phe Ile Pro Leu Phe Asp Phe
Val Ile Tyr Arg Leu Val 325 330
335 Ser Lys Cys Gly Ile Asn Phe Ser Ser Leu Arg Lys Met Ala Val
Gly 340 345 350 Met
Ile Leu Ala Cys Leu Ala Phe Ala Val Ala Ala Ala Val Glu Ile 355
360 365 Lys Ile Asn Glu Met Ala
Pro Ala Gln Pro Gly Pro Gln Glu Val Phe 370 375
380 Leu Gln Val Leu Asn Leu Ala Asp Asp Glu Val
Lys Val Thr Val Val 385 390 395
400 Gly Asn Glu Asn Asn Ser Leu Leu Ile Glu Ser Ile Lys Ser Phe Gln
405 410 415 Lys Thr
Pro His Tyr Ser Lys Leu His Leu Lys Thr Lys Ser Gln Asp 420
425 430 Phe His Phe His Leu Lys Tyr
His Asn Leu Ser Leu Tyr Thr Glu His 435 440
445 Ser Val Gln Glu Lys Asn Trp Tyr Ser Leu Val Ile
Arg Glu Asp Gly 450 455 460
Asn Ser Ile Ser Ser Met Met Val Lys Asp Thr Glu Ser Arg Thr Thr 465
470 475 480 Asn Gly Met
Thr Thr Val Arg Phe Val Asn Thr Leu His Lys Asp Val 485
490 495 Asn Ile Ser Leu Ser Thr Asp Thr
Ser Leu Asn Val Gly Glu Asp Tyr 500 505
510 Gly Val Ser Ala Tyr Arg Thr Val Gln Arg Gly Glu Tyr
Pro Ala Val 515 520 525
His Cys Arg Thr Glu Asp Lys Asn Phe Ser Leu Asn Leu Gly Leu Leu 530
535 540 Asp Phe Gly Ala
Ala Tyr Leu Phe Val Ile Thr Asn Asn Thr Asn Gln 545 550
555 560 Gly Leu Gln Ala Trp Lys Ile Glu Asp
Ile Pro Ala Asn Lys Met Ser 565 570
575 Ile Ala Trp Gln Leu Pro Gln Tyr Ala Leu Val Thr Ala Gly
Glu Val 580 585 590
Met Phe Ser Val Thr Gly Leu Glu Phe Ser Tyr Ser Gln Ala Pro Ser
595 600 605 Ser Met Lys Ser
Val Leu Gln Ala Ala Trp Leu Leu Thr Ile Ala Val 610
615 620 Gly Asn Ile Ile Val Leu Val Val
Ala Gln Phe Ser Gly Leu Val Gln 625 630
635 640 Trp Ala Glu Phe Ile Leu Phe Ser Cys Leu Leu Leu
Val Ile Cys Leu 645 650
655 Ile Phe Ser Ile Met Gly Tyr Tyr Tyr Val Pro Val Lys Thr Glu Asp
660 665 670 Met Arg Gly
Pro Ala Asp Lys His Ile Pro His Ile Gln Gly Asn Met 675
680 685 Ile Lys Leu Glu Thr Lys Lys Thr
Lys Leu 690 695 1231955DNAHomo sapiens
123aagcacaagt ggaggacaat ccagcccggc agcgggtgag agtgggtgct ggccaggacg
60gttccttcag agcaaacagc agggagatgc cggcccgctc cttcccagct cctccccgtg
120cccgctaaca cagcacggcc gcctgcagtc tcctctctgg gtgattgcgc gggcctaaga
180tgtgtcctgg ggcactgtgg gtggccctgc ccctgctgtc cctgctggct ggctccctac
240aggggaagcc actgcagagc tggggacgag ggtctgctgg gggaaacgcc cacagcccac
300tgggggtgcc tggaggtggg ctgcctgagc acaccttcaa cctgaagatg tttctggaga
360acgtgaaggt ggatttcctg cgcagcctta acctgagtgg ggtcccttcg caggacaaaa
420ccagggtgga gccgccgcag tacatgattg acctgtacaa caggtacacg tccgataagt
480cgactacgcc agcgtccaac attgtgcgga gcttcagcat ggaagatgcc atctccataa
540ctgccacaga ggacttcccc ttccagaagc acatcttgct cttcaacatc tccattccta
600ggcatgagca gatcaccaga gctgagctcc gactctatgt ctcctgtcaa aatcacgtgg
660acccctctca tgacctgaaa ggaagcgtgg tcatttatga tgttctggat ggaacagatg
720cctgggatag tgctacagag accaagacct tcctggtgtc ccaggacatt caggatgagg
780gctgggagac cttggaagtg tccagcgccg tgaagcgctg ggtccggtcc gactccacca
840agagcaaaaa taagctggaa gtgactgtgg agagccacag gaagggctgc gacacgctgg
900acatcagtgt ccccccaggt tccagaaacc tgcccttctt tgttgtcttc tccaatgacc
960acagcagtgg gaccaaggag accaggctgg agctgaggga gatgatcagc catgaacaag
1020agagcgtgct caagaagctg tccaaggacg gctccacaga ggcaggtgag agcagtcacg
1080aggaggacac ggatggccac gtggctgcgg ggtcgacttt agccaggcgg aaaaggagcg
1140ccggggctgg cagccactgt caaaagacct ccctgcgggt aaacttcgag gacatcggct
1200gggacagctg gatcattgca cccaaggagt atgaagccta cgagtgtaag ggcggctgct
1260tcttcccctt ggctgacgat gtgacgccga cgaaacacgc tatcgtgcag accctggtgc
1320atctcaagtt ccccacaaag gtgggcaagg cctgctgtgt gcccaccaaa ctgagcccca
1380tctccgtcct ctacaaggat gacatggggg tgcccaccct caagtaccat tacgagggca
1440tgagcgtggc agagtgtggg tgcaggtagt atctgcctgc ggggctgggg aggcaggcca
1500aaggggctcc acatgagagg tcctgcatgc ccctgggcac aacaaggact gattcaatct
1560gcatgccagc ctggaggagg aaagggagcc tgctctccct ccccacaccc cacccaaagc
1620atacaccgct gagctcaact gccagggaag gctaaggaaa tggggatttg agcacaacag
1680gaaagcctgg gagggttgtt gggatgcaag gaggtgatga aaaggagaca gggggaaaaa
1740taatccatag tcagcagaaa acaacagcag tgagccagag gagcacaggc gggcaggtca
1800ctgcagagac tgatggaagt tagagaggtg gaggaggcca gctcgctcca aaacccttgg
1860ggagtagagg gaaggagcag gccgcgtgtc acacccatca ttgtatgtta tttcccacaa
1920cccagttgga ggggcatggc ttccaattta gagac
1955124429PRTHomo sapiens 124Met Cys Pro Gly Ala Leu Trp Val Ala Leu Pro
Leu Leu Ser Leu Leu 1 5 10
15 Ala Gly Ser Leu Gln Gly Lys Pro Leu Gln Ser Trp Gly Arg Gly Ser
20 25 30 Ala Gly
Gly Asn Ala His Ser Pro Leu Gly Val Pro Gly Gly Gly Leu 35
40 45 Pro Glu His Thr Phe Asn Leu
Lys Met Phe Leu Glu Asn Val Lys Val 50 55
60 Asp Phe Leu Arg Ser Leu Asn Leu Ser Gly Val Pro
Ser Gln Asp Lys 65 70 75
80 Thr Arg Val Glu Pro Pro Gln Tyr Met Ile Asp Leu Tyr Asn Arg Tyr
85 90 95 Thr Ser Asp
Lys Ser Thr Thr Pro Ala Ser Asn Ile Val Arg Ser Phe 100
105 110 Ser Met Glu Asp Ala Ile Ser Ile
Thr Ala Thr Glu Asp Phe Pro Phe 115 120
125 Gln Lys His Ile Leu Leu Phe Asn Ile Ser Ile Pro Arg
His Glu Gln 130 135 140
Ile Thr Arg Ala Glu Leu Arg Leu Tyr Val Ser Cys Gln Asn His Val 145
150 155 160 Asp Pro Ser His
Asp Leu Lys Gly Ser Val Val Ile Tyr Asp Val Leu 165
170 175 Asp Gly Thr Asp Ala Trp Asp Ser Ala
Thr Glu Thr Lys Thr Phe Leu 180 185
190 Val Ser Gln Asp Ile Gln Asp Glu Gly Trp Glu Thr Leu Glu
Val Ser 195 200 205
Ser Ala Val Lys Arg Trp Val Arg Ser Asp Ser Thr Lys Ser Lys Asn 210
215 220 Lys Leu Glu Val Thr
Val Glu Ser His Arg Lys Gly Cys Asp Thr Leu 225 230
235 240 Asp Ile Ser Val Pro Pro Gly Ser Arg Asn
Leu Pro Phe Phe Val Val 245 250
255 Phe Ser Asn Asp His Ser Ser Gly Thr Lys Glu Thr Arg Leu Glu
Leu 260 265 270 Arg
Glu Met Ile Ser His Glu Gln Glu Ser Val Leu Lys Lys Leu Ser 275
280 285 Lys Asp Gly Ser Thr Glu
Ala Gly Glu Ser Ser His Glu Glu Asp Thr 290 295
300 Asp Gly His Val Ala Ala Gly Ser Thr Leu Ala
Arg Arg Lys Arg Ser 305 310 315
320 Ala Gly Ala Gly Ser His Cys Gln Lys Thr Ser Leu Arg Val Asn Phe
325 330 335 Glu Asp
Ile Gly Trp Asp Ser Trp Ile Ile Ala Pro Lys Glu Tyr Glu 340
345 350 Ala Tyr Glu Cys Lys Gly Gly
Cys Phe Phe Pro Leu Ala Asp Asp Val 355 360
365 Thr Pro Thr Lys His Ala Ile Val Gln Thr Leu Val
His Leu Lys Phe 370 375 380
Pro Thr Lys Val Gly Lys Ala Cys Cys Val Pro Thr Lys Leu Ser Pro 385
390 395 400 Ile Ser Val
Leu Tyr Lys Asp Asp Met Gly Val Pro Thr Leu Lys Tyr 405
410 415 His Tyr Glu Gly Met Ser Val Ala
Glu Cys Gly Cys Arg 420 425
1251584DNAHomo sapiens 125ggggagagga agagtggtag ggggagggag agagagagga
agagtttcca aacttgtctc 60cagtgacagg agacatttac gttccacaag ataaaactgc
cacttagagc ccagggaagc 120taaaccttcc tggcttggcc taggagctcg agcggagtca
tgggctctct ggtcctgaca 180ctgtgcgctc ttttctgcct ggcagcttac ttggtttctg
gcagccccat catgaaccta 240gagcagtctc ctctggaaga agatatgtcc ctctttggtg
atgttttctc agagcaagac 300ggtgtcgact ttaacacact gctccagagc atgaaggatg
agtttcttaa gacactaaac 360ctctctgaca tccccacgca ggattcagcc aaggtggacc
caccagagta catgttggaa 420ctctacaaca aatttgcaac agatcggacc tccatgccct
ctgccaacat cattaggagt 480ttcaagaatg aagatctgtt ttcccagccg gtcagtttta
atgggctccg aaaatacccc 540ctcctcttca atgtgtccat tcctcaccat gaagaggtca
tcatggctga acttaggcta 600tacacactgg tgcaaaggga tcgtatgata tacgatggag
tagaccggaa aattaccatt 660tttgaagtgc tggagagcaa aggggataat gagggagaaa
gaaacatgct ggtcttggtg 720tctggggaga tatatggaac caacagtgag tgggagactt
ttgatgtcac agatgccatc 780agacgttggc aaaagtcagg ctcatccacc caccagctgg
aggtccacat tgagagcaaa 840cacgatgaag ctgaggatgc cagcagtgga cggctagaaa
tagataccag tgcccagaat 900aagcataacc ctttgctcat cgtgttttct gatgaccaaa
gcagtgacaa ggagaggaag 960gaggaactga atgaaatgat ttcccatgag caacttccag
agctggacaa cttgggcctg 1020gatagctttt ccagtggacc tggggaagag gctttgttgc
agatgagatc aaacatcatc 1080tatgactcca ctgcccgaat cagaaggaac gccaaaggaa
actactgtaa gaggaccccg 1140ctctacatcg acttcaagga gattgggtgg gactcctgga
tcatcgctcc gcctggatac 1200gaagcctatg aatgccgtgg tgtttgtaac taccccctgg
cagagcatct cacacccaca 1260aagcatgcaa ttatccaggc cttggtccac ctcaagaatt
cccagaaagc ttccaaagcc 1320tgctgtgtgc ccacaaagct agagcccatc tccatcctct
atttagacaa aggcgtcgtc 1380acctacaagt ttaaatacga aggcatggcc gtctccgaat
gtggctgtag atagaagaag 1440agtcctatgg cttatttaat aactgtaaat gtgtatattt
ggtgttccta tttaatgaga 1500ttatttaata agggtgtaca gtaatagagg cttgctgcct
tcaggaaatg gacaggtcag 1560tttgttgtag gaaatgcata tttt
1584126424PRTHomo sapiens 126Met Gly Ser Leu Val
Leu Thr Leu Cys Ala Leu Phe Cys Leu Ala Ala 1 5
10 15 Tyr Leu Val Ser Gly Ser Pro Ile Met Asn
Leu Glu Gln Ser Pro Leu 20 25
30 Glu Glu Asp Met Ser Leu Phe Gly Asp Val Phe Ser Glu Gln Asp
Gly 35 40 45 Val
Asp Phe Asn Thr Leu Leu Gln Ser Met Lys Asp Glu Phe Leu Lys 50
55 60 Thr Leu Asn Leu Ser Asp
Ile Pro Thr Gln Asp Ser Ala Lys Val Asp 65 70
75 80 Pro Pro Glu Tyr Met Leu Glu Leu Tyr Asn Lys
Phe Ala Thr Asp Arg 85 90
95 Thr Ser Met Pro Ser Ala Asn Ile Ile Arg Ser Phe Lys Asn Glu Asp
100 105 110 Leu Phe
Ser Gln Pro Val Ser Phe Asn Gly Leu Arg Lys Tyr Pro Leu 115
120 125 Leu Phe Asn Val Ser Ile Pro
His His Glu Glu Val Ile Met Ala Glu 130 135
140 Leu Arg Leu Tyr Thr Leu Val Gln Arg Asp Arg Met
Ile Tyr Asp Gly 145 150 155
160 Val Asp Arg Lys Ile Thr Ile Phe Glu Val Leu Glu Ser Lys Gly Asp
165 170 175 Asn Glu Gly
Glu Arg Asn Met Leu Val Leu Val Ser Gly Glu Ile Tyr 180
185 190 Gly Thr Asn Ser Glu Trp Glu Thr
Phe Asp Val Thr Asp Ala Ile Arg 195 200
205 Arg Trp Gln Lys Ser Gly Ser Ser Thr His Gln Leu Glu
Val His Ile 210 215 220
Glu Ser Lys His Asp Glu Ala Glu Asp Ala Ser Ser Gly Arg Leu Glu 225
230 235 240 Ile Asp Thr Ser
Ala Gln Asn Lys His Asn Pro Leu Leu Ile Val Phe 245
250 255 Ser Asp Asp Gln Ser Ser Asp Lys Glu
Arg Lys Glu Glu Leu Asn Glu 260 265
270 Met Ile Ser His Glu Gln Leu Pro Glu Leu Asp Asn Leu Gly
Leu Asp 275 280 285
Ser Phe Ser Ser Gly Pro Gly Glu Glu Ala Leu Leu Gln Met Arg Ser 290
295 300 Asn Ile Ile Tyr Asp
Ser Thr Ala Arg Ile Arg Arg Asn Ala Lys Gly 305 310
315 320 Asn Tyr Cys Lys Arg Thr Pro Leu Tyr Ile
Asp Phe Lys Glu Ile Gly 325 330
335 Trp Asp Ser Trp Ile Ile Ala Pro Pro Gly Tyr Glu Ala Tyr Glu
Cys 340 345 350 Arg
Gly Val Cys Asn Tyr Pro Leu Ala Glu His Leu Thr Pro Thr Lys 355
360 365 His Ala Ile Ile Gln Ala
Leu Val His Leu Lys Asn Ser Gln Lys Ala 370 375
380 Ser Lys Ala Cys Cys Val Pro Thr Lys Leu Glu
Pro Ile Ser Ile Leu 385 390 395
400 Tyr Leu Asp Lys Gly Val Val Thr Tyr Lys Phe Lys Tyr Glu Gly Met
405 410 415 Ala Val
Ser Glu Cys Gly Cys Arg 420 1273936DNAHomo
sapiens 127agttttaatt gcttccaatg aggtcagcaa aggtatttat cgaaaagccc
tgaataaaag 60gctcacacac acacacaagc acacacgcgc tcacacacag agagaaaatc
cttctgcctg 120ttgatttatg gaaacaatta tgattctgct ggagaacttt tcagctgaga
aatagtttgt 180agctacagta gaaaggctca agttgcacca ggcagacaac agacatggaa
ttcttatata 240tccagctgtt agcaacaaaa caaaagtcaa atagcaaaca gcgtcacagc
aactgaactt 300actacgaact gtttttatga ggatttatca acagagttat ttaaggagga
atcctgtgtt 360gttatcagga actaaaagga taaggctaac aatttggaaa gagcaactac
tctttcttaa 420atcaatctac aattcacaga taggaagagg tcaatgacct aggagtaaca
atcaactcaa 480gattcatttt cattatgtta ttcatgaaca cccggagcac tacactataa
tgcacaaatg 540gatactgaca tggatcctgc caactttgct ctacagatca tgctttcaca
ttatctgtct 600agtgggtact atatctttag cttgcaatga catgactcca gagcaaatgg
ctacaaatgt 660gaactgttcc agccctgagc gacacacaag aagttatgat tacatggaag
gaggggatat 720aagagtgaga agactcttct gtcgaacaca gtggtacctg aggatcgata
aaagaggcaa 780agtaaaaggg acccaagaga tgaagaataa ttacaatatc atggaaatca
ggacagtggc 840agttggaatt gtggcaatca aaggggtgga aagtgaattc tatcttgcaa
tgaacaagga 900aggaaaactc tatgcaaaga aagaatgcaa tgaagattgt aacttcaaag
aactaattct 960ggaaaaccat tacaacacat atgcatcagc taaatggaca cacaacggag
gggaaatgtt 1020tgttgcctta aatcaaaagg ggattcctgt aagaggaaaa aaaacgaaga
aagaacaaaa 1080aacagcccac tttcttccta tggcaataac ttaattgcat atggtatata
aagaaccagt 1140tccagcaggg agatttcttt aagtggactg ttttctttct tctcaaaatt
ttctttcctt 1200ttatttttta gtaatcaaga aaggctggaa aactactgaa aaactgatca
agctggactt 1260gtgcatttat gtttgtttta agacactgca ttaaagaaag atttgaaaag
tatacacaaa 1320aatcagattt agtaactaaa ggttgtaaaa aattgtaaaa ctggttgtac
aatcatgatg 1380ttagtaacag taattttttt cttaaattaa tttaccctta agagtatgtt
agatttgatt 1440atctgataat gattatttaa atattcctat ctgcttataa aatggctgct
ataataataa 1500taatacagat gttgttatat aaggtatatc agacctacag gcttctggca
ggatttgtca 1560gataatcaag ccacactaac tatggaaaat gagcagcatt ttaaatgctt
tctagtgaaa 1620aattataatc tacttaaact ctaatcagaa aaaaaattct caaaaaaact
attatgaaag 1680tcaataaaat agataattta acaaaagtac aggattagaa catgcttata
cctataaata 1740agaacaaaat ttctaatgct gctcaagtgg aaagggtatt gctaaaagga
tgtttccaaa 1800aatcttgtat ataagatagc aacagtgatt gatgataata ctgtacttca
tcttacttgc 1860cacaaaataa cattttataa atcctcaaag taaaattgag aaatctttaa
gtttttttca 1920agtaacataa tctatctttg tataattcat atttgggaat atggctttta
ataatgttct 1980tcccacaaat aatcatgctt ttttcctatg gttacagcat taaactctat
tttaagttgt 2040ttttgaactt tattgttttg ttatttaagt ttatgttatt tataaaaaaa
aaaccttaat 2100aagctgtatc tgtttcatat gcttttaatt ttaaaggaat aacaaaactg
tctggctcaa 2160cggcaagttt ccctcccttt tctgactgac actaagtcta gcacacagca
cttgggccag 2220caaatcctgg aaggcagaca aaaataagag cctgaagcaa tgcttacaat
agatgtctca 2280cacagaacaa tacaaatatg taaaaaatct ttcaccacat attcttgcca
attaattgga 2340tcatataagt aaaatcatta caaatataag tatttacagg attttaaagt
tagaatatat 2400ttgaatgcat gggtagaaaa tatcatattt taaaactatg tatatttaaa
tttagtaatt 2460ttctaatctc tagaaatctc tgctgttcaa aaggtggcag cactgaaagt
tgttttcctg 2520ttagatggca agagcacaat gcccaaaata gaagatgcag ttaagaataa
ggggccctga 2580atgtcatgaa ggcttgaggt cagcctacag ataacaggat tattacaagg
atgaatttcc 2640acttcaaaag tctttcattg gcagatcttg gtagcacttt atatgttcac
caatgggagg 2700tcaatattta tctaatttaa aaggtatgct aaccactgtg gttttaattt
caaaatattt 2760gtcattcaag tccctttaca taaatagtat ttggtaatac atttatagat
gagagttata 2820tgaaaaggct aggtcaacaa aaacaataga ttcatttaat tttcctgtgg
ttgacctata 2880cgaccaggat gtagaaaact agaaagaact gcccttcctc agatatactc
ttgggagaga 2940gcatgaatgg tattctgaac tatcacctga ttcaaggact ttgctagcta
ggttttgagg 3000tcaggcttca gtaactgtag tcttgtgagc atattgaggg cagaggagga
cttagttttt 3060catatgtgtt tccttagtgc ctagcagact atctgttcat aatcagtttt
cagtgtgaat 3120tcactgaatg tttatagaca aaagaaaata cacactaaaa ctaatcttca
ttttaaaagg 3180gtaaaacatg actatacaga aatttaaata gaaatagtgt atatacatat
aaaatacaag 3240ctatgttagg accaaatgct ctttgtctat ggagttatac ttccatcaaa
ttacatagca 3300atgctgaatt aggcaaaacc aacatttagt ggtaaatcca ttcctggtag
tataagtcac 3360ctaaaaaaga cttctagaaa tatgtacttt aattatttgt ttttctccta
tttttaaatt 3420tattatgcaa attttagaaa ataaaatttg ctctagttac acacctttag
aattctagaa 3480tattaaaact gtaaggggcc tccatccctc ttactcattt gtagtctagg
aaattgagat 3540tttgatacac ctaaggtcac gcagctgggt agatatacag ctgtcacaag
agtctagatc 3600agttagcaca tgctttctac tcttcgatta ttagtattat tagctaatgg
tctttggcat 3660gtttttgttt tttatttctg ttgagatata gcctttacat ttgtacacaa
atgtgactat 3720gtcttggcaa tgcacttcat acacaatgac taatctatac tgtgatgatt
tgactcaaaa 3780ggagaaaaga aattatgtag ttttcaattc tgattcctat tcaccttttg
tttatgaatg 3840gaaagctttg tgcaaaatat acatataagc agagtaagcc ttttaaaaat
gttctttgaa 3900agataaaatt aaatacatga gtttctaaca attaga
3936128194PRTHomo sapiens 128Met His Lys Trp Ile Leu Thr Trp
Ile Leu Pro Thr Leu Leu Tyr Arg 1 5 10
15 Ser Cys Phe His Ile Ile Cys Leu Val Gly Thr Ile Ser
Leu Ala Cys 20 25 30
Asn Asp Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Cys Ser Ser
35 40 45 Pro Glu Arg His
Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp Ile 50
55 60 Arg Val Arg Arg Leu Phe Cys Arg
Thr Gln Trp Tyr Leu Arg Ile Asp 65 70
75 80 Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys
Asn Asn Tyr Asn 85 90
95 Ile Met Glu Ile Arg Thr Val Ala Val Gly Ile Val Ala Ile Lys Gly
100 105 110 Val Glu Ser
Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr 115
120 125 Ala Lys Lys Glu Cys Asn Glu Asp
Cys Asn Phe Lys Glu Leu Ile Leu 130 135
140 Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr
His Asn Gly 145 150 155
160 Gly Glu Met Phe Val Ala Leu Asn Gln Lys Gly Ile Pro Val Arg Gly
165 170 175 Lys Lys Thr Lys
Lys Glu Gln Lys Thr Ala His Phe Leu Pro Met Ala 180
185 190 Ile Thr 129627DNAHomo sapiens
129atgtggaaat ggatactgac acattgtgcc tcagcctttc cccacctgcc cggctgctgc
60tgctgctgct ttttgttgct gttcttggtg tcttccgtcc ctgtcacctg ccaagccctt
120ggtcaggaca tggtgtcacc agaggccacc aactcttctt cctcctcctt ctcctctcct
180tccagcgcgg gaaggcatgt gcggagctac aatcaccttc aaggagatgt ccgctggaga
240aagctattct ctttcaccaa gtactttctc aagattgaga agaacgggaa ggtcagcggg
300accaagaagg agaactgccc gtacagcatc ctggagataa catcagtaga aatcggagtt
360gttgccgtca aagccattaa cagcaactat tacttagcca tgaacaagaa ggggaaactc
420tatggctcaa aagaatttaa caatgactgt aagctgaagg agaggataga ggaaaatgga
480tacaatacct atgcatcatt taactggcag cataatggga ggcaaatgta tgtggcattg
540aatggaaaag gagctccaag gagaggacag aaaacacgaa ggaaaaacac ctctgctcac
600tttcttccaa tggtggtaca ctcatag
627130208PRTHomo sapiens 130Met Trp Lys Trp Ile Leu Thr His Cys Ala Ser
Ala Phe Pro His Leu 1 5 10
15 Pro Gly Cys Cys Cys Cys Cys Phe Leu Leu Leu Phe Leu Val Ser Ser
20 25 30 Val Pro
Val Thr Cys Gln Ala Leu Gly Gln Asp Met Val Ser Pro Glu 35
40 45 Ala Thr Asn Ser Ser Ser Ser
Ser Phe Ser Ser Pro Ser Ser Ala Gly 50 55
60 Arg His Val Arg Ser Tyr Asn His Leu Gln Gly Asp
Val Arg Trp Arg 65 70 75
80 Lys Leu Phe Ser Phe Thr Lys Tyr Phe Leu Lys Ile Glu Lys Asn Gly
85 90 95 Lys Val Ser
Gly Thr Lys Lys Glu Asn Cys Pro Tyr Ser Ile Leu Glu 100
105 110 Ile Thr Ser Val Glu Ile Gly Val
Val Ala Val Lys Ala Ile Asn Ser 115 120
125 Asn Tyr Tyr Leu Ala Met Asn Lys Lys Gly Lys Leu Tyr
Gly Ser Lys 130 135 140
Glu Phe Asn Asn Asp Cys Lys Leu Lys Glu Arg Ile Glu Glu Asn Gly 145
150 155 160 Tyr Asn Thr Tyr
Ala Ser Phe Asn Trp Gln His Asn Gly Arg Gln Met 165
170 175 Tyr Val Ala Leu Asn Gly Lys Gly Ala
Pro Arg Arg Gly Gln Lys Thr 180 185
190 Arg Arg Lys Asn Thr Ser Ala His Phe Leu Pro Met Val Val
His Ser 195 200 205
1312157DNAHomo sapiens 131gctcccagcc aagaacctcg gggccgctgc gcggtgggga
ggagttcccc gaaacccggc 60cgctaagcga ggcctcctcc tcccgcagat ccgaacggcc
tgggcggggt caccccggct 120gggacaagaa gccgccgcct gcctgcccgg gcccggggag
ggggctgggg ctggggccgg 180aggcggggtg tgagtgggtg tgtgcggggg gcggaggctt
gatgcaatcc cgataagaaa 240tgctcgggtg tcttgggcac ctacccgtgg ggcccgtaag
gcgctactat ataaggctgc 300cggcccggag ccgccgcgcc gtcagagcag gagcgctgcg
tccaggatct agggccacga 360ccatcccaac ccggcactca cagccccgca gcgcatcccg
gtcgccgccc agcctcccgc 420acccccatcg ccggagctgc gccgagagcc ccagggaggt
gccatgcgga gcgggtgtgt 480ggtggtccac gtatggatcc tggccggcct ctggctggcc
gtggccgggc gccccctcgc 540cttctcggac gcggggcccc acgtgcacta cggctggggc
gaccccatcc gcctgcggca 600cctgtacacc tccggccccc acgggctctc cagctgcttc
ctgcgcatcc gtgccgacgg 660cgtcgtggac tgcgcgcggg gccagagcgc gcacagtttg
ctggagatca aggcagtcgc 720tctgcggacc gtggccatca agggcgtgca cagcgtgcgg
tacctctgca tgggcgccga 780cggcaagatg caggggctgc ttcagtactc ggaggaagac
tgtgctttcg aggaggagat 840ccgcccagat ggctacaatg tgtaccgatc cgagaagcac
cgcctcccgg tctccctgag 900cagtgccaaa cagcggcagc tgtacaagaa cagaggcttt
cttccactct ctcatttcct 960gcccatgctg cccatggtcc cagaggagcc tgaggacctc
aggggccact tggaatctga 1020catgttctct tcgcccctgg agaccgacag catggaccca
tttgggcttg tcaccggact 1080ggaggccgtg aggagtccca gctttgagaa gtaactgaga
ccatgcccgg gcctcttcac 1140tgctgccagg ggctgtggta cctgcagcgt gggggacgtg
cttctacaag aacagtcctg 1200agtccacgtt ctgtttagct ttaggaagaa acatctagaa
gttgtacata ttcagagttt 1260tccattggca gtgccagttt ctagccaata gacttgtctg
atcataacat tgtaagcctg 1320tagcttgccc agctgctgcc tgggccccca ttctgctccc
tcgaggttgc tggacaagct 1380gctgcactgt ctcagttctg cttgaatacc tccatcgatg
gggaactcac ttcctttgga 1440aaaattctta tgtcaagctg aaattctcta attttttctc
atcacttccc caggagcagc 1500cagaagacag gcagtagttt taatttcagg aacaggtgat
ccactctgta aaacagcagg 1560taaatttcac tcaaccccat gtgggaattg atctatatct
ctacttccag ggaccatttg 1620cccttcccaa atccctccag gccagaactg actggagcag
gcatggccca ccaggcttca 1680ggagtagggg aagcctggag ccccactcca gccctgggac
aacttgagaa ttccccctga 1740ggccagttct gtcatggatg ctgtcctgag aataacttgc
tgtcccggtg tcacctgctt 1800ccatctccca gcccaccagc cctctgccca cctcacatgc
ctccccatgg attggggcct 1860cccaggcccc ccaccttatg tcaacctgca cttcttgttc
aaaaatcagg aaaagaaaag 1920atttgaagac cccaagtctt gtcaataact tgctgtgtgg
aagcagcggg ggaagaccta 1980gaaccctttc cccagcactt ggttttccaa catgatattt
atgagtaatt tattttgata 2040tgtacatctc ttattttctt acattattta tgcccccaaa
ttatatttat gtatgtaagt 2100gaggtttgtt ttgtatatta aaatggagtt tgtttgtaaa
aaaaaaaaaa aaaaaaa 2157132216PRTHomo sapiens 132Met Arg Ser Gly Cys
Val Val Val His Val Trp Ile Leu Ala Gly Leu 1 5
10 15 Trp Leu Ala Val Ala Gly Arg Pro Leu Ala
Phe Ser Asp Ala Gly Pro 20 25
30 His Val His Tyr Gly Trp Gly Asp Pro Ile Arg Leu Arg His Leu
Tyr 35 40 45 Thr
Ser Gly Pro His Gly Leu Ser Ser Cys Phe Leu Arg Ile Arg Ala 50
55 60 Asp Gly Val Val Asp Cys
Ala Arg Gly Gln Ser Ala His Ser Leu Leu 65 70
75 80 Glu Ile Lys Ala Val Ala Leu Arg Thr Val Ala
Ile Lys Gly Val His 85 90
95 Ser Val Arg Tyr Leu Cys Met Gly Ala Asp Gly Lys Met Gln Gly Leu
100 105 110 Leu Gln
Tyr Ser Glu Glu Asp Cys Ala Phe Glu Glu Glu Ile Arg Pro 115
120 125 Asp Gly Tyr Asn Val Tyr Arg
Ser Glu Lys His Arg Leu Pro Val Ser 130 135
140 Leu Ser Ser Ala Lys Gln Arg Gln Leu Tyr Lys Asn
Arg Gly Phe Leu 145 150 155
160 Pro Leu Ser His Phe Leu Pro Met Leu Pro Met Val Pro Glu Glu Pro
165 170 175 Glu Asp Leu
Arg Gly His Leu Glu Ser Asp Met Phe Ser Ser Pro Leu 180
185 190 Glu Thr Asp Ser Met Asp Pro Phe
Gly Leu Val Thr Gly Leu Glu Ala 195 200
205 Val Arg Ser Pro Ser Phe Glu Lys 210
215 1331220DNAHomo sapiens 133gggagcgggc gagtaggagg gggcgccggg
ctatatatat agcggctcgg cctcgggcgg 60gcctggcgct cagggaggcg cgcactgctc
ctcagagtcc cagctccagc cgcgcgcttt 120ccgcccggct cgccgctcca tgcagccggg
gtagagcccg gcgcccgggg gccccgtcgc 180ttgcctcccg cacctcctcg gttgcgcact
cctgcccgag gtcggccgtg cgctcccgcg 240ggacgccaca ggcgcagctc tgccccccag
cttcccgggc gcactgaccg cctgaccgac 300gcacggccct cgggccggga tgtcggggcc
cgggacggcc gcggtagcgc tgctcccggc 360ggtcctgctg gccttgctgg cgccctgggc
gggccgaggg ggcgccgccg cacccactgc 420acccaacggc acgctggagg ccgagctgga
gcgccgctgg gagagcctgg tggcgctctc 480gttggcgcgc ctgccggtgg cagcgcagcc
caaggaggcg gccgtccaga gcggcgccgg 540cgactacctg ctgggcatca agcggctgcg
gcggctctac tgcaacgtgg gcatcggctt 600ccacctccag gcgctccccg acggccgcat
cggcggcgcg cacgcggaca cccgcgacag 660cctgctggag ctctcgcccg tggagcgggg
cgtggtgagc atcttcggcg tggccagccg 720gttcttcgtg gccatgagca gcaagggcaa
gctctatggc tcgcccttct tcaccgatga 780gtgcacgttc aaggagattc tccttcccaa
caactacaac gcctacgagt cctacaagta 840ccccggcatg ttcatcgccc tgagcaagaa
tgggaagacc aagaagggga accgagtgtc 900gcccaccatg aaggtcaccc acttcctccc
caggctgtga ccctccagag gacccttgcc 960tcagcctcgg gaagcccctg ggagggcagt
gccgagggtc accttggtgc actttcttcg 1020gatgaagagt ttaatgcaag agtaggtgta
agatatttaa attaattatt taaatgtgta 1080tatattgcca ccaaattatt tatagttctg
cgggtgtgtt ttttaatttt ctggggggaa 1140aaaaagacaa aacaaaaaac caactctgac
ttttctggtg caacagtgga gaatcttacc 1200attggatttc tttaacttgt
1220134206PRTHomo sapiens 134Met Ser Gly
Pro Gly Thr Ala Ala Val Ala Leu Leu Pro Ala Val Leu 1 5
10 15 Leu Ala Leu Leu Ala Pro Trp Ala
Gly Arg Gly Gly Ala Ala Ala Pro 20 25
30 Thr Ala Pro Asn Gly Thr Leu Glu Ala Glu Leu Glu Arg
Arg Trp Glu 35 40 45
Ser Leu Val Ala Leu Ser Leu Ala Arg Leu Pro Val Ala Ala Gln Pro 50
55 60 Lys Glu Ala Ala
Val Gln Ser Gly Ala Gly Asp Tyr Leu Leu Gly Ile 65 70
75 80 Lys Arg Leu Arg Arg Leu Tyr Cys Asn
Val Gly Ile Gly Phe His Leu 85 90
95 Gln Ala Leu Pro Asp Gly Arg Ile Gly Gly Ala His Ala Asp
Thr Arg 100 105 110
Asp Ser Leu Leu Glu Leu Ser Pro Val Glu Arg Gly Val Val Ser Ile
115 120 125 Phe Gly Val Ala
Ser Arg Phe Phe Val Ala Met Ser Ser Lys Gly Lys 130
135 140 Leu Tyr Gly Ser Pro Phe Phe Thr
Asp Glu Cys Thr Phe Lys Glu Ile 145 150
155 160 Leu Leu Pro Asn Asn Tyr Asn Ala Tyr Glu Ser Tyr
Lys Tyr Pro Gly 165 170
175 Met Phe Ile Ala Leu Ser Lys Asn Gly Lys Thr Lys Lys Gly Asn Arg
180 185 190 Val Ser Pro
Thr Met Lys Val Thr His Phe Leu Pro Arg Leu 195
200 205 1351548DNAHomo sapiens 135gacctttcag
agccaggagg gctttcgggg gcgtggggcg cgctgcggag cggagccgcg 60gctcgacggc
ggtgcgctgg cggcgagtgt atgcagacgg cgcccggccc gaaccccgag 120ccccgcgggg
ctccccaccc gccggcctcc cgcccctccc gcgcctccgc ctggggacca 180cgtcggcctt
ttgttggcga accgtccttt ctttcagcgc tttgcgcagc aacggaaatt 240tcattgctcc
tgggtggaaa ttaaagggac tcgcgttccc tctctccctc tccctctccc 300actctccctc
tctttctctc tctcgcccac ccttccccct tcttccccca cctttcccgc 360gaagccggag
tcagcatctc caggcgcggg atcccgctcc gagcacctcg cagctgtccg 420gctgccgccc
cttccatggg cgccgcgctc gcctgcagcc gccgccgccg cggggcgggc 480gcgatgccac
gatgggccta atctggctgc tactgctcag cctgctggag cccggctggc 540ccgcagcggg
ccctggggcg cggttgcggc gcgatgcggg cggccgtggc ggcgtctacg 600agcaccttgg
cggggcgccc cggcgccgca agctctactg cgccacgaag taccacctcc 660agctgcaccc
gagcggccgc gtcaacggca gcctggagaa cagcgcctac agtattttgg 720agataacggc
agtggaggtg ggcattgtgg ccatcagggg tctcttctcc gggcggtacc 780tggccatgaa
caagagggga cgactctatg cttcggagca ctacagcgcc gagtgcgagt 840ttgtggagcg
gatccacgag ctgggctata atacgtatgc ctcccggctg taccggacgg 900tgtctagtac
gcctggggcc cgccggcagc ccagcgccga gagactgtgg tacgtgtctg 960tgaacggcaa
gggccggccc cgcaggggct tcaagacccg ccgcacacag aagtcctccc 1020tgttcctgcc
ccgcgtgctg gaccacaggg accacgagat ggtgcggcag ctacagagtg 1080ggctgcccag
accccctggt aagggggtcc agccccgacg gcggcggcag aagcagagcc 1140cggataacct
ggagccctct cacgttcagg cttcgagact gggctcccag ctggaggcca 1200gtgcgcacta
gctgggcctg gtggccaccg ccagagctcc tggcgacatc ttggcgtggc 1260agcctcttga
ctctgactct cctccttgag cccttgcccc tgcgtcccgc gtctgggttc 1320tcagctattt
ccagagccag ctcaaatcag ggtccagtgg gaactgaaga gggcccaagt 1380cggagctcgg
agggggctgc ctgcaatgca gggcatttgt gggtctgtgt ggcaggaagc 1440cggcagggaa
gggcctgagt gccagccctg gcagactgag gagcctccca ggagcagcgg 1500ggcagtgtgg
ggctttgtgt catcacaaca ttaaagtatt ttattcta
1548136239PRTHomo sapiens 136Met Gly Leu Ile Trp Leu Leu Leu Leu Ser Leu
Leu Glu Pro Gly Trp 1 5 10
15 Pro Ala Ala Gly Pro Gly Ala Arg Leu Arg Arg Asp Ala Gly Gly Arg
20 25 30 Gly Gly
Val Tyr Glu His Leu Gly Gly Ala Pro Arg Arg Arg Lys Leu 35
40 45 Tyr Cys Ala Thr Lys Tyr His
Leu Gln Leu His Pro Ser Gly Arg Val 50 55
60 Asn Gly Ser Leu Glu Asn Ser Ala Tyr Ser Ile Leu
Glu Ile Thr Ala 65 70 75
80 Val Glu Val Gly Ile Val Ala Ile Arg Gly Leu Phe Ser Gly Arg Tyr
85 90 95 Leu Ala Met
Asn Lys Arg Gly Arg Leu Tyr Ala Ser Glu His Tyr Ser 100
105 110 Ala Glu Cys Glu Phe Val Glu Arg
Ile His Glu Leu Gly Tyr Asn Thr 115 120
125 Tyr Ala Ser Arg Leu Tyr Arg Thr Val Ser Ser Thr Pro
Gly Ala Arg 130 135 140
Arg Gln Pro Ser Ala Glu Arg Leu Trp Tyr Val Ser Val Asn Gly Lys 145
150 155 160 Gly Arg Pro Arg
Arg Gly Phe Lys Thr Arg Arg Thr Gln Lys Ser Ser 165
170 175 Leu Phe Leu Pro Arg Val Leu Asp His
Arg Asp His Glu Met Val Arg 180 185
190 Gln Leu Gln Ser Gly Leu Pro Arg Pro Pro Gly Lys Gly Val
Gln Pro 195 200 205
Arg Arg Arg Arg Gln Lys Gln Ser Pro Asp Asn Leu Glu Pro Ser His 210
215 220 Val Gln Ala Ser Arg
Leu Gly Ser Gln Leu Glu Ala Ser Ala His 225 230
235 1375408DNAHomo sapiens 137gtgccagcgc ccatgcaaat
ctgctgtgca tccagagagc aaagtgggat gatctgtcac 60tacacctgca gcaccacgct
cggaggacag ctcctgcctg cagcttccag acccaggaag 120cctgagggga aggaaggaag
tacgggcgaa atcatcagat tggcttccca gatttgggaa 180tctgaagcgg gcccacatct
tccggccaac ttccattgaa cttcccagca ctcgaaaggg 240accgaaatgg agagcaaaga
accccagctc aaagggattg tgacaaggtt attcagccag 300cagggatact tcctgcagat
gcacccagat ggtaccattg atgggaccaa ggacgaaaac 360agcgactaca ctctcttcaa
tctaattccc gtgggcctgc gtgtagtggc catccaagga 420gtgaaggcta gcctctatgt
ggccatgaat ggtgaaggct atctctacag ttcagatgtt 480ttcactccag aatgcaaatt
caaggaatct gtgtttgaaa actactatgt gatctattct 540tccacactgt accgccagca
agaatcaggc cgagcttggt ttctgggact caataaagaa 600ggtcaaatta tgaaggggaa
cagagtgaag aaaaccaagc cctcatcaca ttttgtaccg 660aaacctattg aagtgtgtat
gtacagagaa ccatcgctac atgaaattgg agaaaaacaa 720gggcgttcaa ggaaaagttc
tggaacacca accatgaatg gaggcaaagt tgtgaatcaa 780gattcaacat agctgagaac
tctccccttc ttccctctct catcccttcc ccttcccttc 840cttcccattt acccatttcc
ttccagtaaa tccacccaag gagaggaaaa taaaatgaca 900acgcaagacc tagtggctaa
gattctgcac tcaaaatctt cctttgtgta ggacaagaaa 960attgaaccaa agcttgcttg
ttgcaatgtg gtagaaaatt cacgtgcaca aagattagca 1020cacttaaaag caaaggaaaa
aataaatcag aactccataa atattaaatt aaactgtatt 1080gttattagta gaaggctaat
tgtaatgaag acattaataa agatgaaata aacttattac 1140tttaaaggaa aggatttgga
gaattgaact cacaaactga tgttatatac tcaatagctt 1200aaactcatga taatgctgcg
atgtgtggtt ttgcttgatt ttgtatttta tttgggcatc 1260tggaattgac acaccattac
attctgtttg caggattttt tttgtaacca tgaaattgaa 1320catttccaaa ttataaacta
tgttaatacc tataaaatat atagccagga accatttatc 1380atcaagaaaa gtgtaagaaa
ttatttttga gatgtaattt aagattgttt tatgtaaaag 1440gaaaatcttg tatggcatcg
aatagcctta atgagtttaa ttctttcaca aaaatgattt 1500caaattatcc tagagtataa
catttttatc aaagatatta tttccggagt tcttctttct 1560ttcttttttt ttttttttta
gtaatttagc aaaaacatta ctgttctaat gctgaagtga 1620cttttgccag tgccatgtcc
aggtggtgag gtataagtta cttgctctta gcatttggtc 1680tgattttttt gctttgtgga
cacctttgag agtatccaca aagcaatgtc tcaggtgtgg 1740acacctgaga gcatgtttta
gaaagctttg taccctgtct tgtggcagga aagaaagaac 1800aggggtttta cataaggaaa
taagtcctag gaaattagtc aacgcaaatt gcatttgcgt 1860ttgtacctta ccacagtctt
atattgtttt ttaaactctg ccatgaaatt tggagacatg 1920actgtgaaat tcctaactta
ctatcttaca aagccagtag ctaatttgtt gctctatgta 1980tgatcctgtt acaagtccag
tttgcaattc atttgtttcc tagaacacag aagggtacca 2040gtaatacact aaattttcaa
ggtgtgtaga gaaataatat ggaattagca gctatgactc 2100caacagacag gattgtgtga
gcagctgaaa ggagcaaaaa agaactcagt gtaagagaag 2160gcacatacat agttaagaat
actaaagtat ttttaaaaat caaggaagaa ataaatgtta 2220cacaatttgc attggaataa
atagatctat ttagtcctac aaatcaggag tggtgtagag 2280acatccaaat ttaaagaaaa
aaaaacacaa aacagaatgt taaaaaatgt atgcagattt 2340atggatatta tcaatgagaa
gacatagcat gtaacttctc ctatatctct actgtccagc 2400atgtattgtt ccaaatatga
ctccctaaaa tatatacact ttgcagaagc tctaggccct 2460cacctcaaac cttgccattg
gttgccgtat ttcaaggtca atatagtttc cctcacttta 2520cacaatcatt attcttcaat
agtggaccat atccttcacc aggtatccta tttctgttat 2580ctagaggtta gcagaaaatg
aaatgaagga atttccctaa gcagttggga agaacaaatt 2640gtatgcatgt aggcaaagat
tttgaagata catttgcaag agatatttgt ttaaccaaaa 2700tatttggaaa gtaacaaata
aagacattta aattttctaa aaatggactt gctcttctag 2760gaaaagaata cccctggggc
aaaaatataa ctctagctgt atttcttctt gtcactcttg 2820attcaacttg attataaata
cacctgtcac taccagaacc aaaaaaaaaa agaaaaaaat 2880cccaagcaca aagcttattt
tatttgaaaa aaataaaaaa gaaacttcaa cactatggga 2940cactggctct tttagcatga
aatgacttga gcttttgtag tgatgataca catacacact 3000catcagtaaa acgatggttt
cataaataac acaattgatg caaatcataa aaatcaatta 3060caattatgat ttcatgacaa
aatatattta attaagtttg ttatgaaaaa aatagagata 3120tgaatcacta acaaaattcc
tccattttca gtggctattc atcatttatc atctagactc 3180acatttgtct ccttcctgat
agcagttaag aaaaaattct aaccacacaa tttgtatatt 3240gtttttctcc gtattatgtt
aagcaaatgt tcactgcagt aaaatgtttt ggaaattagc 3300tttgtcttat ttccagttta
gttcagagaa ttaattggaa acctgatttc ttttacacat 3360aaacctgaca aaaaatgtag
cttagagcaa agggtgaatg tttgcttaac tcctgcttac 3420ttctcaagta catgaaaact
ttaatagaat atgccagtat tcactgagtt tttaaaaata 3480ttaccatgtg taaacatata
atatccaact tcatccaaaa atatggttga gtttaagtac 3540tttgtttttc aggcttattt
caagtataat aattctttga ttttcattgt tctgatttct 3600gggtcttcaa ttcattcgtc
acttttcctt tttaagtaaa ataagctttt tttttttttt 3660tttttttttt ttggagttgc
attgggattt ttcccaggaa aaaatatggc ttttagtaat 3720gctttgcaat tggctacgca
gatataaatt aagatatgtt tattctgagt tcttattgga 3780ataagtttca aaatcaacga
gcttaagaat gaaaacaaaa cttttgagag tctcacaaaa 3840tagctttctg gtcaatacac
cttacttgat ttttaagctc gcagaataaa gtatagaaac 3900aaatggagct gaagttccat
ttgctaattc agagactttt gtgcttccgc aaattggagg 3960gcagcaagcc atcctattct
catagtaatc gttttggctt tgaaatttac atacaattta 4020atagcacatt tttagccatt
atggattggc gcaataaaga gatatcaatg taatgcaatg 4080tgatgcttta tgggcctcat
tctaattcag aaagcttgtt taaaagaact aagactcttc 4140tgtttaataa aatagcaaca
atctaatatc tagattggta gtcctgcggt gccactagtg 4200ggagatgaga gtattaagac
aagagtaagg acaaggaaag acttaaaggt tgcatattga 4260aaagtttgga attcctaatt
tgggagcact gatttcttgg tgaagaagta agtatgacta 4320cgttgccagt aattttttaa
aaacatagac ccagaaatag caaatcgatt tcaccctcat 4380accttagtct acaaggcctt
gctcttgaga aggttttcca tgatattgct taatttcatc 4440tgcacaagat gagacacaaa
cataaaaatt ccctgctcat tttaatacca taaaaggctg 4500aggttatttc tctgtcataa
aattgtaaat agcatttttt aagtcaaaat tacatttaaa 4560acagtggatt gttctacaaa
tatatatgtg tatatataca tatgcttctg aaataaggat 4620atattatatg agtttttatt
tgatttgtgg tctttagtca taggtaatca aaaataaaga 4680gatttgaatg caaaacttta
tacattaatg tacatttcta atgatggtac aaattgccac 4740tttataataa aaaagaaaca
ggtgggaata ataatcaaag cacgtgttcc ttcagtactt 4800tggtgatttt taatccccct
tgtgatgcac aggaaattat tttttagtta caaaaagtta 4860tcttagaaat ctatacttcc
caatacagat ttcatgttaa gtcatatcaa attgagaatt 4920tgtggtgaaa gaataggaaa
aggatgctag atgctgatct ttctttttca ggatttttcc 4980tggagcccaa gttaaaaatt
caatacttaa atctaagtta agtgaaaatt aataatgttc 5040agaatgatgt attgagcttt
agtaacagac ggaagcaaaa aaaaataaga atatttaaca 5100ttatgataat agccttaaaa
taatgtaata aaaattgcat cattaaatgt tctattagtt 5160ggaaagaatg agctgatgtt
tctttgtctt tgctccaagt acaatttaaa gacagtgaca 5220ttcattttac ttaaaattgt
tcaaaaagtc caaaacatac tcccatggct agaattggta 5280ttagctccaa tacaaggtta
aatgttacaa tcttaagaaa ttattgacac tgaaatgttt 5340agtaaacatg ttgtatgaga
aactaaacaa attaatgttt catttttcca ttaaagcaca 5400gattattc
5408138181PRTHomo sapiens
138Met Glu Ser Lys Glu Pro Gln Leu Lys Gly Ile Val Thr Arg Leu Phe 1
5 10 15 Ser Gln Gln Gly
Tyr Phe Leu Gln Met His Pro Asp Gly Thr Ile Asp 20
25 30 Gly Thr Lys Asp Glu Asn Ser Asp Tyr
Thr Leu Phe Asn Leu Ile Pro 35 40
45 Val Gly Leu Arg Val Val Ala Ile Gln Gly Val Lys Ala Ser
Leu Tyr 50 55 60
Val Ala Met Asn Gly Glu Gly Tyr Leu Tyr Ser Ser Asp Val Phe Thr 65
70 75 80 Pro Glu Cys Lys Phe
Lys Glu Ser Val Phe Glu Asn Tyr Tyr Val Ile 85
90 95 Tyr Ser Ser Thr Leu Tyr Arg Gln Gln Glu
Ser Gly Arg Ala Trp Phe 100 105
110 Leu Gly Leu Asn Lys Glu Gly Gln Ile Met Lys Gly Asn Arg Val
Lys 115 120 125 Lys
Thr Lys Pro Ser Ser His Phe Val Pro Lys Pro Ile Glu Val Cys 130
135 140 Met Tyr Arg Glu Pro Ser
Leu His Glu Ile Gly Glu Lys Gln Gly Arg 145 150
155 160 Ser Arg Lys Ser Ser Gly Thr Pro Thr Met Asn
Gly Gly Lys Val Val 165 170
175 Asn Gln Asp Ser Thr 180 1391354DNAHomo sapiens
139cccctcctcc tccctctttt ctctcctcct cctccccttt ctctcctcct cgcccccctg
60aaaacctgtg gctcggagag accttggctt ctctgggact ctacccctgg ggacttccca
120catctgctcc tgagcttggg ggcagggggg caaccgcctg aggaacctct ccagcgatgg
180gagccgcccg cctgctgccc aacctcactc tgtgcttaca gctgctgatt ctctgctgtc
240aaactcagta cgtgagggac cagggcgcca tgaccgacca gctgagcagg cggcagatcc
300gcgagtacca actctacagc aggaccagtg gcaagcacgt gcaggtcacc gggcgtcgca
360tctccgccac cgccgaggac ggcaacaagt ttgccaagct catagtggag acggacacgt
420ttggcagccg ggttcgcatc aaaggggctg agagtgagaa gtacatctgt atgaacaaga
480ggggcaagct catcgggaag cccagcggga agagcaaaga ctgcgtgttc acggagatcg
540tgctggagaa caactatacg gccttccaga acgcccggca cgagggctgg ttcatggcct
600tcacgcggca ggggcggccc cgccaggctt cccgcagccg ccagaaccag cgcgaggccc
660acttcatcaa gcgcctctac caaggccagc tgcccttccc caaccacgcc gagaagcaga
720agcagttcga gtttgtgggc tccgccccca cccgccggac caagcgcaca cggcggcccc
780agcccctcac gtagtctggg aggcaggggg cagcagcccc tgggccgcct ccccacccct
840ttcccttctt aatccaagga ctgggctggg gtggcgggag gggagccaga tccccgaggg
900aggaccctga gggccgcgaa gcatccgagc ccccagctgg gaaggggcag gccggtgccc
960caggggcggc tggcacagtg cccccttccc ggacgggtgg caggccctgg agaggaactg
1020agtgtcaccc tgatctcagg ccaccagcct ctgccggcct cccagccggg ctcctgaagc
1080ccgctgaaag gtcagcgact gaaggccttg cagacaaccg tctggaggtg gctgtcctca
1140aaatctgctt ctcggatctc cctcagtctg cccccagccc ccaaactcct cctggctaga
1200ctgtaggaag ggacttttgt ttgtttgttt gtttcaggaa aaaagaaagg gagagagagg
1260aaaatagagg gttgtccact cctcacattc cacgacccag gcctgcaccc cacccccaac
1320tcccagcccc ggaataaaac cattttcctg caaa
1354140205PRTHomo sapiens 140Met Gly Ala Ala Arg Leu Leu Pro Asn Leu Thr
Leu Cys Leu Gln Leu 1 5 10
15 Leu Ile Leu Cys Cys Gln Thr Gln Tyr Val Arg Asp Gln Gly Ala Met
20 25 30 Thr Asp
Gln Leu Ser Arg Arg Gln Ile Arg Glu Tyr Gln Leu Tyr Ser 35
40 45 Arg Thr Ser Gly Lys His Val
Gln Val Thr Gly Arg Arg Ile Ser Ala 50 55
60 Thr Ala Glu Asp Gly Asn Lys Phe Ala Lys Leu Ile
Val Glu Thr Asp 65 70 75
80 Thr Phe Gly Ser Arg Val Arg Ile Lys Gly Ala Glu Ser Glu Lys Tyr
85 90 95 Ile Cys Met
Asn Lys Arg Gly Lys Leu Ile Gly Lys Pro Ser Gly Lys 100
105 110 Ser Lys Asp Cys Val Phe Thr Glu
Ile Val Leu Glu Asn Asn Tyr Thr 115 120
125 Ala Phe Gln Asn Ala Arg His Glu Gly Trp Phe Met Ala
Phe Thr Arg 130 135 140
Gln Gly Arg Pro Arg Gln Ala Ser Arg Ser Arg Gln Asn Gln Arg Glu 145
150 155 160 Ala His Phe Ile
Lys Arg Leu Tyr Gln Gly Gln Leu Pro Phe Pro Asn 165
170 175 His Ala Glu Lys Gln Lys Gln Phe Glu
Phe Val Gly Ser Ala Pro Thr 180 185
190 Arg Arg Thr Lys Arg Thr Arg Arg Pro Gln Pro Leu Thr
195 200 205 141744DNAHomo sapiens
141tttagggcca ttaattctga ccacgtgcct gagaggcaag gtggatggcc ctgggacaga
60aactgttcat cactatgtcc cggggagcag gacgtctgca gggcacgctg tgggctctcg
120tcttcctagg catcctagtg ggcatggtgg tgccctcgcc tgcaggcacc cgtgccaaca
180acacgctgct ggactcgagg ggctggggca ccctgctgtc caggtctcgc gcggggctag
240ctggagagat tgccggggtg aactgggaaa gtggctattt ggtggggatc aagcggcagc
300ggaggctcta ctgcaacgtg ggcatcggct ttcacctcca ggtgctcccc gacggccgga
360tcagcgggac ccacgaggag aacccctaca gcctgctgga aatttccact gtggagcgag
420gcgtggtgag tctctttgga gtgagaagtg ccctcttcgt tgccatgaac agtaaaggaa
480gattgtacgc aacgcccagc ttccaagaag aatgcaagtt cagagaaacc ctcctgccca
540acaattacaa tgcctacgag tcagacttgt accaagggac ctacattgcc ctgagcaaat
600acggacgggt aaagcggggc agcaaggtgt ccccgatcat gactgtcact catttccttc
660ccaggatcta aggacccaca aaagaaggct tacagattta aagcatcatc tgttcgattg
720aaattttgca ccagcgaaga attc
744142208PRTHomo sapiens 142Met Ala Leu Gly Gln Lys Leu Phe Ile Thr Met
Ser Arg Gly Ala Gly 1 5 10
15 Arg Leu Gln Gly Thr Leu Trp Ala Leu Val Phe Leu Gly Ile Leu Val
20 25 30 Gly Met
Val Val Pro Ser Pro Ala Gly Thr Arg Ala Asn Asn Thr Leu 35
40 45 Leu Asp Ser Arg Gly Trp Gly
Thr Leu Leu Ser Arg Ser Arg Ala Gly 50 55
60 Leu Ala Gly Glu Ile Ala Gly Val Asn Trp Glu Ser
Gly Tyr Leu Val 65 70 75
80 Gly Ile Lys Arg Gln Arg Arg Leu Tyr Cys Asn Val Gly Ile Gly Phe
85 90 95 His Leu Gln
Val Leu Pro Asp Gly Arg Ile Ser Gly Thr His Glu Glu 100
105 110 Asn Pro Tyr Ser Leu Leu Glu Ile
Ser Thr Val Glu Arg Gly Val Val 115 120
125 Ser Leu Phe Gly Val Arg Ser Ala Leu Phe Val Ala Met
Asn Ser Lys 130 135 140
Gly Arg Leu Tyr Ala Thr Pro Ser Phe Gln Glu Glu Cys Lys Phe Arg 145
150 155 160 Glu Thr Leu Leu
Pro Asn Asn Tyr Asn Ala Tyr Glu Ser Asp Leu Tyr 165
170 175 Gln Gly Thr Tyr Ile Ala Leu Ser Lys
Tyr Gly Arg Val Lys Arg Gly 180 185
190 Ser Lys Val Ser Pro Ile Met Thr Val Thr His Phe Leu Pro
Arg Ile 195 200 205
143751DNAHomo sapiens 143gcccgggagc gacgagcgcg cagcgaaccg ggtgccgggt
catgcgccgc cgcctgtggc 60tgggcctggc ctggctgctg ctggcgcggg cgccggacgc
cgcgggaacc ccgagcgcgt 120cgcggggacc gcgcagctac ccgcacctgg agggcgacgt
gcgctggcgg cgcctcttct 180cctccactca cttcttcctg cgcgtggatc ccggcggccg
cgtgcagggc acccgctggc 240gccacggcca ggacagcatc ctggagatcc gctctgtaca
cgtgggcgtc gtggtcatca 300aagcagtgtc ctcaggcttc tacgtggcca tgaaccgccg
gggccgcctc tacgggtcgg 360ttccgggagc gcatcgaaga gaacggccac aacacctacg
cctcacagcg ctggcgccgc 420cgcggccagc ccatgttcct ggcgctggac aggagggggg
ggccccggcc aggcggccgg 480acgcggcggt accacctgtc cgcccacttc ctgcccgtcc
tggtctcctg aggccctgag 540aggccggcgg ctccccaagg tgcctgggct ggtggcgagg
ggcccggcca cgcttgttct 600tccccctgcg ggctctgtaa gcgctgagtg cccaccgtgt
gcgggcgctg tggacacagc 660ccaggagccc tccagggggg tcccagcctg agggggtggt
ggccaccaag caggttcaat 720cctgagttgg ggacctcgag gacccaacag g
751144165PRTHomo sapiens 144Met Arg Arg Arg Leu
Trp Leu Gly Leu Ala Trp Leu Leu Leu Ala Arg 1 5
10 15 Ala Pro Asp Ala Ala Gly Thr Pro Ser Ala
Ser Arg Gly Pro Arg Ser 20 25
30 Tyr Pro His Leu Glu Gly Asp Val Arg Trp Arg Arg Leu Phe Ser
Ser 35 40 45 Thr
His Phe Phe Leu Arg Val Asp Pro Gly Gly Arg Val Gln Gly Thr 50
55 60 Arg Trp Arg His Gly Gln
Asp Ser Ile Leu Glu Ile Arg Ser Val His 65 70
75 80 Val Gly Val Val Val Ile Lys Ala Val Ser Ser
Gly Phe Tyr Val Ala 85 90
95 Met Asn Arg Arg Gly Arg Leu Tyr Gly Ser Val Pro Gly Ala His Arg
100 105 110 Arg Glu
Arg Pro Gln His Leu Arg Leu Thr Ala Leu Ala Pro Pro Arg 115
120 125 Pro Ala His Val Pro Gly Ala
Gly Gln Glu Gly Gly Ala Pro Ala Arg 130 135
140 Arg Pro Asp Ala Ala Val Pro Pro Val Arg Pro Leu
Pro Ala Arg Pro 145 150 155
160 Gly Leu Leu Arg Pro 165 1452414DNAHomo sapiens
145ctctgagtag gaccgggccc ccacgtgact cagcctgcct ctccatctcc tcagctccca
60ccccccatat ccttgatgaa tgtctctctc tccagagcct cagctcaaag gcatcgtcac
120caaactgttc tgccgccagg gtttctacct ccaggcgaat cccgacggaa gcatccaggg
180caccccagag gataccagct ccttcaccca cttcaacctg atccctgtgg gcctccgtgt
240ggtcaccatc cagagcgcca agctgggtca ctacatggcc atgaatgctg agggactgct
300ctacagttcg ccgcatttca cagctgagtg tcgctttaag gagtgtgtct ttgagaatta
360ctacgtcctg tacgcctctg ctctctaccg ccagcgtcgt tctggccggg cctggtacct
420cggcctggac aaggagggcc aggtcatgaa gggaaaccga gttaagaaga ccaaggcagc
480tgcccacttt ctgcccaagc tcctggaggt ggccatgtac caggagcctt ctctccacag
540tgtccccgag gcctcccctt ccagtccccc tgccccctga aatgtagtcc ctggactgga
600ggttccctgc actcccagtg agccagccac caccacaacc tgtctcccag tcctgctctc
660acccctgctg ccacacacat gccctgagca gccaggtccc actaggtgct ctaccctgag
720ggagcctagg ggctgactgt gacttccgag gctgctgaga cccttagatc tttgggccta
780ggagggagtc agagaggggg atgtctgaag atggtcctgg ctgatcactt ctttctttcc
840acactcacac aaccccatgc cttttcctga gatggcgctg ggagttccca catggacagc
900cagggcataa acacttccca ccccggctca gccagttcct ggagtcctgt gccccttttc
960attgccactg agccatttct agattcactg gagctcagga ttcatgtgtc cttctttccc
1020tactctacct tctaccttgg tctggacaca ttctggaaca ctggacaccc tcgccagggc
1080cacttctgca ctagggctct gtgctggaac ccaggcatgc tgccagcctt ttctctggat
1140ctgtcaggcc tctgtcattg actcagatgg acccctggtt tccaagtaga aagaggctag
1200atttgggcct tgtctagctg ttggctttgg cctgaaccgg aaccagtctc agatgaccac
1260gggtttaacc ttcttatccc agagacaccc aattctagag ctttatggag ccgtacttcc
1320ccctgaatcc tagctctagg acatagatca tgactctcag cccttttacc caggatggag
1380ctggggcctg tatagccata ttattgttct aagtaagttc tagccccacc ctcccgcctt
1440cttgagtgat acctattacg gatgagttct ggaaaagacc cagctatgat tcataaaaac
1500acttctggat gaatcaagaa ccatttcttg tttttcctag ataattctct aaaaatatga
1560ttcttccata tagaatgcta agcttatttt tacatgcagt ttctagctcc ttcaacccag
1620ctgaggtcgt gccagggaga cagagtctgg agaagggcag aggaattttg gaaggatccc
1680tggctcatag tagggaagct gggatggggg aggggtcaaa attatggcat gactgaacct
1740gcatctgtgt tgggtggaca tgaatactta gctacctcag caggaattcc ttccaggtcc
1800cctttaaagc tgaggtcctt agagtaatat gtccttaata aaaaggacaa atggatacag
1860ccttgaccct cccagtgagg agaccccaat tcagcaataa gtctcaccct tctcccctac
1920aggtcaggcc aagaagggtg aaggcctctt gcactccaga cctcatacgc cccaacagct
1980tctaattgga tagaacttgc tttaccttac agctcacaac ctcagctggg ttttaggtac
2040ccaaaaaggg cctgtctaga ttttttcaga aaaacgtgga gtgctagggg cagcctggaa
2100aagatgggga acctgctagt gaactaggag ggagacttcc atagcctcag acttggatag
2160ggtaggctga gggggcccta agggagggac taaggctcca aggcaggtca cttttcctta
2220ggctgttcta cttctggctt gttgcaagag gagtagatgc cccctcaccc acacaaaccc
2280cactcagtct ccacccaact cctggcactg ctcccagggg atcgggtctc cactccagct
2340ttctcaatta aagacgattt atacaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa
2400aaaaaaaaaa aaaa
2414146166PRTHomo sapiens 146Met Ser Leu Ser Pro Glu Pro Gln Leu Lys Gly
Ile Val Thr Lys Leu 1 5 10
15 Phe Cys Arg Gln Gly Phe Tyr Leu Gln Ala Asn Pro Asp Gly Ser Ile
20 25 30 Gln Gly
Thr Pro Glu Asp Thr Ser Ser Phe Thr His Phe Asn Leu Ile 35
40 45 Pro Val Gly Leu Arg Val Val
Thr Ile Gln Ser Ala Lys Leu Gly His 50 55
60 Tyr Met Ala Met Asn Ala Glu Gly Leu Leu Tyr Ser
Ser Pro His Phe 65 70 75
80 Thr Ala Glu Cys Arg Phe Lys Glu Cys Val Phe Glu Asn Tyr Tyr Val
85 90 95 Leu Tyr Ala
Ser Ala Leu Tyr Arg Gln Arg Arg Ser Gly Arg Ala Trp 100
105 110 Tyr Leu Gly Leu Asp Lys Glu Gly
Gln Val Met Lys Gly Asn Arg Val 115 120
125 Lys Lys Thr Lys Ala Ala Ala His Phe Leu Pro Lys Leu
Leu Glu Val 130 135 140
Ala Met Tyr Gln Glu Pro Ser Leu His Ser Val Pro Glu Ala Ser Pro 145
150 155 160 Ser Ser Pro Pro
Ala Pro 165 1476774DNAHomo sapiens 147cggccccaga
aaacccgagc gagtaggggg cggcgcgcag gagggaggag aactgggggc 60gcgggaggct
ggtgggtgtg gggggtggag atgtagaaga tgtgacgccg cggcccggcg 120ggtgccagat
tagcggacgc ggtgcccgcg gttgcaacgg gatcccgggc gctgcagctt 180gggaggcggc
tctccccagg cggcgtccgc ggagacaccc atccgtgaac cccaggtccc 240gggccgccgg
ctcgccgcgc accaggggcc ggcggacaga agagcggccg agcggctcga 300ggctggggga
ccgcgggcgc ggccgcgcgc tgccgggcgg gaggctgggg ggccggggcc 360ggggccgtgc
cccggagcgg gtcggaggcc ggggccgggg ccgggggacg gcggctcccc 420gcgcggctcc
agcggctcgg ggatcccggc cgggccccgc agggaccatg gcagccggga 480gcatcaccac
gctgcccgcc ttgcccgagg atggcggcag cggcgccttc ccgcccggcc 540acttcaagga
ccccaagcgg ctgtactgca aaaacggggg cttcttcctg cgcatccacc 600ccgacggccg
agttgacggg gtccgggaga agagcgaccc tcacatcaag ctacaacttc 660aagcagaaga
gagaggagtt gtgtctatca aaggagtgtg tgctaaccgt tacctggcta 720tgaaggaaga
tggaagatta ctggcttcta aatgtgttac ggatgagtgt ttcttttttg 780aacgattgga
atctaataac tacaatactt accggtcaag gaaatacacc agttggtatg 840tggcactgaa
acgaactggg cagtataaac ttggatccaa aacaggacct gggcagaaag 900ctatactttt
tcttccaatg tctgctaaga gctgatttta atggccacat ctaatctcat 960ttcacatgaa
agaagaagta tattttagaa atttgttaat gagagtaaaa gaaaataaat 1020gtgtatagct
cagtttggat aattggtcaa acaatttttt atccagtagt aaaatatgta 1080accattgtcc
cagtaaagaa aaataacaaa agttgtaaaa tgtatattct cccttttata 1140ttgcatctgc
tgttacccag tgaagcttac ctagagcaat gatctttttc acgcatttgc 1200tttattcgaa
aagaggcttt taaaatgtgc atgtttagaa acaaaatttc ttcatggaaa 1260tcatatacat
tagaaaatca cagtcagatg tttaatcaat ccaaaatgtc cactatttct 1320tatgtcattc
gttagtctac atgtttctaa acatataaat gtgaatttaa tcaattcctt 1380tcatagtttt
ataattctct ggcagttcct tatgatagag tttataaaac agtcctgtgt 1440aaactgctgg
aagttcttcc acagtcaggt caattttgtc aaacccttct ctgtacccat 1500acagcagcag
cctagcaact ctgctggtga tgggagttgt attttcagtc ttcgccaggt 1560cattgagatc
catccactca catcttaagc attcttcctg gcaaaaattt atggtgaatg 1620aatatggctt
taggcggcag atgatataca tatctgactt cccaaaagct ccaggatttg 1680tgtgctgttg
ccgaatactc aggacggacc tgaattctga ttttatacca gtctcttcaa 1740aaacttctcg
aaccgctgtg tctcctacgt aaaaaaagag atgtacaaat caataataat 1800tacactttta
gaaactgtat catcaaagat tttcagttaa agtagcatta tgtaaaggct 1860caaaacatta
ccctaacaaa gtaaagtttt caatacaaat tctttgcctt gtggatatca 1920agaaatccca
aaatattttc ttaccactgt aaattcaaga agcttttgaa atgctgaata 1980tttctttggc
tgctacttgg aggcttatct acctgtacat ttttggggtc agctcttttt 2040aacttcttgc
tgctcttttt cccaaaaggt aaaaatatag attgaaaagt taaaacattt 2100tgcatggctg
cagttccttt gtttcttgag ataagattcc aaagaactta gattcatttc 2160ttcaacaccg
aaatgctgga ggtgtttgat cagttttcaa gaaacttgga atataaataa 2220ttttataatt
caacaaaggt tttcacattt tataaggttg atttttcaat taaatgcaaa 2280tttgtgtggc
aggattttta ttgccattaa catatttttg tggctgcttt ttctacacat 2340ccagatggtc
cctctaactg ggctttctct aattttgtga tgttctgtca ttgtctccca 2400aagtatttag
gagaagccct ttaaaaagct gccttcctct accactttgc tggaaagctt 2460cacaattgtc
acagacaaag atttttgttc caatactcgt tttgcctcta tttttcttgt 2520ttgtcaaata
gtaaatgata tttgcccttg cagtaattct actggtgaaa aacatgcaaa 2580gaagaggaag
tcacagaaac atgtctcaat tcccatgtgc tgtgactgta gactgtctta 2640ccatagactg
tcttacccat cccctggata tgctcttgtt ttttccctct aatagctatg 2700gaaagatgca
tagaaagagt ataatgtttt aaaacataag gcattcgtct gccatttttc 2760aattacatgc
tgacttccct tacaattgag atttgcccat aggttaaaca tggttagaaa 2820caactgaaag
cataaaagaa aaatctaggc cgggtgcagt ggctcatgcc tatattccct 2880gcactttggg
aggccaaagc aggaggatcg cttgagccca ggagttcaag accaacctgg 2940tgaaaccccg
tctctacaaa aaaacacaaa aaatagccag gcatggtggc gtgtacatgt 3000ggtctcagat
acttgggagg ctgaggtggg agggttgatc acttgaggct gagaggtcaa 3060ggttgcagtg
agccataatc gtgccactgc agtccagcct aggcaacaga gtgagacttt 3120gtctcaaaaa
aagagaaatt ttccttaata agaaaagtaa tttttactct gatgtgcaat 3180acatttgtta
ttaaatttat tatttaagat ggtagcacta gtcttaaatt gtataaaata 3240tcccctaaca
tgtttaaatg tccattttta ttcattatgc tttgaaaaat aattatgggg 3300aaatacatgt
ttgttattaa atttattatt aaagatagta gcactagtct taaatttgat 3360ataacatctc
ctaacttgtt taaatgtcca tttttattct ttatgtttga aaataaatta 3420tggggatcct
atttagctct tagtaccact aatcaaaagt tcggcatgta gctcatgatc 3480tatgctgttt
ctatgtcgtg gaagcaccgg atgggggtag tgagcaaatc tgccctgctc 3540agcagtcacc
atagcagctg actgaaaatc agcactgcct gagtagtttt gatcagttta 3600acttgaatca
ctaactgact gaaaattgaa tgggcaaata agtgcttttg tctccagagt 3660atgcgggaga
cccttccacc tcaagatgga tatttcttcc ccaaggattt caagatgaat 3720tgaaattttt
aatcaagata gtgtgcttta ttctgttgta ttttttatta ttttaatata 3780ctgtaagcca
aactgaaata acatttgctg ttttataggt ttgaagaaca taggaaaaac 3840taagaggttt
tgtttttatt tttgctgatg aagagatatg tttaaatatg ttgtattgtt 3900ttgtttagtt
acaggacaat aatgaaatgg agtttatatt tgttatttct attttgttat 3960atttaataat
agaattagat tgaaataaaa tataatggga aataatctgc agaatgtggg 4020ttttcctggt
gtttccctct gactctagtg cactgatgat ctctgataag gctcagctgc 4080tttatagttc
tctggctaat gcagcagata ctcttcctgc cagtggtaat acgatttttt 4140aagaaggcag
tttgtcaatt ttaatcttgt ggataccttt atactcttag ggtattattt 4200tatacaaaag
ccttgaggat tgcattctat tttctatatg accctcttga tatttaaaaa 4260acactatgga
taacaattct tcatttacct agtattatga aagaatgaag gagttcaaac 4320aaatgtgttt
cccagttaac tagggtttac tgtttgagcc aatataaatg tttaactgtt 4380tgtgatggca
gtattcctaa agtacattgc atgttttcct aaatacagag tttaaataat 4440ttcagtaatt
cttagatgat tcagcttcat cattaagaat atcttttgtt ttatgttgag 4500ttagaaatgc
cttcatatag acatagtctt tcagacctct actgtcagtt ttcatttcta 4560gctgctttca
gggttttatg aattttcagg caaagcttta atttatacta agcttaggaa 4620gtatggctaa
tgccaacggc agtttttttc ttcttaattc cacatgactg aggcatatat 4680gatctctggg
taggtgagtt gttgtgacaa ccacaagcac tttttttttt tttaaagaaa 4740aaaaggtagt
gaatttttaa tcatctggac tttaagaagg attctggagt atacttaggc 4800ctgaaattat
atatatttgg cttggaaatg tgtttttctt caattacatc tacaagtaag 4860tacagctgaa
attcagagga cccataagag ttcacatgaa aaaaatcaat ttatttgaaa 4920aggcaagatg
caggagagag gaagccttgc aaacctgcag actgcttttt gcccaatata 4980gattgggtaa
ggctgcaaaa cataagctta attagctcac atgctctgct ctcacgtggc 5040accagtggat
agtgtgagag aattaggctg tagaacaaat ggccttctct ttcagcattc 5100acaccactac
aaaatcatct tttatatcaa cagaagaata agcataaact aagcaaaagg 5160tcaataagta
cctgaaacca agattggcta gagatatatc ttaatgcaat ccattttctg 5220atggattgtt
acgagttggc tatataatgt atgtatggta ttttgatttg tgtaaaagtt 5280ttaaaaatca
agctttaagt acatggacat ttttaaataa aatatttaaa gacaatttag 5340aaaattgcct
taatatcatt gttggctaaa tagaataggg gacatgcata ttaaggaaaa 5400ggtcatggag
aaataatatt ggtatcaaac aaatacattg atttgtcatg atacacattg 5460aatttgatcc
aatagtttaa ggaataggta ggaaaatttg gtttctattt ttcgatttcc 5520tgtaaatcag
tgacataaat aattcttagc ttattttata tttccttgtc ttaaatactg 5580agctcagtaa
gttgtgttag gggattattt ctcagttgag actttcttat atgacatttt 5640actatgtttt
gacttcctga ctattaaaaa taaatagtag atacaatttt cataaagtga 5700agaattatat
aatcactgct ttataactga ctttattata tttatttcaa agttcattta 5760aaggctacta
ttcatcctct gtgatggaat ggtcaggaat ttgttttctc atagtttaat 5820tccaacaaca
atattagtcg tatccaaaat aacctttaat gctaaacttt actgatgtat 5880atccaaagct
tctcattttc agacagatta atccagaagc agtcataaac agaagaatag 5940gtggtatgtt
cctaatgata ttatttctac taatggaata aactgtaata ttagaaatta 6000tgctgctaat
tatatcagct ctgaggtaat ttctgaaatg ttcagactca gtcggaacaa 6060attggaaaat
ttaaattttt attcttagct ataaagcaag aaagtaaaca cattaatttc 6120ctcaacattt
ttaagccaat taaaaatata aaagatacac accaatatct tcttcaggct 6180ctgacaggcc
tcctggaaac ttccacatat ttttcaactg cagtataaag tcagaaaata 6240aagttaacat
aactttcact aacacacaca tatgtagatt tcacaaaatc cacctataat 6300tggtcaaagt
ggttgagaat atatttttta gtaattgcat gcaaaatttt tctagcttcc 6360atcctttctc
cctcgtttct tctttttttg ggggagctgg taactgatga aatcttttcc 6420caccttttct
cttcaggaaa tataagtggt tttgtttggt taacgtgata cattctgtat 6480gaatgaaaca
ttggagggaa acatctactg aatttctgta atttaaaata ttttgctgct 6540agttaactat
gaacagatag aagaatctta cagatgctgc tataaataag tagaaaatat 6600aaatttcatc
actaaaatat gctattttaa aatctatttc ctatattgta tttctaatca 6660gatgtattac
tcttattatt tctattgtat gtgttaatga ttttatgtaa aaatgtaatt 6720gcttttcatg
agtagtatga ataaaattga ttagtttgtg ttttcttgtc tccc
6774148288PRTHomo sapiens 148Met Val Gly Val Gly Gly Gly Asp Val Glu Asp
Val Thr Pro Arg Pro 1 5 10
15 Gly Gly Cys Gln Ile Ser Gly Arg Gly Ala Arg Gly Cys Asn Gly Ile
20 25 30 Pro Gly
Ala Ala Ala Trp Glu Ala Ala Leu Pro Arg Arg Arg Pro Arg 35
40 45 Arg His Pro Ser Val Asn Pro
Arg Ser Arg Ala Ala Gly Ser Pro Arg 50 55
60 Thr Arg Gly Arg Arg Thr Glu Glu Arg Pro Ser Gly
Ser Arg Leu Gly 65 70 75
80 Asp Arg Gly Arg Gly Arg Ala Leu Pro Gly Gly Arg Leu Gly Gly Arg
85 90 95 Gly Arg Gly
Arg Ala Pro Glu Arg Val Gly Gly Arg Gly Arg Gly Arg 100
105 110 Gly Thr Ala Ala Pro Arg Ala Ala
Pro Ala Ala Arg Gly Ser Arg Pro 115 120
125 Gly Pro Ala Gly Thr Met Ala Ala Gly Ser Ile Thr Thr
Leu Pro Ala 130 135 140
Leu Pro Glu Asp Gly Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys 145
150 155 160 Asp Pro Lys Arg
Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile 165
170 175 His Pro Asp Gly Arg Val Asp Gly Val
Arg Glu Lys Ser Asp Pro His 180 185
190 Ile Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser
Ile Lys 195 200 205
Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu 210
215 220 Leu Ala Ser Lys Cys
Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu 225 230
235 240 Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser
Arg Lys Tyr Thr Ser Trp 245 250
255 Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys
Thr 260 265 270 Gly
Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 275
280 285 1493018DNAHomo sapiens
149cggcaaaaag gagggaatcc agtctaggat cctcacacca gctacttgca agggagaagg
60aaaaggccag taaggcctgg gccaggagag tcccgacagg agtgtcaggt ttcaatctca
120gcaccagcca ctcagagcag ggcacgatgt tgggggcccg cctcaggctc tgggtctgtg
180ccttgtgcag cgtctgcagc atgagcgtcc tcagagccta tcccaatgcc tccccactgc
240tcggctccag ctggggtggc ctgatccacc tgtacacagc cacagccagg aacagctacc
300acctgcagat ccacaagaat ggccatgtgg atggcgcacc ccatcagacc atctacagtg
360ccctgatgat cagatcagag gatgctggct ttgtggtgat tacaggtgtg atgagcagaa
420gatacctctg catggatttc agaggcaaca tttttggatc acactatttc gacccggaga
480actgcaggtt ccaacaccag acgctggaaa acgggtacga cgtctaccac tctcctcagt
540atcacttcct ggtcagtctg ggccgggcga agagagcctt cctgccaggc atgaacccac
600ccccgtactc ccagttcctg tcccggagga acgagatccc cctaattcac ttcaacaccc
660ccataccacg gcggcacacc cggagcgccg aggacgactc ggagcgggac cccctgaacg
720tgctgaagcc ccgggcccgg atgaccccgg ccccggcctc ctgttcacag gagctcccga
780gcgccgagga caacagcccg atggccagtg acccattagg ggtggtcagg ggcggtcgag
840tgaacacgca cgctggggga acgggcccgg aaggctgccg ccccttcgcc aagttcatct
900agggtcgctg gaagggcacc ctctttaacc catccctcag caaacgcagc tcttcccaag
960gaccaggtcc cttgacgttc cgaggatggg aaaggtgaca ggggcatgta tggaatttgc
1020tgcttctctg gggtcccttc cacaggaggt cctgtgagaa ccaacctttg aggcccaagt
1080catggggttt caccgccttc ctcactccat atagaacacc tttcccaata ggaaacccca
1140acaggtaaac tagaaatttc cccttcatga aggtagagag aaggggtctc tcccaacata
1200tttctcttcc ttgtgcctct cctctttatc acttttaagc ataaaaaaaa aaaaaaaaaa
1260aaaaaaaaaa aaaagcagtg ggttcctgag ctcaagactt tgaaggtgta gggaagagga
1320aatcggagat cccagaagct tctccactgc cctatgcatt tatgttagat gccccgatcc
1380cactggcatt tgagtgtgca aaccttgaca ttaacagctg aatggggcaa gttgatgaaa
1440acactacttt caagccttcg ttcttccttg agcatctctg gggaagagct gtcaaaagac
1500tggtggtagg ctggtgaaaa cttgacagct agacttgatg cttgctgaaa tgaggcagga
1560atcataatag aaaactcagc ctccctacag ggtgagcacc ttctgtctcg ctgtctccct
1620ctgtgcagcc acagccagag ggcccagaat ggccccactc tgttcccaag cagttcatga
1680tacagcctca ccttttggcc ccatctctgg tttttgaaaa tttggtctaa ggaataaata
1740gcttttacac tggctcacga aaatctgccc tgctagaatt tgcttttcaa aatggaaata
1800aattccaact ctcctaagag gcatttaatt aaggctctac ttccaggttg agtaggaatc
1860cattctgaac aaactacaaa aatgtgactg ggaagggggc tttgagagac tgggactgct
1920ctgggttagg ttttctgtgg actgaaaaat cgtgtccttt tctctaaatg aagtggcatc
1980aaggactcag ggggaaagaa atcaggggac atgttataga agttatgaaa agacaaccac
2040atggtcaggc tcttgtctgt ggtctctagg gctctgcagc agcagtggct cttcgattag
2100ttaaaactct cctaggctga cacatctggg tctcaatccc cttggaaatt cttggtgcat
2160taaatgaagc cttaccccat tactgcggtt cttcctgtaa gggggctcca ttttcctccc
2220tctctttaaa tgaccaccta aaggacagta tattaacaag caaagtcgat tcaacaacag
2280cttcttccca gtcacttttt tttttctcac tgccatcaca tactaacctt atactttgat
2340ctattctttt tggttatgag agaaatgttg ggcaactgtt tttacctgat ggttttaagc
2400tgaacttgaa ggactggttc ctattctgaa acagtaaaac tatgtataat agtatatagc
2460catgcatggc aaatatttta atatttctgt tttcatttcc tgttggaaat attatcctgc
2520ataatagcta ttggaggctc ctcagtgaaa gatcccaaaa ggattttggt ggaaaactag
2580ttgtaatctc acaaactcaa cactaccatc aggggttttc tttatggcaa agccaaaata
2640gctcctacaa tttcttatat ccctcgtcat gtggcagtat ttatttattt atttggaagt
2700ttgcctatcc ttctatattt atagatattt ataaaaatgt aacccctttt tcctttcttc
2760tgtttaaaat aaaaataaaa tttatctcag cttctgttag cttatcctct ttgtagtact
2820acttaaaagc atgtcggaat ataagaataa aaaggattat gggaggggaa cattagggaa
2880atccagagaa ggcaaaattg aaaaaaagat tttagaattt taaaattttc aaagatttct
2940tccattcata aggagactca atgattttaa ttgatctaga cagaattatt taagttttat
3000caatattgga tttctggt
3018150251PRTHomo sapiens 150Met Leu Gly Ala Arg Leu Arg Leu Trp Val Cys
Ala Leu Cys Ser Val 1 5 10
15 Cys Ser Met Ser Val Leu Arg Ala Tyr Pro Asn Ala Ser Pro Leu Leu
20 25 30 Gly Ser
Ser Trp Gly Gly Leu Ile His Leu Tyr Thr Ala Thr Ala Arg 35
40 45 Asn Ser Tyr His Leu Gln Ile
His Lys Asn Gly His Val Asp Gly Ala 50 55
60 Pro His Gln Thr Ile Tyr Ser Ala Leu Met Ile Arg
Ser Glu Asp Ala 65 70 75
80 Gly Phe Val Val Ile Thr Gly Val Met Ser Arg Arg Tyr Leu Cys Met
85 90 95 Asp Phe Arg
Gly Asn Ile Phe Gly Ser His Tyr Phe Asp Pro Glu Asn 100
105 110 Cys Arg Phe Gln His Gln Thr Leu
Glu Asn Gly Tyr Asp Val Tyr His 115 120
125 Ser Pro Gln Tyr His Phe Leu Val Ser Leu Gly Arg Ala
Lys Arg Ala 130 135 140
Phe Leu Pro Gly Met Asn Pro Pro Pro Tyr Ser Gln Phe Leu Ser Arg 145
150 155 160 Arg Asn Glu Ile
Pro Leu Ile His Phe Asn Thr Pro Ile Pro Arg Arg 165
170 175 His Thr Arg Ser Ala Glu Asp Asp Ser
Glu Arg Asp Pro Leu Asn Val 180 185
190 Leu Lys Pro Arg Ala Arg Met Thr Pro Ala Pro Ala Ser Cys
Ser Gln 195 200 205
Glu Leu Pro Ser Ala Glu Asp Asn Ser Pro Met Ala Ser Asp Pro Leu 210
215 220 Gly Val Val Arg Gly
Gly Arg Val Asn Thr His Ala Gly Gly Thr Gly 225 230
235 240 Pro Glu Gly Cys Arg Pro Phe Ala Lys Phe
Ile 245 250 1514162DNAHomo sapiens
151agaagtccat tcggctcaca catttgcccc aagacaaacc acgttaaaat aacacccagg
60gtagctgctg ccaccgtctt ctgtctctac ctccctcctg gctggccaat ggctctgtgt
120tcctgggcct gctgctggct gtccagagta ggggttgctt agagctgtgt gcatccctgc
180gggtggtgtg ggagtgggcg gttgtctaaa ggcaggtccc ctctactgat aaacaaggac
240cggagataga cctagaggct gacattcttg gctcccccag cctacacccc ccccacctcg
300atttcccaca gagccctagg gacgggtagc cagctctgtg gcatggtatc tggaggcagg
360ccagcaacct gatgtgcatg ccacggcccg tccctctccc cactcagagc tgcagtagcc
420tggaggttca gagagccggg ctactctgag aagaagacac caagtggatt ctgcttcccc
480tgggacagca ctgagcgagt gtggagagag gtacagccct cggcctacaa gctctttagt
540cttgaaagcg ccacaagcag cagctgctga gccatggctg aaggggaaat caccaccttc
600acagccctga ccgagaagtt taatctgcct ccagggaatt acaagaagcc caaactcctc
660tactgtagca acgggggcca cttcctgagg atccttccgg atggcacagt ggatgggaca
720agggacagga gcgaccagca cattcagctg cagctcagtg cggaaagcgt gggggaggtg
780tatataaaga gtaccgagac tggccagtac ttggccatgg acaccgacgg gcttttatac
840ggctcacaga caccaaatga ggaatgtttg ttcctggaaa ggctggagga gaaccattac
900aacacctata tatccaagaa gcatgcagag aagaattggt ttgttggcct caagaagaat
960gggagctgca aacgcggtcc tcggactcac tatggccaga aagcaatctt gtttctcccc
1020ctgccagtct cttctgatta aagagatctg ttctgggtgt tgaccactcc agagaagttt
1080cgaggggtcc tcacctggtt gacccaaaaa tgttcccttg accattggct gcgctaaccc
1140ccagcccaca gagcctgaat ttgtaagcaa cttgcttcta aatgcccagt tcacttcttt
1200gcagagcctt ttacccctgc acagtttaga acagagggac caaattgctt ctaggagtca
1260actggctggc cagtctgggt ctgggtttgg atctccaatt gcctcttgca ggctgagtcc
1320ctccatgcaa aagtggggct aaatgaagtg tgttaagggg tcggctaagt gggacattag
1380taactgcaca ctatttccct ctactgagta aaccctatct gtgattcccc caaacatctg
1440gcatggctcc cttttgtcct tcctgtgccc tgcaaatatt agcaaagaag cttcatgcca
1500ggttaggaag gcagcattcc atgaccagaa acagggacaa agaaatcccc ccttcagaac
1560agaggcattt aaaatggaaa agagagattg gattttggtg ggtaacttag aaggatggca
1620tctccatgta gaataaatga agaaagggag gcccagccgc aggaaggcag aataaatcct
1680tgggagtcat taccacgcct tgaccttccc aaggttactc agcagcagag agccctgggt
1740gacttcaggt ggagagcact agaagtggtt tcctgataac aagcaaggat atcagagctg
1800ggaaattcat gtggatctgg ggactgagtg tgggagtgca gagaaagaaa gggaaactgg
1860ctgaggggat accataaaaa gaggatgatt tcagaaggag aaggaaaaag aaagtaatgc
1920cacacattgt gcttggcccc tggtaagcag aggctttggg gtcctagccc agtgcttctc
1980caacactgaa gtgcttgcag atcatctggg gacctggttt gaatggagat tctgattcag
2040tgggttgggg gcagagtttc tgcagttcca tcaggtcccc cccaggtgca ggtgctgaca
2100atactgctgc cttacccgcc atacattaag gagcagggtc ctggtcctaa agagttattc
2160aaatgaaggt ggttcgacgc cccgaacctc acctgacctc aactaaccct taaaaatgca
2220cacctcatga gtctacctga gcattcaggc agcactgaca atagttatgc ctgtactaag
2280gagcatgatt ttaagaggct ttggcccaat gcctataaaa tgcccatttc gaagatatac
2340aaaaacatac ttcaaaaatg ttaaaccctt accaacagct tttcccagga gaccatttgt
2400attaccatta cttgtataaa tacacttcct gcttaaactt gacccaggtg gctagcaaat
2460tagaaacacc attcatctct aacatatgat actgatgcca tgtaaaggcc tttaataagt
2520cattgaaatt tactgtgaga ctgtatgttt taattgcatt taaaaatata tagcttgaaa
2580gcagttaaac tgattagtat tcaggcactg agaatgatag taataggata caatgtataa
2640gctactcact tatctgatac ttatttacct ataaaatgag atttttgttt tccactgtgc
2700tattacaaat tttcttttga aagtaggaac tcttaagcaa tggtaattgt gaataaaaat
2760tgatgagagt gttagctcct gtttcatatg aaattgaagt aattgttaac taaaaacaat
2820tccttagtaa ctgaactgtc atatttagaa tggaaggaaa atgacagttt gtgaaagttc
2880aaagcaatag tgcaattgaa gaattgacct aagtaagctg acattatggt taataatagt
2940attttagatt tgtgcagcaa aataatttca taactttttt gtttttgtta cttggataag
3000atcaatctgt tttattttag taaatctttg caggcaagtt agagaaaatg cagtgtggct
3060taacgtctct ttagtatgaa gatttggcca gaaaaagata cccagagagg aaatctaaga
3120taattataat ggtccatact ttttattgta tgaatcaaac tcaagcataa cattggccaa
3180ggaaaattaa ataccattgc taacttgtga aatggaagtc tgtgatttcg gagatgcaaa
3240gcattgtagt aaaaacacca atgtgacctc gaccatctca gcccagatat cattcatata
3300tctgttcaat gactattaag gtgcctactg tgtgctaggc actgtactgg atactgggga
3360ccttgtctgt ctggtttgct gctgtatctt ctcccagggc attatattta tgatgaaaga
3420tgctgtggat tcaattcttt cagtcaagaa taaacacaga ctttgtaggt tcctgctgaa
3480taaagcaaat cccagaaacc cagattttgg aagaatcagc aaccccagca taaaataaac
3540ccctatcaaa atgtcagagg acatggcaag gtaaacttag cattttcaac tttagaaccg
3600ggtcagcttc agggggactg ctttcaaatc agccaaagag cctgtcagat cttcttagaa
3660ggaagaggtt ggtagttccc tgctctgttt tgaacatgct ctagtttatt aacctgggga
3720cattcccatt gctgtcttaa gtaagtctca tagccagctc ctgtcacgtg actctcatat
3780ggattcattt tcgggccagc tctgaacaaa gcatcatgaa catatgtgct tttggtcgtt
3840tgcaatgtga tggtggtgga ggtaggtatt ggtttccttg gaaggcatga taagaaagat
3900tcacaatggc caacagtgtg tatgaacaaa aaactgattg gagcatcagc tagtactgaa
3960ggtccttgct ttgtgtcaga ggcaaaggaa cccaaggcgc caagtcctca gccttgagtg
4020tactgctgac aactaaactc acaggctgca aagcagacct ctgatgaaga tgcctgttat
4080ttcacatcac tgtctttttg tgtatcatag tctgcacctt acaaatatta ataaatgttc
4140caataatagg tgaaaaaaaa aa
4162152155PRTHomo sapiens 152Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala
Leu Thr Glu Lys Phe 1 5 10
15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser
20 25 30 Asn Gly
Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35
40 45 Thr Arg Asp Arg Ser Asp Gln
His Ile Gln Leu Gln Leu Ser Ala Glu 50 55
60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr
Gly Gln Tyr Leu 65 70 75
80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu
85 90 95 Glu Cys Leu
Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100
105 110 Ile Ser Lys Lys His Ala Glu Lys
Asn Trp Phe Val Gly Leu Lys Lys 115 120
125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly
Gln Lys Ala 130 135 140
Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150
155 153940DNAHomo sapiens 153ctgtcagctg aggatccagc cgaaagagga
gccaggcact caggccacct gagtctactc 60acctggacaa ctggaatctg gcaccaattc
taaaccactc agcttctccg agctcacacc 120ccggagatca cctgaggacc cgagccattg
atggactcgg acgagaccgg gttcgagcac 180tcaggactgt gggtttctgt gctggctggt
cttctgctgg gagcctgcca ggcacacccc 240atccctgact ccagtcctct cctgcaattc
gggggccaag tccggcagcg gtacctctac 300acagatgatg cccagcagac agaagcccac
ctggagatca gggaggatgg gacggtgggg 360ggcgctgctg accagagccc cgaaagtctc
ctgcagctga aagccttgaa gccgggagtt 420attcaaatct tgggagtcaa gacatccagg
ttcctgtgcc agcggccaga tggggccctg 480tatggatcgc tccactttga ccctgaggcc
tgcagcttcc gggagctgct tcttgaggac 540ggatacaatg tttaccagtc cgaagcccac
ggcctcccgc tgcacctgcc agggaacaag 600tccccacacc gggaccctgc accccgagga
ccagctcgct tcctgccact accaggcctg 660ccccccgcac tcccggagcc acccggaatc
ctggcccccc agccccccga tgtgggctcc 720tcggaccctc tgagcatggt gggaccttcc
cagggccgaa gccccagcta cgcttcctga 780agccagaggc tgtttactat gacatctcct
ctttatttat taggttattt atcttattta 840tttttttatt tttcttactt gagataataa
agagttccag aggagaaaaa aaaaaaaaaa 900aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa
aaaaaaaaaa 940154209PRTHomo sapiens 154Met Asp
Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 1 5
10 15 Val Leu Ala Gly Leu Leu Leu
Gly Ala Cys Gln Ala His Pro Ile Pro 20 25
30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
Arg Gln Arg Tyr 35 40 45
Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
50 55 60 Glu Asp Gly
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 65
70 75 80 Leu Gln Leu Lys Ala Leu Lys
Pro Gly Val Ile Gln Ile Leu Gly Val 85
90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp
Gly Ala Leu Tyr Gly 100 105
110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu
Leu 115 120 125 Glu
Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 130
135 140 His Leu Pro Gly Asn Lys
Ser Pro His Arg Asp Pro Ala Pro Arg Gly 145 150
155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro
Pro Ala Leu Pro Glu 165 170
175 Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
180 185 190 Pro Leu
Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195
200 205 Ser 155856DNAHomo sapiens
155accttgcgtc cgcagtaccg acccgcacgc tcttcagcgc atccctagtg aaggaggttc
60tcccccagcc cgtggctgtt gcacttgctg gtcctctgcc tccaagccca gcatgtgagg
120gagcagagcc tggtgacgga tcagctcagc cgccgcctca tccggaccta ccaactctac
180agccgcacca gcgggaagca cgtgcaggtc ctggccaaca agcgcatcaa cgccatggca
240gaggacggcg accccttcgc aaagctcatc gtggagacgg acacctttgg aagcagagtt
300cgagtccgag gagccgagac gggcctctac atctgcatga acaagaaggg gaagctgatc
360gccaagagca acggcaaagg caaggactgc gtcttcacgg agattgtgct ggagaacaac
420tacacagcgc tgcagaatgc caagtacgag ggctggtaca tggccttcac ccgcaagggc
480cggccccgca agggctccaa gacgcggcag caccagcgtg aggtccactt catgaagcgg
540ctgccccggg gccaccacac caccgagcag agcctgcgct tcgagttcct caactacccg
600cccttcacgc gcagcctgcg cggcagccag aggacttggg cccccgagcc ccgataggtg
660ctgcctggcc ctccccacaa tgccagaccg cagagaggct catcctgtag ggcacccaaa
720actcaagcaa gatgagctgt gcgctgctct gcaggctggg gaggtgctgg gggagccctg
780ggttccggtt gttgatattg tttgctgttg ggtttttgct gttttttttt tttttttttt
840ttttaaaaca aaagag
856156140PRTHomo sapiens 156Met Ala Glu Asp Gly Asp Pro Phe Ala Lys Leu
Ile Val Glu Thr Asp 1 5 10
15 Thr Phe Gly Ser Arg Val Arg Val Arg Gly Ala Glu Thr Gly Leu Tyr
20 25 30 Ile Cys
Met Asn Lys Lys Gly Lys Leu Ile Ala Lys Ser Asn Gly Lys 35
40 45 Gly Lys Asp Cys Val Phe Thr
Glu Ile Val Leu Glu Asn Asn Tyr Thr 50 55
60 Ala Leu Gln Asn Ala Lys Tyr Glu Gly Trp Tyr Met
Ala Phe Thr Arg 65 70 75
80 Lys Gly Arg Pro Arg Lys Gly Ser Lys Thr Arg Gln His Gln Arg Glu
85 90 95 Val His Phe
Met Lys Arg Leu Pro Arg Gly His His Thr Thr Glu Gln 100
105 110 Ser Leu Arg Phe Glu Phe Leu Asn
Tyr Pro Pro Phe Thr Arg Ser Leu 115 120
125 Arg Gly Ser Gln Arg Thr Trp Ala Pro Glu Pro Arg
130 135 140 1574545DNAHomo sapiens
157actctgcgcg ccggcggggg ctgcgcagga ggagcgctcc gcccggctac aacgctccgc
60gagccggcgc ggcaacacct gttcgcggca gcctgggcgg cacgcgagct cccggacgcg
120gctctcctcg ctcgccgctc gccacccgtt ctaagccaat ggacatctgc cgagcctctg
180gagaatcctg gatactagct ttggacgcct aaagtttctt cttctttttg ttttattatt
240attatcattt tttggagggg ggaccgggag gggagatttg tcgccgccac caacgtgaga
300tttttttttc cccttgaagg attcatgctg atgtctgcag agtcggttag agagtaaaaa
360cagcgcatgc cttcctggag tcaggatccg taaattctga cgtagcccgt gcatcttaaa
420aatccctata ataacgccta ggcatttaag ttgctatggt cattctgatc tcaaaccaaa
480tggagaaact acggattttt tttccttatt acggtcggat gggatgaaga ccttcctgcc
540tgctaagagc tggggatcta tctatagaga tacatagata tgtttatcaa tatgtcagtg
600tgtgagtata aagtggtggt ttcttagact atcagtggtt tgaccttgaa cctgtgccag
660tgaaacagca gattactttt atttatgcat ttaatggatt gaagaaaaga accttttttt
720tctctctctc tctgcaactg cagtaaggga ggggagttgg atatacctcg cctaatatct
780cctgggttga caccatcatt attgtttatt cttgtgctcc aaaagccgag tcctctgatg
840gctcccttag gtgaagttgg gaactatttc ggtgtgcagg atgcggtacc gtttgggaat
900gtgcccgtgt tgccggtgga cagcccggtt ttgttaagtg accacctggg tcagtccgaa
960gcaggggggc tccccagggg acccgcagtc acggacttgg atcatttaaa ggggattctc
1020aggcggaggc agctatactg caggactgga tttcacttag aaatcttccc caatggtact
1080atccagggaa ccaggaaaga ccacagccga tttggcattc tggaatttat cagtatagca
1140gtgggcctgg tcagcattcg aggcgtggac agtggactct acctcgggat gaatgagaag
1200ggggagctgt atggatcaga aaaactaacc caagagtgtg tattcagaga acagttcgaa
1260gaaaactggt ataatacgta ctcatcaaac ctatataagc acgtggacac tggaaggcga
1320tactatgttg cattaaataa agatgggacc ccgagagaag ggactaggac taaacggcac
1380cagaaattca cacatttttt acctagacca gtggaccccg acaaagtacc tgaactgtat
1440aaggatattc taagccaaag ttgacaaaga cagtttcttc acttgagccc ttaaaaaagt
1500aaccactata aaggtttcac gcggtgggtt cttattgatt cgctgtgtca tcacatcagc
1560tccactgttg ccaaactttg tcgcatgcat aatgtatgat ggaggcttgg atgggaatat
1620gctgattttg ttctgcactt aaaggcttct cctcctggag ggctgcctag ggccacttgc
1680ttgatttatc atgagagaag aggagagaga gagagactga gcgctaggag tgtgtgtatg
1740tgtgtgtgtg tgtgtgtgtg tgtgtgtgta tgtgtgtagc gggagatgtg ggcggagcga
1800gagcaaaagg actgcggcct gatgcatgct ggaaaaagac acgcttttca tttctgatca
1860gttgtacttc atcctatatc agcacagctg ccatacttcg acttatcagg attctggctg
1920gtggcctgcg cgagggtgca gtcttactta aaagactttc agttaattct cactggtatc
1980atcgcagtga acttaaagca aagacctctt agtaaaaaat aaaaaaaaat aaaaaataaa
2040aataaaaaaa gttaaattta tttatagaaa ttccaaaggc aacattttat ttattttata
2100tatttattta ttatatagag tttattttta atgaaacatg tacaggccag ataggcattt
2160tggaagcttt aggctctgta agcattaaat ggcaaagtcc gctatgaacc tgtggtaaat
2220tcatgcaagt agatataatg gtgcatggat ataagaaatt ctaatgaccc taatgtacta
2280aaggcgacaa tctcttttgt gcccatatta ttgtaaactt atgcacatcg ctcatgacac
2340tgagtattca ctcttcagac tgcttgtttc atagcttatc ccagaggatt aaagataaac
2400tgggtctcaa actttgattc tgtgtctgca atatttcctc tctcataagt gactccacta
2460ttgtaacttc atggttggaa aatatgaggg ttgatatatg tcttacttgt ttaaatctgt
2520cgcagaatat accaaagcta aataataact atgctttcat tttagccgat ctccagaatg
2580acagtattaa catcaaacat tgtattgatt tagaattctc aaaaaaggaa aaaaaagtac
2640atagcacaga ctattttttt taaagacgta agaatcagat taacaggatc atacttgtaa
2700actttttttg gttcacttgg ctatcaaata tgaaattata gaagtatcat aggggtcatt
2760gtaacatctt ttagagaaaa tggctatcag tgtgaactgt cataattacg tggtaatagc
2820acccttagta aaacttgcaa aatgaaacta ataaatcgtt atcaataatg acaatgaggg
2880ggaaagtatt atacttgttg actgtgtttt gttttttaaa atggtctcca caagcgctca
2940atttttttag aggggatatt actatataga atatctttta caaggctttt ataacatttt
3000atgctgaaaa gcataagaat acgtatttct ttagtagcaa taattttgga acttgccctt
3060gggcaagcga gactatttct tactatatac taaggagaaa agagccaaat tcttaaagca
3120atatttaaga aaaaaggaat ttataacaaa ttctcatcta catatgacac tttctagcca
3180gttgtgttga gaagtgcaaa gtgacggttt aaacatgtgt tgggatttat tgaactaatt
3240ttaaaattta ctattcaaac tttattttgc tctgatgcac attctctatg aaaaataaaa
3300gtgtgtcact ggtgagtgac agctgttatg agctagaagc gcatgactta ttgtgacgat
3360gtcttgcctt tctgtggtcc aagttggagt acatggcaat gccctcctgc tgatgtgcat
3420taaggaaaat ctaagtctaa tatttggaat taagatatat tttaggggga ggggacagaa
3480gcaatgtaaa atagttgatt tatgataaag ctcagaatgt cctcttcatt tattttcttg
3540ttttattttc ctttctaaac agaaactgca tttaattcca aaaagtagta ttcttattta
3600ttatttaacc ctttgctgct gctaaaatgt gcacatattc aggctttagt ttttccaaaa
3660ggcatttttt ttttggctga aaaatattaa acatttgacc acagggaaga atcaagtttc
3720taggatgtca taggtatact atgtagcact gaaaaaattg attttaggtg acagccaaaa
3780gtagtcttaa agtagcatga gaccttagat aatcgaccta aaagaaagaa aattgtgaaa
3840aagacaaaaa tcttcatgca ttcctataaa acgctacttt aaggtctact tttggagtta
3900attttgtttg gtactttttt tttttttaag acgagcaaat tgttatatgc ttttggcaat
3960tgatacaata aactgtaatg gtctgtaaat aaataaatat tgactcatgc gatttatgta
4020aatagtggaa ctgggagagt ggatggctca gggtttcggt gtgggcattg tctcttgggc
4080agtagagtga gtcatcccca gctcatgggt ttgcatccag ttcttgtctt aagagaccca
4140aagcccagtg aatggcagcc ctgagccact gtggaatggg ggttctggtt tcacaaacag
4200atgcttagat agccaaacca ctgtcttgtt ggtgccaaca cttgcactgt ggtcaaagac
4260ttaccgagca tgggctgaac aaccttccca tctgtcatgt gaatgtcccc aagcagtggt
4320gaaggacatg ctaggtcagt gttggggaac ctgccctgcc aggtcctgtt ttgtagataa
4380acaaatggct gccttctggt gtttttattc tatttcatct cattaacact acaaccttgt
4440gttatttact tgataatctg taattgtatg taaatacata caggattatg taatttgtgt
4500aaatacataa ttacagagtt ttgaaaactg aaaaaaaaaa aaaaa
4545158208PRTHomo sapiens 158Met Ala Pro Leu Gly Glu Val Gly Asn Tyr Phe
Gly Val Gln Asp Ala 1 5 10
15 Val Pro Phe Gly Asn Val Pro Val Leu Pro Val Asp Ser Pro Val Leu
20 25 30 Leu Ser
Asp His Leu Gly Gln Ser Glu Ala Gly Gly Leu Pro Arg Gly 35
40 45 Pro Ala Val Thr Asp Leu Asp
His Leu Lys Gly Ile Leu Arg Arg Arg 50 55
60 Gln Leu Tyr Cys Arg Thr Gly Phe His Leu Glu Ile
Phe Pro Asn Gly 65 70 75
80 Thr Ile Gln Gly Thr Arg Lys Asp His Ser Arg Phe Gly Ile Leu Glu
85 90 95 Phe Ile Ser
Ile Ala Val Gly Leu Val Ser Ile Arg Gly Val Asp Ser 100
105 110 Gly Leu Tyr Leu Gly Met Asn Glu
Lys Gly Glu Leu Tyr Gly Ser Glu 115 120
125 Lys Leu Thr Gln Glu Cys Val Phe Arg Glu Gln Phe Glu
Glu Asn Trp 130 135 140
Tyr Asn Thr Tyr Ser Ser Asn Leu Tyr Lys His Val Asp Thr Gly Arg 145
150 155 160 Arg Tyr Tyr Val
Ala Leu Asn Lys Asp Gly Thr Pro Arg Glu Gly Thr 165
170 175 Arg Thr Lys Arg His Gln Lys Phe Thr
His Phe Leu Pro Arg Pro Val 180 185
190 Asp Pro Asp Lys Val Pro Glu Leu Tyr Lys Asp Ile Leu Ser
Gln Ser 195 200 205
1595118DNAHomo sapiens 159ctcagtaggg ccagatcgct cttccagcgc gggttggtcc
accaggcaga gccccagcca 60gggcctgtca ggtacccagg gagaccggaa atgtagccag
gagacagcag cgctcacagt 120cacctggttt cagtgtcagc ctggttgctc ctagatgttc
ctaacttgct ccatctcaga 180ccaaagactc cacgggccat tgggctcctt cttacacagg
ctccagagga gcgtggacac 240caccggcggt ctgaagattt ggcagccagc agtctccaga
ggggggtcgg aggcgcgcaa 300gtgggtgttt tggaaatatt tgctgtgtct caggggattg
taggaatacg aggagttttc 360agcaacaaat ttttagcgat gtcaaaaaaa ggaaaactcc
atgcaagtgc caagttcaca 420gatgactgca agttcaggga gcgttttcaa gaaaatagct
ataataccta tgcctcagca 480atacatagaa ctgaaaaaac agggcgggag tggtatgtgg
ccctgaataa aagaggaaaa 540gccaaacgag ggtgcagccc ccgggttaaa ccccagcata
tctctaccca ttttctgcca 600agattcaagc agtcggagca gccagaactt tctttcacgg
ttactgttcc tgaaaagaaa 660aagccaccta gccctatcaa gccaaagatt cccctttctg
cacctcggaa aaataccaac 720tcagtgaaat acagactcaa gtttcgcttt ggataatatt
cctcttggcc ttgtgagaaa 780ccattctttc ccctcaggag tttctatagg tgtcttcaga
gttctgaaga aaaattactg 840gacacagctt cagctatact tacactgtat tgaagtcacg
tcatttgttt caatgtgact 900gaaacaaaat gttttttgat aggaaggaaa ctggaattct
ttgtactaat acagggagca 960cactccttca gttcagcaag acataaagcc ttttgcttta
tgcttgaggg atatttagaa 1020ctttgtattt tcggaaagtt aaataacagg gactacgtat
ttttctgact tttacagatt 1080aacctgaaag aacatacatg atacattttt atttttggtt
tccaaagaat attttgatgc 1140agataaaata ttttgttaac ttttgttttt ttttgtttgt
tttcttaaaa gtacctctgc 1200attgagcata ttttcttact tttattattt taattaatat
gacataagca atcattttat 1260gctgtttatg aattataaat gtgtttatag ctcatttgta
atatggaaat cttttacatt 1320tttcctattc actgcacttt tttattgttt ttatttctag
ccatacctca gataatatgt 1380ttagttttac attttaaaat gtttaaattc tctttcacag
caccaaaggc tcagcttgga 1440tttgtgtgta tgtgtatgtc aattcatgac attatgtgga
atcctaaacc tttggtggct 1500gggatatgat gggttagaag caaggagaaa atataaggac
tttttgatgg aattaaatgt 1560gggaggtaag gaaaaggatt tagaggtaaa agtacactaa
gtttgcaaca tttattgaga 1620tctaagtctg tcttgccttc atttctcttt ttatctcccc
cttgccctca ttcttgaaca 1680gctggaggaa tacattttat tctgtccatg aagcatacac
tatgaaattc aagtgcttaa 1740aaatacttct atgactctct gctatcccac tgtatagatc
cacagggagc aaacacttag 1800aaatgataga gaactgaagg agatcaatgg tttaacagtt
atccatgcca agtcccattg 1860tcagaaatat tcttattact cagtcaaaca ctctttgagc
ttcccttcct aaaggtaacc 1920aatccagtga atagatgtgc ccttttataa ggaaacttct
gatgtttatt aaaaaaactg 1980gccttttgat agaggtaact taatttggga atttgttgtg
ttgaaatggc atttaatttc 2040aacctaaata ctgactgctg gacataaatc acagaaaatt
taacttaaga aaatttacaa 2100aatttattct caggtaatca ttttaataaa gttctgcaaa
atacacgttt atcttacatt 2160cagaaatgtg gcaaaaaagg catagctaaa ggctaaacat
atggctttag tagtaacaaa 2220agggttcata gaaacttcat ggtttgcatt taaacatgtt
taaagtgtac ttataaacta 2280tttttttctt aaagcaaact atgatttatt ttggtgcaca
aatacaaagt ggaaacttac 2340caaaattgaa ctagctacca tataagcaga ttgctttaat
ttgatgggaa aatagtacac 2400acatatatat aacaaataat atattaaaaa acccatccat
caactaaaac attatatgta 2460tacatcagta tagtgtttta ttataaagcc aattatctga
ttaagcattc tttccactga 2520atgcataatg tttaaatagc ataaaatgaa atgctacaaa
aattgaacta atttatactt 2580taaagtattt ctgggttaaa tgaaacaatg aaatttttta
gtatgttcaa ctctcatcca 2640aatggcatat gaccctgttt acacagccta aagctaaaaa
tattactcta gtttattcta 2700atctattgtt aagtattgtg cactgtatac caagttctta
gggcacatga aaaattttag 2760ctgccaaaca ggaactagta aacatatgtt cctaataagt
gaagggaaag ataataatga 2820tggtcaacaa taagccacgt caatgcataa gttgtatagg
ctaaatgttg cttgtaggct 2880acattaaact caaatgtaat agtttatctt atactcctgg
tttgatttga ttagcatatt 2940aacgtgaaag taggatagct actaaatata tattatgcaa
gtcaggaatc attaatttca 3000aaatttaaag ccatgctaaa attaaaaaga aaatattaaa
ttacacaatt acacttgtct 3060ttactggcca tacaaaatga tttttttttt ttttttgaga
cagagtcttg ctctgtcacc 3120aggctggagt gcagtggcat gatctcggct cactgcaacc
tccaactccc tggtttaagg 3180gattctcctg cctcagcctc ccaagtagct gggattacag
actcatgcca ccacgccagc 3240taatttttgt atttttagta gagacggggt ttcaccatgt
tggtcaggat ggtctcaatc 3300ctggcctctt gatagtcctg acctcatgat ctgcccacct
cggcctcccc aaagtgctgg 3360gattacaggt acaatgatgt ataattaatg cttagtgaag
cataaagtta cctacatcaa 3420ttaattaaat gaacttatgt acagaaaaca tgtataaata
taagtctata ctaatgctta 3480caactttcta agagggttct tgcttatgta gctttttatt
attttaagta actagaacca 3540ccaaatatca aataaaatta tttggttatg gttatgttca
tctaaacaca acaataactt 3600ttatattaat atttaggagt ctattttgtc tataggtgac
aaacatctcc agactaacat 3660gtcagtttta tcaattatat tatgtttaat tatttaagat
ttctttatgt ggaacatcta 3720tagagataaa tagaaatttt caataagatg tagtaacact
gtgatttatc tttcaagagt 3780ctctcttcac ttccttctaa agagactaat ttgagagtac
aggtgcatat taattttctt 3840ggttctttca gctgaattat attggtccag aagttcaaaa
tcatgtgaca ataataaggg 3900atactgacag aagttatttc caagtttgtg tatatattat
aaaaattaca tatataaaac 3960taaggctttt atttctgtta tttttaagct tttatttctt
gtagctaaaa ataaaacatc 4020ataaatctgg taggtaaatt tcttattaaa tcaatcttga
aatagaaaat gtaataactt 4080tcttaccatt aacatttttt acccttccat agaagggagg
gaataaatca tgacttatcc 4140cattttcaat aacaaaacga aactatggca ctaaccaaaa
acttgcattc tggcataatt 4200tttacagttg cagagaattg tttctgggct cattaaaaaa
agtagtattg cagacattgc 4260tgcaatggga agcagacaat aacttcttaa aggaattcta
cacctccttt aagatttact 4320taattgctac atctaaattc tgataattta aaatccattt
taggtgataa aattttttaa 4380aagttttgaa ggaaacctct ggataaatgg acaaggccta
attttttttt gtagtcaatc 4440caactgtact ggccaatttt tgaaataaga ttatatgatt
aggtattagc agagacaaag 4500agttacctcc tccatcttac tctgccctat ttgaaagtct
caggggagaa aagggaacaa 4560gatgctgatc caacctgagt ggagtcaggt gaggcatctt
tacatctaag aatttttttt 4620taaattttat tattattata cttcaagttc tagggtacat
gtccacaatg cacatgtctg 4680tcacacatgc acacatgtgc catgctggtg tgctgcaccc
accaacctgt catccagcat 4740taggtatatc tcctaatgct atccctcccc tctccaccca
ccccacagca ggccccggta 4800tgtgatgttc cccttcgtgt gtccatgtgt tcttattgtt
caattcccac ctatgagtga 4860gaatatgtgg tgtttggttt ttggtccttg caatagtttg
ctgagaatga tggtttccag 4920cttcatccat gtccctacaa agaacatgaa ctcatcattt
tttatggctg catagtattc 4980catggtgtat atgtgccaca ttttcttaat ccagtctatc
attgttggac atttgggttg 5040gttccaagtc tttgctattg tgaatagtgc tgcaataaac
atatgtgtgc atgtgtcttt 5100aaaaaaaaaa aaaaaaaa
5118160125PRTHomo sapiens 160Met Ser Lys Lys Gly
Lys Leu His Ala Ser Ala Lys Phe Thr Asp Asp 1 5
10 15 Cys Lys Phe Arg Glu Arg Phe Gln Glu Asn
Ser Tyr Asn Thr Tyr Ala 20 25
30 Ser Ala Ile His Arg Thr Glu Lys Thr Gly Arg Glu Trp Tyr Val
Ala 35 40 45 Leu
Asn Lys Arg Gly Lys Ala Lys Arg Gly Cys Ser Pro Arg Val Lys 50
55 60 Pro Gln His Ile Ser Thr
His Phe Leu Pro Arg Phe Lys Gln Ser Glu 65 70
75 80 Gln Pro Glu Leu Ser Phe Thr Val Thr Val Pro
Glu Lys Lys Lys Pro 85 90
95 Pro Ser Pro Ile Lys Pro Lys Ile Pro Leu Ser Ala Pro Arg Lys Asn
100 105 110 Thr Asn
Ser Val Lys Tyr Arg Leu Lys Phe Arg Phe Gly 115
120 125 1612172DNAHomo sapiens 161gtggctctct aggaccggag
agttctttgg aaggagagcg cgagcgaggg agcgggcgag 60ctccgagggg gtgtgggtgt
agggagagag agaaagagag caggcagcgg cggcggcggc 120agcggtgggg aaaagcggat
tccgccccga accacaccga ggggagctcg tggtcgagac 180ttgccgccct aagcactctc
ccaagtccga cccgctcggc gaggacttcc gtcttctgag 240cgaaccttgt caagcaagct
gggatctatg agtggaaagg tgaccaagcc caaagaggag 300aaagatgctt ctaaggagcc
tcagcttaag ggtatagtta ccaagctata cagccgacaa 360ggctaccact tgcagctgca
ggcggatgga accattgatg gcaccaaaga tgaggacagc 420acttacactc tgtttaacct
catccctgtg ggtctgcgag tggtggctat ccaaggagtt 480caaaccaagc tgtacttggc
aatgaacagt gagggatact tgtacacctc ggaacttttc 540acacctgagt gcaaattcaa
agaatcagtg tttgaaaatt attatgtgac atattcatca 600atgatatacc gtcagcagca
gtcaggccga gggtggtatc tgggtctgaa caaagaagga 660gagatcatga aaggcaacca
tgtgaagaag aacaagcctg cagctcattt tctgcctaaa 720ccactgaaag tggccatgta
caaggagcca tcactgcacg atctcacgga gttctcccga 780tctggaagcg ggaccccaac
caagagcaga agtgtctctg gcgtgctgaa cggaggcaaa 840tccatgagcc acaatgaatc
aacgtagcca gtgagggcaa aagaagggct ctgtaacaga 900accttacctc caggtgctgt
tgaattcttc tagcagtcct tcacccaaaa gttcaaattt 960gtcagtgaca tttaccaaac
aaacaggcag agttcactat tctatctgcc attagacctt 1020cttatcatcc atactaaagc
cccattattt agattgagct tgtgcataag aatgccaagc 1080attttagtga actaaatctg
agagaaggac tgccaaattt tctcatgatc tcacctatac 1140tttggggatg ataatccaaa
agtatttcac agcactaatg ctgatcaaaa tttgctctcc 1200caccaagaaa atgtaaaaga
ccacaattgt tcttcaaaaa caaacaaaac aaaacaaaac 1260aaaattaact gcttaaatgt
tttgtcgggg caaacaaaat tatgtgaatt gtgttgtttt 1320cttggcttga tgttttctat
ctacgcttga ttcacatgta ctcttttctt tggcatagtg 1380caactttatg atttctgaaa
ttcaatggtt ctattgactt tttgcgtcac ttaatccaaa 1440tcaaccaaat tcagggttga
atctgaattg gcttctcagg ctcaaggtaa cagtgttctt 1500gtggtttgac caattgtttt
tctttctttt tttttttttt tagatttgtg gtattctggt 1560caagttattg tgctgtactt
tgtgcgtaga aattgagttg tattgtcaac cccagtcagt 1620aaagagaact tcaaaaaatt
atcctcaagt gtagatttct cttaattcca tttgtgtatc 1680atgttaaact attgttgtgg
cttcttgtgt aaagacagga actgtggaac tgtgatgttg 1740tcttttgtgt tgttaaaata
agaaatgtct tatctgtata tgtatgagtc ttcctgtcat 1800tgtatttggc acatgaatat
tgtgtacaag gaattgttaa gactggtttt ccctcaacaa 1860catatattat acttgctact
ggaaaagtgt ttaagactta gctaggtttc catttagatc 1920ttcatatctg ttgcatggaa
gaaagttggg ttcttggcat agagttgcat gatatgtaag 1980attttgtgca ttcataattg
ttaaaaatct gtgttccaaa agtggacata gcatgtacag 2040gcagttttct gtcctgtgca
caaaaagttt aaaaaagttg tttaatattt gttgttgtat 2100acccaaatac gcaccgaata
aactctttat attcattcaa agaaaaaaaa aaaaaaaaaa 2160aaaaaaaaaa aa
2172162199PRTHomo sapiens
162Met Ser Gly Lys Val Thr Lys Pro Lys Glu Glu Lys Asp Ala Ser Lys 1
5 10 15 Glu Pro Gln Leu
Lys Gly Ile Val Thr Lys Leu Tyr Ser Arg Gln Gly 20
25 30 Tyr His Leu Gln Leu Gln Ala Asp Gly
Thr Ile Asp Gly Thr Lys Asp 35 40
45 Glu Asp Ser Thr Tyr Thr Leu Phe Asn Leu Ile Pro Val Gly
Leu Arg 50 55 60
Val Val Ala Ile Gln Gly Val Gln Thr Lys Leu Tyr Leu Ala Met Asn 65
70 75 80 Ser Glu Gly Tyr Leu
Tyr Thr Ser Glu Leu Phe Thr Pro Glu Cys Lys 85
90 95 Phe Lys Glu Ser Val Phe Glu Asn Tyr Tyr
Val Thr Tyr Ser Ser Met 100 105
110 Ile Tyr Arg Gln Gln Gln Ser Gly Arg Gly Trp Tyr Leu Gly Leu
Asn 115 120 125 Lys
Glu Gly Glu Ile Met Lys Gly Asn His Val Lys Lys Asn Lys Pro 130
135 140 Ala Ala His Phe Leu Pro
Lys Pro Leu Lys Val Ala Met Tyr Lys Glu 145 150
155 160 Pro Ser Leu His Asp Leu Thr Glu Phe Ser Arg
Ser Gly Ser Gly Thr 165 170
175 Pro Thr Lys Ser Arg Ser Val Ser Gly Val Leu Asn Gly Gly Lys Ser
180 185 190 Met Ser
His Asn Glu Ser Thr 195 1631999DNAHomo sapiens
163cacggccgga gagacgcgga ggaggagaca tgagccggcg ggcgcccaga cggagcggcc
60gtgacgcttt cgcgctgcag ccgcgcgccc cgaccccgga gcgctgaccc ctggccccac
120gcagctccgc gcccgggccg gagagcgcaa ctcggcttcc agacccgccg cgcatgctgt
180ccccggactg agccgggcag ccagcctccc acggacgccc ggacggccgg ccggccagca
240gtgagcgagc ttccccgcac cggccaggcg cctcctgcac agcggctgcc gccccgcagc
300ccctgcgcca gcccggaggg cgcagcgctc gggaggagcc gcgcggggcg ctgatgccgc
360agggcgcgcc gcggagcgcc ccggagcagc agagtctgca gcagcagcag ccggcgagga
420gggagcagca gcagcggcgg cggcggcggc ggcggcggcg gaggcgcccg gtcccggccg
480cgcggagcgg acatgtgcag gctgggctag gagccgccgc ctccctcccg cccagcgatg
540tattcagcgc cctccgcctg cacttgcctg tgtttacact tcctgctgct gtgcttccag
600gtacaggtgc tggttgccga ggagaacgtg gacttccgca tccacgtgga gaaccagacg
660cgggctcggg acgatgtgag ccgtaagcag ctgcggctgt accagctcta cagccggacc
720agtgggaaac acatccaggt cctgggccgc aggatcagtg cccgcggcga ggatggggac
780aagtatgccc agctcctagt ggagacagac accttcggta gtcaagtccg gatcaagggc
840aaggagacgg aattctacct gtgcatgaac cgcaaaggca agctcgtggg gaagcccgat
900ggcaccagca aggagtgtgt gttcatcgag aaggttctgg agaacaacta cacggccctg
960atgtcggcta agtactccgg ctggtacgtg ggcttcacca agaaggggcg gccgcggaag
1020ggccccaaga cccgggagaa ccagcaggac gtgcatttca tgaagcgcta ccccaagggg
1080cagccggagc ttcagaagcc cttcaagtac acgacggtga ccaagaggtc ccgtcggatc
1140cggcccacac accctgccta ggccaccccg ccgcggcccc tcaggtcgcc ctggccacac
1200tcacactccc agaaaactgc atcagaggaa tatttttaca tgaaaaataa ggaagaagct
1260ctatttttgt acattgtgtt taaaagaaga caaaaactga accaaaactc ttggggggag
1320gggtgataag gattttattg ttgacttgaa acccccgatg acaaaagact cacgcaaagg
1380gactgtagtc aacccacagg tgcttgtctc tctctaggaa cagacaactc taaactcgtc
1440cccagaggag gacttgaatg aggaaaccaa cactttgaga aaccaaagtc ctttttccca
1500aaggttctga aaggaaaaaa aaaaaaaaca aaaaaaaaga aaaacaaaga gaaagtagta
1560ctccgcccac caacaaactc cccctaactt tcccaatcct ctgttcctgc cccaaactcc
1620aacaaaaatc gctctctggt ttgcagtcat ttatttattg tccgctgcaa gctgccccga
1680gacaccgcgc agggaaggcg tgcccctggg aattctccgc gcctcgacct cccgacgaca
1740gacgcctcgt ccaatcatgg tgaccctgcc ttgctcgcag ttctggagga tgctgctatc
1800gaccttccgt gactcacgtg acctagtaca ccaatgataa gggaatattt taaaaccagc
1860tatattatat atattatata tatataagct atttatttca cctctctgta tattgcagtt
1920tcatgaacca agtattactg cctcaacaat taaaaacaac agacaaatta tttaaaaaac
1980caaaaaaaaa aaaaaaaaa
1999164207PRTHomo sapiens 164Met Tyr Ser Ala Pro Ser Ala Cys Thr Cys Leu
Cys Leu His Phe Leu 1 5 10
15 Leu Leu Cys Phe Gln Val Gln Val Leu Val Ala Glu Glu Asn Val Asp
20 25 30 Phe Arg
Ile His Val Glu Asn Gln Thr Arg Ala Arg Asp Asp Val Ser 35
40 45 Arg Lys Gln Leu Arg Leu Tyr
Gln Leu Tyr Ser Arg Thr Ser Gly Lys 50 55
60 His Ile Gln Val Leu Gly Arg Arg Ile Ser Ala Arg
Gly Glu Asp Gly 65 70 75
80 Asp Lys Tyr Ala Gln Leu Leu Val Glu Thr Asp Thr Phe Gly Ser Gln
85 90 95 Val Arg Ile
Lys Gly Lys Glu Thr Glu Phe Tyr Leu Cys Met Asn Arg 100
105 110 Lys Gly Lys Leu Val Gly Lys Pro
Asp Gly Thr Ser Lys Glu Cys Val 115 120
125 Phe Ile Glu Lys Val Leu Glu Asn Asn Tyr Thr Ala Leu
Met Ser Ala 130 135 140
Lys Tyr Ser Gly Trp Tyr Val Gly Phe Thr Lys Lys Gly Arg Pro Arg 145
150 155 160 Lys Gly Pro Lys
Thr Arg Glu Asn Gln Gln Asp Val His Phe Met Lys 165
170 175 Arg Tyr Pro Lys Gly Gln Pro Glu Leu
Gln Lys Pro Phe Lys Tyr Thr 180 185
190 Thr Val Thr Lys Arg Ser Arg Arg Ile Arg Pro Thr His Pro
Ala 195 200 205
1651016DNAHomo sapiens 165agcgacctca gaggagtaac cgggccttaa ctttttgcgc
tcgttttgct ataatttttc 60tctatccacc tccatcccac ccccacaaca ctctttactg
ggggggtctt ttgtgttccg 120gatctccccc tccatggctc ccttagccga agtcgggggc
tttctgggcg gcctggaggg 180cttgggccag caggtgggtt cgcatttcct gttgcctcct
gccggggagc ggccgccgct 240gctgggcgag cgcaggagcg cggcggagcg gagcgcgcgc
ggcgggccgg gggctgcgca 300gctggcgcac ctgcacggca tcctgcgccg ccggcagctc
tattgccgca ccggcttcca 360cctgcagatc ctgcccgacg gcagcgtgca gggcacccgg
caggaccaca gcctcttcgg 420tatcttggaa ttcatcagtg tggcagtggg actggtcagt
attagaggtg tggacagtgg 480tctctatctt ggaatgaatg acaaaggaga actctatgga
tcagagaaac ttacttccga 540atgcatcttt agggagcagt ttgaagagaa ctggtataac
acctattcat ctaacatata 600taaacatgga gacactggcc gcaggtattt tgtggcactt
aacaaagacg gaactccaag 660agatggcgcc aggtccaaga ggcatcagaa atttacacat
ttcttaccta gaccagtgga 720tccagaaaga gttccagaat tgtacaagga cctactgatg
tacacttgaa gtgcgatagt 780gacattatgg aagagtcaaa ccacaaccat tctttcttgt
catagttccc atcataaaat 840aatgacccaa ggagacgttc aaaatattaa agtctatttt
ctactgagag actggatttg 900gaaagaatat tgagaaaaaa aaccaaaaaa aattttgact
agaaatagat catgatcact 960ctttatatgt ggattaagtt cccttagata cattggatta
gtccttacca gtagac 1016166211PRTHomo sapiens 166Met Ala Pro Leu Ala
Glu Val Gly Gly Phe Leu Gly Gly Leu Glu Gly 1 5
10 15 Leu Gly Gln Gln Val Gly Ser His Phe Leu
Leu Pro Pro Ala Gly Glu 20 25
30 Arg Pro Pro Leu Leu Gly Glu Arg Arg Ser Ala Ala Glu Arg Ser
Ala 35 40 45 Arg
Gly Gly Pro Gly Ala Ala Gln Leu Ala His Leu His Gly Ile Leu 50
55 60 Arg Arg Arg Gln Leu Tyr
Cys Arg Thr Gly Phe His Leu Gln Ile Leu 65 70
75 80 Pro Asp Gly Ser Val Gln Gly Thr Arg Gln Asp
His Ser Leu Phe Gly 85 90
95 Ile Leu Glu Phe Ile Ser Val Ala Val Gly Leu Val Ser Ile Arg Gly
100 105 110 Val Asp
Ser Gly Leu Tyr Leu Gly Met Asn Asp Lys Gly Glu Leu Tyr 115
120 125 Gly Ser Glu Lys Leu Thr Ser
Glu Cys Ile Phe Arg Glu Gln Phe Glu 130 135
140 Glu Asn Trp Tyr Asn Thr Tyr Ser Ser Asn Ile Tyr
Lys His Gly Asp 145 150 155
160 Thr Gly Arg Arg Tyr Phe Val Ala Leu Asn Lys Asp Gly Thr Pro Arg
165 170 175 Asp Gly Ala
Arg Ser Lys Arg His Gln Lys Phe Thr His Phe Leu Pro 180
185 190 Arg Pro Val Asp Pro Glu Arg Val
Pro Glu Leu Tyr Lys Asp Leu Leu 195 200
205 Met Tyr Thr 210 1672720DNAHomo sapiens
167atggccgcgg ccatcgctag cggcttgatc cgccagaagc ggcaggcgcg ggagcagcac
60tgggaccggc cgtctgccag caggaggcgg agcagcccca gcaagaaccg cgggctctgc
120aacggcaacc tggtggatat cttctccaaa gtgcgcatct tcggcctcaa gaagcgcagg
180ttgcggcgcc aagatcccca gctcaagggt atagtgacca ggttatattg caggcaaggc
240tactacttgc aaatgcaccc cgatggagct ctcgatggaa ccaaggatga cagcactaat
300tctacactct tcaacctcat accagtggga ctacgtgttg ttgccatcca gggagtgaaa
360acagggttgt atatagccat gaatggagaa ggttacctct acccatcaga actttttacc
420cctgaatgca agtttaaaga atctgttttt gaaaattatt atgtaatcta ctcatccatg
480ttgtacagac aacaggaatc tggtagagcc tggtttttgg gattaaataa ggaagggcaa
540gctatgaaag ggaacagagt aaagaaaacc aaaccagcag ctcattttct acccaagcca
600ttggaagttg ccatgtaccg agaaccatct ttgcatgatg ttggggaaac ggtcccgaag
660cctggggtga cgccaagtaa aagcacaagt gcgtctgcaa taatgaatgg aggcaaacca
720gtcaacaaga gtaagacaac atagccagat cctcacaggt gttgtgactt attcgtcctg
780agcacagttg agtgatttat cctcaccaga cattcctgct ccgtggctga agagcagcag
840gaagtaagct aatgcttatt ctttgctgtc tccgaacttc tctgttgcaa gtggataaat
900ctcaacctgt tgcacccccc acaacaagaa gacacctgga taaccagcta aactcagacc
960atggaatgcc ctaccagata tggaatgcct ttttaatatc ttttctgtga ctgtgacact
1020tcatgtgaat gacatacttc acaagtacac tcgatacctt gcctgctgac agctacccat
1080aatccttttt gagtcctgtt tcagcgaaat ctatgtgttt aagttcaatt ttgtagcaca
1140caaataatat tgagtaattt ctagttagac gctgtaaacc tgtgctatta cggatttctc
1200ttcttcccat ttttacaggg ctgctcgctc cactgtctgt gaccttttgc agggattttg
1260ttcctctaaa tcttaaatgt tgcagttggc ttaggtcgga gagcaatcag ggaatcagga
1320agccttctaa acctattatt acaaattgca tctataaaga aagattaaga aagattgttg
1380tctctggctc acactatcga ttaaacacac atatacgctc tgtccagtag cagatactgt
1440gctcccaagg tcggcattgc ctgggtggga aatggctcaa acacaatcca gggaagctct
1500ctatgatatg tgtttgacat ccccctctag tttctttgtg tgtgtgtgtt ttatacatat
1560cacaagctta ctggtaatgg taacatttgc cttgcccagc gagcaagacc cactggtttt
1620tgagaaagtg ggtccaaaga tttctgtagg ccttgtaggc ctgattaagg ttcatttttc
1680atctattaat tctcattatt tggaaaaaaa aaaaaaggaa aatcagtaat tataacctac
1740aagaattgcg ctacctaaat ccatttcaga tatactccgt cctgttttta atgaaccaaa
1800cttaacgcca tccccgtttc tggctgcgtt cccctcatac tcagcagagc atgggcaaga
1860cggctgttgt gttctttcct gcagcagcaa tgcaaacgtt agttataaat taattagact
1920ttaatatttt tggtgtttaa tgacaagttt ttaaactgga catattagga aaaatatttt
1980ttttagctca gcatgctgag tccggtactg tgtatttcac cagtacatgc ctctagctca
2040gcatctgggg ctcatgttgc ccagtggctg ggttagaggt gccttgccat gatctcagaa
2100tacagtctgt tgaattatcc tagatgaaaa taaaggcaaa ccaacacatt catccatgag
2160gattttggtc cattccattt attttctttt attttgcatt cttaatttcc tttttagttt
2220aacactgttt gtttgagctt agggaagaca actaccaaga aaggccagga acagttgact
2280acacaatgaa gattccatgc aaaatgttca atattggatc taaaggggtt caaaatgttt
2340catactaaac tgtttgggaa tttatttgtt aactctgtgt acacctaata aaattcaatg
2400ttttcttctc agaagagttc attgagacca aactgaacct catttattga aaattatatg
2460tgggatcaat gtactggcct cttgttattc tttctatgtg ggaggatgac ccagtcatca
2520ttttccccat ctgcactgta tttattggga aattattttg tcactgcttt cataaatctt
2580cttcatgaca gcccttgccc agcattaaaa aattctggcc tgcttagctg attaaaggtt
2640tagtagaaat ttaactgttt gtttatgctt atttcatttt catattggat tctacttgaa
2700taaataaaaa gttagcagaa
2720168247PRTHomo sapiens 168Met Ala Ala Ala Ile Ala Ser Gly Leu Ile Arg
Gln Lys Arg Gln Ala 1 5 10
15 Arg Glu Gln His Trp Asp Arg Pro Ser Ala Ser Arg Arg Arg Ser Ser
20 25 30 Pro Ser
Lys Asn Arg Gly Leu Cys Asn Gly Asn Leu Val Asp Ile Phe 35
40 45 Ser Lys Val Arg Ile Phe Gly
Leu Lys Lys Arg Arg Leu Arg Arg Gln 50 55
60 Asp Pro Gln Leu Lys Gly Ile Val Thr Arg Leu Tyr
Cys Arg Gln Gly 65 70 75
80 Tyr Tyr Leu Gln Met His Pro Asp Gly Ala Leu Asp Gly Thr Lys Asp
85 90 95 Asp Ser Thr
Asn Ser Thr Leu Phe Asn Leu Ile Pro Val Gly Leu Arg 100
105 110 Val Val Ala Ile Gln Gly Val Lys
Thr Gly Leu Tyr Ile Ala Met Asn 115 120
125 Gly Glu Gly Tyr Leu Tyr Pro Ser Glu Leu Phe Thr Pro
Glu Cys Lys 130 135 140
Phe Lys Glu Ser Val Phe Glu Asn Tyr Tyr Val Ile Tyr Ser Ser Met 145
150 155 160 Leu Tyr Arg Gln
Gln Glu Ser Gly Arg Ala Trp Phe Leu Gly Leu Asn 165
170 175 Lys Glu Gly Gln Ala Met Lys Gly Asn
Arg Val Lys Lys Thr Lys Pro 180 185
190 Ala Ala His Phe Leu Pro Lys Pro Leu Glu Val Ala Met Tyr
Arg Glu 195 200 205
Pro Ser Leu His Asp Val Gly Glu Thr Val Pro Lys Pro Gly Val Thr 210
215 220 Pro Ser Lys Ser Thr
Ser Ala Ser Ala Ile Met Asn Gly Gly Lys Pro 225 230
235 240 Val Asn Lys Ser Lys Thr Thr
245 1692175DNAHomo sapiens 169agtacagtat aaaacttcac
agtgccaata ccatgaagag gagctcagac agctcttacc 60acatgataca agagccggct
ggtggaagag tggggaccag aaagagaatt tgctgaagag 120gagaaggaaa aaaaaaacac
caaaaaaaaa aataaaaaaa tccacacaca caaaaaaacc 180tgcgcgtgag gggggaggaa
aagcagggcc ttttaaaaag gcaatcacaa caacttttgc 240tgccaggatg cccttgcttt
ggctgagagg atttctgttg gcaagttgct ggattatagt 300gaggagttcc cccaccccag
gatccgaggg gcacagcgcg gcccccgact gtccgtcctg 360tgcgctggcc gccctcccaa
aggatgtacc caactctcag ccagagatgg tggaggccgt 420caagaagcac attttaaaca
tgctgcactt gaagaagaga cccgatgtca cccagccggt 480acccaaggcg gcgcttctga
acgcgatcag aaagcttcat gtgggcaaag tcggggagaa 540cgggtatgtg gagatagagg
atgacattgg aaggagggca gaaatgaatg aacttatgga 600gcagacctcg gagatcatca
cgtttgccga gtcaggaaca gccaggaaga cgctgcactt 660cgagatttcc aaggaaggca
gtgacctgtc agtggtggag cgtgcagaag tctggctctt 720cctaaaagtc cccaaggcca
acaggaccag gaccaaagtc accatccgcc tcttccagca 780gcagaagcac ccgcagggca
gcttggacac aggggaagag gccgaggaag tgggcttaaa 840gggggagagg agtgaactgt
tgctctctga aaaagtagta gacgctcgga agagcacctg 900gcatgtcttc cctgtctcca
gcagcatcca gcggttgctg gaccagggca agagctccct 960ggacgttcgg attgcctgtg
agcagtgcca ggagagtggc gccagcttgg ttctcctggg 1020caagaagaag aagaaagaag
aggaggggga agggaaaaag aagggcggag gtgaaggtgg 1080ggcaggagca gatgaggaaa
aggagcagtc gcacagacct ttcctcatgc tgcaggcccg 1140gcagtctgaa gaccaccctc
atcgccggcg tcggcggggc ttggagtgtg atggcaaggt 1200caacatctgc tgtaagaaac
agttctttgt cagtttcaag gacatcggct ggaatgactg 1260gatcattgct ccctctggct
atcatgccaa ctactgcgag ggtgagtgcc cgagccatat 1320agcaggcacg tccgggtcct
cactgtcctt ccactcaaca gtcatcaacc actaccgcat 1380gcggggccat agcccctttg
ccaacctcaa atcgtgctgt gtgcccacca agctgagacc 1440catgtccatg ttgtactatg
atgatggtca aaacatcatc aaaaaggaca ttcagaacat 1500gatcgtggag gagtgtgggt
gctcatagag ttgcccagcc cagggggaaa gggagcaaga 1560gttgtccaga gaagacagtg
gcaaaatgaa gaaattttta aggtttctga gttaaccaga 1620aaaatagaaa ttaaaaacaa
aacaaaaaaa aaaacaaaaa aaaacaaaag taaattaaaa 1680acaaaacctg atgaaacaga
tgaaggaaga tgtggaaaaa atccttagcc agggctcaga 1740gatgaagcag tgaaagagac
aggaattggg agggaaaggg agaatggtgt accctttatt 1800tcttctgaaa tcacactgat
gacatcagtt gtttaaacgg ggtattgtcc tttcccccct 1860tgaggttccc ttgtgagcct
tgaatcaacc aatctagtct gcagtagtgt ggactagaac 1920aacccaaata gcatctagaa
agccatgagt ttgaaagggc ccatcacagg cactttccta 1980cccaattacc caggtcataa
ggtatgtctg tgtgacactt atctctgtgt atatcagcat 2040acacacacac acacacacac
acacacacac acacaggcat ttccacacat tacatatata 2100cacatactgg taaaagaaca
atcgtgtgca ggtggtcaca cttccttttt ctgtaccact 2160tttgcaacaa aacaa
2175170426PRTHomo sapiens
170Met Pro Leu Leu Trp Leu Arg Gly Phe Leu Leu Ala Ser Cys Trp Ile 1
5 10 15 Ile Val Arg Ser
Ser Pro Thr Pro Gly Ser Glu Gly His Ser Ala Ala 20
25 30 Pro Asp Cys Pro Ser Cys Ala Leu Ala
Ala Leu Pro Lys Asp Val Pro 35 40
45 Asn Ser Gln Pro Glu Met Val Glu Ala Val Lys Lys His Ile
Leu Asn 50 55 60
Met Leu His Leu Lys Lys Arg Pro Asp Val Thr Gln Pro Val Pro Lys 65
70 75 80 Ala Ala Leu Leu Asn
Ala Ile Arg Lys Leu His Val Gly Lys Val Gly 85
90 95 Glu Asn Gly Tyr Val Glu Ile Glu Asp Asp
Ile Gly Arg Arg Ala Glu 100 105
110 Met Asn Glu Leu Met Glu Gln Thr Ser Glu Ile Ile Thr Phe Ala
Glu 115 120 125 Ser
Gly Thr Ala Arg Lys Thr Leu His Phe Glu Ile Ser Lys Glu Gly 130
135 140 Ser Asp Leu Ser Val Val
Glu Arg Ala Glu Val Trp Leu Phe Leu Lys 145 150
155 160 Val Pro Lys Ala Asn Arg Thr Arg Thr Lys Val
Thr Ile Arg Leu Phe 165 170
175 Gln Gln Gln Lys His Pro Gln Gly Ser Leu Asp Thr Gly Glu Glu Ala
180 185 190 Glu Glu
Val Gly Leu Lys Gly Glu Arg Ser Glu Leu Leu Leu Ser Glu 195
200 205 Lys Val Val Asp Ala Arg Lys
Ser Thr Trp His Val Phe Pro Val Ser 210 215
220 Ser Ser Ile Gln Arg Leu Leu Asp Gln Gly Lys Ser
Ser Leu Asp Val 225 230 235
240 Arg Ile Ala Cys Glu Gln Cys Gln Glu Ser Gly Ala Ser Leu Val Leu
245 250 255 Leu Gly Lys
Lys Lys Lys Lys Glu Glu Glu Gly Glu Gly Lys Lys Lys 260
265 270 Gly Gly Gly Glu Gly Gly Ala Gly
Ala Asp Glu Glu Lys Glu Gln Ser 275 280
285 His Arg Pro Phe Leu Met Leu Gln Ala Arg Gln Ser Glu
Asp His Pro 290 295 300
His Arg Arg Arg Arg Arg Gly Leu Glu Cys Asp Gly Lys Val Asn Ile 305
310 315 320 Cys Cys Lys Lys
Gln Phe Phe Val Ser Phe Lys Asp Ile Gly Trp Asn 325
330 335 Asp Trp Ile Ile Ala Pro Ser Gly Tyr
His Ala Asn Tyr Cys Glu Gly 340 345
350 Glu Cys Pro Ser His Ile Ala Gly Thr Ser Gly Ser Ser Leu
Ser Phe 355 360 365
His Ser Thr Val Ile Asn His Tyr Arg Met Arg Gly His Ser Pro Phe 370
375 380 Ala Asn Leu Lys Ser
Cys Cys Val Pro Thr Lys Leu Arg Pro Met Ser 385 390
395 400 Met Leu Tyr Tyr Asp Asp Gly Gln Asn Ile
Ile Lys Lys Asp Ile Gln 405 410
415 Asn Met Ile Val Glu Glu Cys Gly Cys Ser 420
425 1712583DNAHomo sapiens 171agccggtccc cgccgccgcc
gcccttcgcg ccctgggcca tctccctccc acctccctcc 60gcggagcagc cagacagcga
gggccccggc cgggggcagg ggggacgccc cgtccggggc 120acccccccgg ctctgagccg
cccgcggggc cggcctcggc ccggagcgga ggaaggagtc 180gccgaggagc agcctgaggc
cccagagtct gagacgagcc gccgccgccc ccgccactgc 240ggggaggagg gggaggagga
gcgggaggag ggacgagctg gtcgggagaa gaggaaaaaa 300acttttgaga cttttccgtt
gccgctggga gccggaggcg cggggacctc ttggcgcgac 360gctgccccgc gaggaggcag
gacttgggga ccccagaccg cctccctttg ccgccgggga 420cgcttgctcc ctccctgccc
cctacacggc gtccctcagg cgcccccatt ccggaccagc 480cctcgggagt cgccgacccg
gcctcccgca aagacttttc cccagacctc gggcgcaccc 540cctgcacgcc gccttcatcc
ccggcctgtc tcctgagccc ccgcgcatcc tagacccttt 600ctcctccagg agacggatct
ctctccgacc tgccacagat cccctattca agaccaccca 660ccttctggta ccagatcgcg
cccatctagg ttatttccgt gggatactga gacacccccg 720gtccaagcct cccctccacc
actgcgccct tctccctgag gacctcagct ttccctcgag 780gccctcctac cttttgccgg
gagaccccca gcccctgcag gggcggggcc tccccaccac 840accagccctg ttcgcgctct
cggcagtgcc ggggggcgcc gcctccccca tgccgccctc 900cgggctgcgg ctgctgccgc
tgctgctacc gctgctgtgg ctactggtgc tgacgcctgg 960ccggccggcc gcgggactat
ccacctgcaa gactatcgac atggagctgg tgaagcggaa 1020gcgcatcgag gccatccgcg
gccagatcct gtccaagctg cggctcgcca gccccccgag 1080ccagggggag gtgccgcccg
gcccgctgcc cgaggccgtg ctcgccctgt acaacagcac 1140ccgcgaccgg gtggccgggg
agagtgcaga accggagccc gagcctgagg ccgactacta 1200cgccaaggag gtcacccgcg
tgctaatggt ggaaacccac aacgaaatct atgacaagtt 1260caagcagagt acacacagca
tatatatgtt cttcaacaca tcagagctcc gagaagcggt 1320acctgaaccc gtgttgctct
cccgggcaga gctgcgtctg ctgaggctca agttaaaagt 1380ggagcagcac gtggagctgt
accagaaata cagcaacaat tcctggcgat acctcagcaa 1440ccggctgctg gcacccagcg
actcgccaga gtggttatct tttgatgtca ccggagttgt 1500gcggcagtgg ttgagccgtg
gaggggaaat tgagggcttt cgccttagcg cccactgctc 1560ctgtgacagc agggataaca
cactgcaagt ggacatcaac gggttcacta ccggccgccg 1620aggtgacctg gccaccattc
atggcatgaa ccggcctttc ctgcttctca tggccacccc 1680gctggagagg gcccagcatc
tgcaaagctc ccggcaccgc cgagccctgg acaccaacta 1740ttgcttcagc tccacggaga
agaactgctg cgtgcggcag ctgtacattg acttccgcaa 1800ggacctcggc tggaagtgga
tccacgagcc caagggctac catgccaact tctgcctcgg 1860gccctgcccc tacatttgga
gcctggacac gcagtacagc aaggtcctgg ccctgtacaa 1920ccagcataac ccgggcgcct
cggcggcgcc gtgctgcgtg ccgcaggcgc tggagccgct 1980gcccatcgtg tactacgtgg
gccgcaagcc caaggtggag cagctgtcca acatgatcgt 2040gcgctcctgc aagtgcagct
gaggtcccgc cccgccccgc cccgccccgg caggcccggc 2100cccaccccgc cccgcccccg
ctgccttgcc catgggggct gtatttaagg acacccgtgc 2160cccaagccca cctggggccc
cattaaagat ggagagagga ctgcggatct ctgtgtcatt 2220gggcgcctgc ctggggtctc
catccctgac gttcccccac tcccactccc tctctctccc 2280tctctgcctc ctcctgcctg
tctgcactat tcctttgccc ggcatcaagg cacaggggac 2340cagtggggaa cactactgta
gttagatcta tttattgagc accttgggca ctgttgaagt 2400gccttacatt aatgaactca
ttcagtcacc atagcaacac tctgagatgc agggactctg 2460ataacaccca ttttaaaggt
gaggaaacaa gcccagagag gttaagggag gagttcctgc 2520ccaccaggaa cctgctttag
tgggggatag tgaagaagac aataaaagat agtagttcag 2580gcc
2583172390PRTHomo sapiens
172Met Pro Pro Ser Gly Leu Arg Leu Leu Pro Leu Leu Leu Pro Leu Leu 1
5 10 15 Trp Leu Leu Val
Leu Thr Pro Gly Arg Pro Ala Ala Gly Leu Ser Thr 20
25 30 Cys Lys Thr Ile Asp Met Glu Leu Val
Lys Arg Lys Arg Ile Glu Ala 35 40
45 Ile Arg Gly Gln Ile Leu Ser Lys Leu Arg Leu Ala Ser Pro
Pro Ser 50 55 60
Gln Gly Glu Val Pro Pro Gly Pro Leu Pro Glu Ala Val Leu Ala Leu 65
70 75 80 Tyr Asn Ser Thr Arg
Asp Arg Val Ala Gly Glu Ser Ala Glu Pro Glu 85
90 95 Pro Glu Pro Glu Ala Asp Tyr Tyr Ala Lys
Glu Val Thr Arg Val Leu 100 105
110 Met Val Glu Thr His Asn Glu Ile Tyr Asp Lys Phe Lys Gln Ser
Thr 115 120 125 His
Ser Ile Tyr Met Phe Phe Asn Thr Ser Glu Leu Arg Glu Ala Val 130
135 140 Pro Glu Pro Val Leu Leu
Ser Arg Ala Glu Leu Arg Leu Leu Arg Leu 145 150
155 160 Lys Leu Lys Val Glu Gln His Val Glu Leu Tyr
Gln Lys Tyr Ser Asn 165 170
175 Asn Ser Trp Arg Tyr Leu Ser Asn Arg Leu Leu Ala Pro Ser Asp Ser
180 185 190 Pro Glu
Trp Leu Ser Phe Asp Val Thr Gly Val Val Arg Gln Trp Leu 195
200 205 Ser Arg Gly Gly Glu Ile Glu
Gly Phe Arg Leu Ser Ala His Cys Ser 210 215
220 Cys Asp Ser Arg Asp Asn Thr Leu Gln Val Asp Ile
Asn Gly Phe Thr 225 230 235
240 Thr Gly Arg Arg Gly Asp Leu Ala Thr Ile His Gly Met Asn Arg Pro
245 250 255 Phe Leu Leu
Leu Met Ala Thr Pro Leu Glu Arg Ala Gln His Leu Gln 260
265 270 Ser Ser Arg His Arg Arg Ala Leu
Asp Thr Asn Tyr Cys Phe Ser Ser 275 280
285 Thr Glu Lys Asn Cys Cys Val Arg Gln Leu Tyr Ile Asp
Phe Arg Lys 290 295 300
Asp Leu Gly Trp Lys Trp Ile His Glu Pro Lys Gly Tyr His Ala Asn 305
310 315 320 Phe Cys Leu Gly
Pro Cys Pro Tyr Ile Trp Ser Leu Asp Thr Gln Tyr 325
330 335 Ser Lys Val Leu Ala Leu Tyr Asn Gln
His Asn Pro Gly Ala Ser Ala 340 345
350 Ala Pro Cys Cys Val Pro Gln Ala Leu Glu Pro Leu Pro Ile
Val Tyr 355 360 365
Tyr Val Gly Arg Lys Pro Lys Val Glu Gln Leu Ser Asn Met Ile Val 370
375 380 Arg Ser Cys Lys Cys
Ser 385 390 1735966DNAHomo sapiens 173gtgatgttat
ctgctggcag cagaaggttc gctccgagcg gagctccaga agctcctgac 60aagagaaaga
cagattgaga tagagataga aagagaaaga gagaaagaga cagcagagcg 120agagcgcaag
tgaaagaggc aggggagggg gatggagaat attagcctga cggtctaggg 180agtcatccag
gaacaaactg aggggctgcc cggctgcaga caggaggaga cagagaggat 240ctattttagg
gtggcaagtg cctacctacc ctaagcgagc aattccacgt tggggagaag 300ccagcagagg
ttgggaaagg gtgggagtcc aagggagccc ctgcgcaacc ccctcaggaa 360taaaactccc
cagccagggt gtcgcaaggg ctgccgttgt gatccgcagg gggtgaacgc 420aaccgcgacg
gctgatcgtc tgtggctggg ttggcgtttg gagcaagaga aggaggagca 480ggagaaggag
ggagctggag gctggaagcg tttgcaagcg gcggcggcag caacgtggag 540taaccaagcg
ggtcagcgcg cgcccgccag ggtgtaggcc acggagcgca gctcccagag 600caggatccgc
gccgcctcag cagcctctgc ggcccctgcg gcacccgacc gagtaccgag 660cgccctgcga
agcgcaccct cctccccgcg gtgcgctggg ctcgccccca gcgcgcgcac 720acgcacacac
acacacacac acacacacgc acgcacacac gtgtgcgctt ctctgctccg 780gagctgctgc
tgctcctgct ctcagcgccg cagtggaagg caggaccgaa ccgctccttc 840tttaaatata
taaatttcag cccaggtcag cctcggcggc ccccctcacc gcgctcccgg 900cgcccctccc
gtcagttcgc cagctgccag ccccgggacc ttttcatctc ttcccttttg 960gccggaggag
ccgagttcag atccgccact ccgcacccga gactgacaca ctgaactcca 1020cttcctcctc
ttaaatttat ttctacttaa tagccactcg tctctttttt tccccatctc 1080attgctccaa
gaattttttt cttcttactc gccaaagtca gggttccctc tgcccgtccc 1140gtattaatat
ttccactttt ggaactactg gccttttctt tttaaaggaa ttcaagcagg 1200atacgttttt
ctgttgggca ttgactagat tgtttgcaaa agtttcgcat caaaaacaac 1260aacaacaaaa
aaccaaacaa ctctccttga tctatacttt gagaattgtt gatttctttt 1320ttttattctg
acttttaaaa acaacttttt tttccacttt tttaaaaaat gcactactgt 1380gtgctgagcg
cttttctgat cctgcatctg gtcacggtcg cgctcagcct gtctacctgc 1440agcacactcg
atatggacca gttcatgcgc aagaggatcg aggcgatccg cgggcagatc 1500ctgagcaagc
tgaagctcac cagtccccca gaagactatc ctgagcccga ggaagtcccc 1560ccggaggtga
tttccatcta caacagcacc agggacttgc tccaggagaa ggcgagccgg 1620agggcggccg
cctgcgagcg cgagaggagc gacgaagagt actacgccaa ggaggtttac 1680aaaatagaca
tgccgccctt cttcccctcc gaaactgtct gcccagttgt tacaacaccc 1740tctggctcag
tgggcagctt gtgctccaga cagtcccagg tgctctgtgg gtaccttgat 1800gccatcccgc
ccactttcta cagaccctac ttcagaattg ttcgatttga cgtctcagca 1860atggagaaga
atgcttccaa tttggtgaaa gcagagttca gagtctttcg tttgcagaac 1920ccaaaagcca
gagtgcctga acaacggatt gagctatatc agattctcaa gtccaaagat 1980ttaacatctc
caacccagcg ctacatcgac agcaaagttg tgaaaacaag agcagaaggc 2040gaatggctct
ccttcgatgt aactgatgct gttcatgaat ggcttcacca taaagacagg 2100aacctgggat
ttaaaataag cttacactgt ccctgctgca cttttgtacc atctaataat 2160tacatcatcc
caaataaaag tgaagaacta gaagcaagat ttgcaggtat tgatggcacc 2220tccacatata
ccagtggtga tcagaaaact ataaagtcca ctaggaaaaa aaacagtggg 2280aagaccccac
atctcctgct aatgttattg ccctcctaca gacttgagtc acaacagacc 2340aaccggcgga
agaagcgtgc tttggatgcg gcctattgct ttagaaatgt gcaggataat 2400tgctgcctac
gtccacttta cattgatttc aagagggatc tagggtggaa atggatacac 2460gaacccaaag
ggtacaatgc caacttctgt gctggagcat gcccgtattt atggagttca 2520gacactcagc
acagcagggt cctgagctta tataatacca taaatccaga agcatctgct 2580tctccttgct
gcgtgtccca agatttagaa cctctaacca ttctctacta cattggcaaa 2640acacccaaga
ttgaacagct ttctaatatg attgtaaagt cttgcaaatg cagctaaaat 2700tcttggaaaa
gtggcaagac caaaatgaca atgatgatga taatgatgat gacgacgaca 2760acgatgatgc
ttgtaacaag aaaacataag agagccttgg ttcatcagtg ttaaaaaatt 2820tttgaaaagg
cggtactagt tcagacactt tggaagtttg tgttctgttt gttaaaactg 2880gcatctgaca
caaaaaaagt tgaaggcctt attctacatt tcacctactt tgtaagtgag 2940agagacaaga
agcaaatttt ttttaaagaa aaaaataaac actggaagaa tttattagtg 3000ttaattatgt
gaacaacgac aacaacaaca acaacaacaa acaggaaaat cccattaagt 3060ggagttgctg
tacgtaccgt tcctatcccg cgcctcactt gatttttctg tattgctatg 3120caataggcac
ccttcccatt cttactctta gagttaacag tgagttattt attgtgtgtt 3180actatataat
gaacgtttca ttgcccttgg aaaataaaac aggtgtataa agtggagacc 3240aaatactttg
ccagaaactc atggatggct taaggaactt gaactcaaac gagccagaaa 3300aaaagaggtc
atattaatgg gatgaaaacc caagtgagtt attatatgac cgagaaagtc 3360tgcattaaga
taaagaccct gaaaacacat gttatgtatc agctgcctaa ggaagcttct 3420tgtaaggtcc
aaaaactaaa aagactgtta ataaaagaaa ctttcagtca gaataagtct 3480gtaagttttt
ttttttcttt ttaattgtaa atggttcttt gtcagtttag taaaccagtg 3540aaatgttgaa
atgttttgac atgtactggt caaacttcag accttaaaat attgctgtat 3600agctatgcta
taggtttttt cctttgtttt ggtatatgta accataccta tattattaaa 3660atagatggat
atagaagcca gcataattga aaacacatct gcagatctct tttgcaaact 3720attaaatcaa
aacattaact actttatgtg taatgtgtaa atttttacca tattttttat 3780attctgtaat
aatgtcaact atgatttaga ttgacttaaa tttgggctct ttttaatgat 3840cactcacaaa
tgtatgtttc ttttagctgg ccagtacttt tgagtaaagc ccctatagtt 3900tgacttgcac
tacaaatgca tttttttttt aataacattt gccctacttg tgctttgtgt 3960ttctttcatt
attatgacat aagctacctg ggtccacttg tcttttcttt tttttgtttc 4020acagaaaaga
tgggttcgag ttcagtggtc ttcatcttcc aagcatcatt actaaccaag 4080tcagacgtta
acaaattttt atgttaggaa aaggaggaat gttatagata catagaaaat 4140tgaagtaaaa
tgttttcatt ttagcaagga tttagggttc taactaaaac tcagaatctt 4200tattgagtta
agaaaagttt ctctaccttg gtttaatcaa tatttttgta aaatcctatt 4260gttattacaa
agaggacact tcataggaaa catctttttc tttagtcagg tttttaatat 4320tcagggggaa
attgaaagat atatatttta gtcgattttt caaaagggga aaaaagtcca 4380ggtcagcata
agtcattttg tgtatttcac tgaagttata aggtttttat aaatgttctt 4440tgaaggggaa
aaggcacaag ccaatttttc ctatgatcaa aaaattcttt ctttcctctg 4500agtgagagtt
atctatatct gaggctaaag tttaccttgc tttaataaat aatttgccac 4560atcattgcag
aagaggtatc ctcatgctgg ggttaataga atatgtcagt ttatcacttg 4620tcgcttattt
agctttaaaa taaaaattaa taggcaaagc aatggaatat ttgcagtttc 4680acctaaagag
cagcataagg aggcgggaat ccaaagtgaa gttgtttgat atggtctact 4740tcttttttgg
aatttcctga ccattaatta aagaattgga tttgcaagtt tgaaaactgg 4800aaaagcaaga
gatgggatgc cataatagta aacagccctt gtgttggatg taacccaatc 4860ccagatttga
gtgtgtgttg attatttttt tgtcttccac ttttctatta tgtgtaaatc 4920acttttattt
ctgcagacat tttcctctca gataggatga cattttgttt tgtattattt 4980tgtctttcct
catgaatgca ctgataatat tttaaatgct ctattttaag atctcttgaa 5040tctgtttttt
ttttttttaa tttgggggtt ctgtaaggtc tttatttccc ataagtaaat 5100attgccatgg
gaggggggtg gaggtggcaa ggaaggggtg aagtgctagt atgcaagtgg 5160gcagcaatta
tttttgtgtt aatcagcagt acaatttgat cgttggcatg gttaaaaaat 5220ggaatataag
attagctgtt ttgtattttg atgaccaatt acgctgtatt ttaacacgat 5280gtatgtctgt
ttttgtggtg ctctagtggt aaataaatta tttcgatgat atgtggatgt 5340ctttttccta
tcagtaccat catcgagtct agaaaacacc tgtgatgcaa taagactatc 5400tcaagctgga
aaagtcatac cacctttccg attgccctct gtgctttctc ccttaaggac 5460agtcacttca
gaagtcatgc tttaaagcac aagagtcagg ccatatccat caaggataga 5520agaaatccct
gtgccgtctt tttattccct tatttattgc tatttggtaa ttgtttgaga 5580tttagtttcc
atccagcttg actgccgacc agaaaaaatg cagagagatg tttgcaccat 5640gctttggctt
tctggttcta tgttctgcca acgccagggc caaaagaact ggtctagaca 5700gtatcccctg
tagccccata acttggatag ttgctgagcc agccagatat aacaagagcc 5760acgtgctttc
tggggttggt tgtttgggat cagctacttg cctgtcagtt tcactggtac 5820cactgcacca
caaacaaaaa aacccaccct atttcctcca atttttttgg ctgctaccta 5880caagaccaga
ctcctcaaac gagttgccaa tctcttaata aataggatta ataaaaaaag 5940taattgtgac
tcaaaaaaaa aaaaaa
5966174442PRTHomo sapiens 174Met His Tyr Cys Val Leu Ser Ala Phe Leu Ile
Leu His Leu Val Thr 1 5 10
15 Val Ala Leu Ser Leu Ser Thr Cys Ser Thr Leu Asp Met Asp Gln Phe
20 25 30 Met Arg
Lys Arg Ile Glu Ala Ile Arg Gly Gln Ile Leu Ser Lys Leu 35
40 45 Lys Leu Thr Ser Pro Pro Glu
Asp Tyr Pro Glu Pro Glu Glu Val Pro 50 55
60 Pro Glu Val Ile Ser Ile Tyr Asn Ser Thr Arg Asp
Leu Leu Gln Glu 65 70 75
80 Lys Ala Ser Arg Arg Ala Ala Ala Cys Glu Arg Glu Arg Ser Asp Glu
85 90 95 Glu Tyr Tyr
Ala Lys Glu Val Tyr Lys Ile Asp Met Pro Pro Phe Phe 100
105 110 Pro Ser Glu Thr Val Cys Pro Val
Val Thr Thr Pro Ser Gly Ser Val 115 120
125 Gly Ser Leu Cys Ser Arg Gln Ser Gln Val Leu Cys Gly
Tyr Leu Asp 130 135 140
Ala Ile Pro Pro Thr Phe Tyr Arg Pro Tyr Phe Arg Ile Val Arg Phe 145
150 155 160 Asp Val Ser Ala
Met Glu Lys Asn Ala Ser Asn Leu Val Lys Ala Glu 165
170 175 Phe Arg Val Phe Arg Leu Gln Asn Pro
Lys Ala Arg Val Pro Glu Gln 180 185
190 Arg Ile Glu Leu Tyr Gln Ile Leu Lys Ser Lys Asp Leu Thr
Ser Pro 195 200 205
Thr Gln Arg Tyr Ile Asp Ser Lys Val Val Lys Thr Arg Ala Glu Gly 210
215 220 Glu Trp Leu Ser Phe
Asp Val Thr Asp Ala Val His Glu Trp Leu His 225 230
235 240 His Lys Asp Arg Asn Leu Gly Phe Lys Ile
Ser Leu His Cys Pro Cys 245 250
255 Cys Thr Phe Val Pro Ser Asn Asn Tyr Ile Ile Pro Asn Lys Ser
Glu 260 265 270 Glu
Leu Glu Ala Arg Phe Ala Gly Ile Asp Gly Thr Ser Thr Tyr Thr 275
280 285 Ser Gly Asp Gln Lys Thr
Ile Lys Ser Thr Arg Lys Lys Asn Ser Gly 290 295
300 Lys Thr Pro His Leu Leu Leu Met Leu Leu Pro
Ser Tyr Arg Leu Glu 305 310 315
320 Ser Gln Gln Thr Asn Arg Arg Lys Lys Arg Ala Leu Asp Ala Ala Tyr
325 330 335 Cys Phe
Arg Asn Val Gln Asp Asn Cys Cys Leu Arg Pro Leu Tyr Ile 340
345 350 Asp Phe Lys Arg Asp Leu Gly
Trp Lys Trp Ile His Glu Pro Lys Gly 355 360
365 Tyr Asn Ala Asn Phe Cys Ala Gly Ala Cys Pro Tyr
Leu Trp Ser Ser 370 375 380
Asp Thr Gln His Ser Arg Val Leu Ser Leu Tyr Asn Thr Ile Asn Pro 385
390 395 400 Glu Ala Ser
Ala Ser Pro Cys Cys Val Ser Gln Asp Leu Glu Pro Leu 405
410 415 Thr Ile Leu Tyr Tyr Ile Gly Lys
Thr Pro Lys Ile Glu Gln Leu Ser 420 425
430 Asn Met Ile Val Lys Ser Cys Lys Cys Ser 435
440 1753183DNAHomo sapiens 175gacagaagca
atggccgagg cagaagacaa gccgaggtgc tggtgaccct gggcgtctga 60gtggatgatt
ggggctgctg cgctcagagg cctgcctccc tgccttccaa tgcatataac 120cccacacccc
agccaatgaa gacgagaggc agcgtgaaca aagtcattta gaaagccccc 180gaggaagtgt
aaacaaaaga gaaagcatga atggagtgcc tgagagacaa gtgtgtcctg 240tactgccccc
acctttagct gggccagcaa ctgcccggcc ctgcttctcc ccacctactc 300actggtgatc
tttttttttt tacttttttt tcccttttct tttccattct cttttcttat 360tttctttcaa
ggcaaggcaa ggattttgat tttgggaccc agccatggtc cttctgcttc 420ttctttaaaa
tacccacttt ctccccatcg ccaagcggcg tttggcaata tcagatatcc 480actctattta
tttttaccta aggaaaaact ccagctccct tcccactccc agctgccttg 540ccacccctcc
cagccctctg cttgccctcc acctggcctg ctgggagtca gagcccagca 600aaacctgttt
agacacatgg acaagaatcc cagcgctaca aggcacacag tccgcttctt 660cgtcctcagg
gttgccagcg cttcctggaa gtcctgaagc tctcgcagtg cagtgagttc 720atgcaccttc
ttgccaagcc tcagtctttg ggatctgggg aggccgcctg gttttcctcc 780ctccttctgc
acgtctgctg gggtctcttc ctctccaggc cttgccgtcc ccctggcctc 840tcttcccagc
tcacacatga agatgcactt gcaaagggct ctggtggtcc tggccctgct 900gaactttgcc
acggtcagcc tctctctgtc cacttgcacc accttggact tcggccacat 960caagaagaag
agggtggaag ccattagggg acagatcttg agcaagctca ggctcaccag 1020cccccctgag
ccaacggtga tgacccacgt cccctatcag gtcctggccc tttacaacag 1080cacccgggag
ctgctggagg agatgcatgg ggagagggag gaaggctgca cccaggaaaa 1140caccgagtcg
gaatactatg ccaaagaaat ccataaattc gacatgatcc aggggctggc 1200ggagcacaac
gaactggctg tctgccctaa aggaattacc tccaaggttt tccgcttcaa 1260tgtgtcctca
gtggagaaaa atagaaccaa cctattccga gcagaattcc gggtcttgcg 1320ggtgcccaac
cccagctcta agcggaatga gcagaggatc gagctcttcc agatccttcg 1380gccagatgag
cacattgcca aacagcgcta tatcggtggc aagaatctgc ccacacgggg 1440cactgccgag
tggctgtcct ttgatgtcac tgacactgtg cgtgagtggc tgttgagaag 1500agagtccaac
ttaggtctag aaatcagcat tcactgtcca tgtcacacct ttcagcccaa 1560tggagatatc
ctggaaaaca ttcacgaggt gatggaaatc aaattcaaag gcgtggacaa 1620tgaggatgac
catggccgtg gagatctggg gcgcctcaag aagcagaagg atcaccacaa 1680ccctcatcta
atcctcatga tgattccccc acaccggctc gacaacccgg gccagggggg 1740tcagaggaag
aagcgggctt tggacaccaa ttactgcttc cgcaacttgg aggagaactg 1800ctgtgtgcgc
cccctctaca ttgacttccg acaggatctg ggctggaagt gggtccatga 1860acctaagggc
tactatgcca acttctgctc aggcccttgc ccatacctcc gcagtgcaga 1920cacaacccac
agcacggtgc tgggactgta caacactctg aaccctgaag catctgcctc 1980gccttgctgc
gtgccccagg acctggagcc cctgaccatc ctgtactatg ttgggaggac 2040ccccaaagtg
gagcagctct ccaacatggt ggtgaagtct tgtaaatgta gctgagaccc 2100cacgtgcgac
agagagaggg gagagagaac caccactgcc tgactgcccg ctcctcggga 2160aacacacaag
caacaaacct cactgagagg cctggagccc acaaccttcg gctccgggca 2220aatggctgag
atggaggttt ccttttggaa catttctttc ttgctggctc tgagaatcac 2280ggtggtaaag
aaagtgtggg tttggttaga ggaaggctga actcttcaga acacacagac 2340tttctgtgac
gcagacagag gggatgggga tagaggaaag ggatggtaag ttgagatgtt 2400gtgtggcaat
gggatttggg ctaccctaaa gggagaagga agggcagaga atggctgggt 2460cagggccaga
ctggaagaca cttcagatct gaggttggat ttgctcattg ctgtaccaca 2520tctgctctag
ggaatctgga ttatgttata caaggcaagc attttttttt tttttttaaa 2580gacaggttac
gaagacaaag tcccagaatt gtatctcata ctgtctggga ttaagggcaa 2640atctattact
tttgcaaact gtcctctaca tcaattaaca tcgtgggtca ctacagggag 2700aaaatccagg
tcatgcagtt cctggcccat caactgtatt gggccttttg gatatgctga 2760acgcagaaga
aagggtggaa atcaaccctc tcctgtctgc cctctgggtc cctcctctca 2820cctctccctc
gatcatattt ccccttggac acttggttag acgccttcca ggtcaggatg 2880cacatttctg
gattgtggtt ccatgcagcc ttggggcatt atgggttctt cccccacttc 2940ccctccaaga
ccctgtgttc atttggtgtt cctggaagca ggtgctacaa catgtgaggc 3000attcggggaa
gctgcacatg tgccacacag tgacttggcc ccagacgcat agactgaggt 3060ataaagacaa
gtatgaatat tactctcaaa atctttgtat aaataaatat ttttggggca 3120tcctggatga
tttcatcttc tggaatattg tttctagaac agtaaaagcc ttattctaag 3180gtg
3183176412PRTHomo
sapiens 176Met Lys Met His Leu Gln Arg Ala Leu Val Val Leu Ala Leu Leu
Asn 1 5 10 15 Phe
Ala Thr Val Ser Leu Ser Leu Ser Thr Cys Thr Thr Leu Asp Phe
20 25 30 Gly His Ile Lys Lys
Lys Arg Val Glu Ala Ile Arg Gly Gln Ile Leu 35
40 45 Ser Lys Leu Arg Leu Thr Ser Pro Pro
Glu Pro Thr Val Met Thr His 50 55
60 Val Pro Tyr Gln Val Leu Ala Leu Tyr Asn Ser Thr Arg
Glu Leu Leu 65 70 75
80 Glu Glu Met His Gly Glu Arg Glu Glu Gly Cys Thr Gln Glu Asn Thr
85 90 95 Glu Ser Glu Tyr
Tyr Ala Lys Glu Ile His Lys Phe Asp Met Ile Gln 100
105 110 Gly Leu Ala Glu His Asn Glu Leu Ala
Val Cys Pro Lys Gly Ile Thr 115 120
125 Ser Lys Val Phe Arg Phe Asn Val Ser Ser Val Glu Lys Asn
Arg Thr 130 135 140
Asn Leu Phe Arg Ala Glu Phe Arg Val Leu Arg Val Pro Asn Pro Ser 145
150 155 160 Ser Lys Arg Asn Glu
Gln Arg Ile Glu Leu Phe Gln Ile Leu Arg Pro 165
170 175 Asp Glu His Ile Ala Lys Gln Arg Tyr Ile
Gly Gly Lys Asn Leu Pro 180 185
190 Thr Arg Gly Thr Ala Glu Trp Leu Ser Phe Asp Val Thr Asp Thr
Val 195 200 205 Arg
Glu Trp Leu Leu Arg Arg Glu Ser Asn Leu Gly Leu Glu Ile Ser 210
215 220 Ile His Cys Pro Cys His
Thr Phe Gln Pro Asn Gly Asp Ile Leu Glu 225 230
235 240 Asn Ile His Glu Val Met Glu Ile Lys Phe Lys
Gly Val Asp Asn Glu 245 250
255 Asp Asp His Gly Arg Gly Asp Leu Gly Arg Leu Lys Lys Gln Lys Asp
260 265 270 His His
Asn Pro His Leu Ile Leu Met Met Ile Pro Pro His Arg Leu 275
280 285 Asp Asn Pro Gly Gln Gly Gly
Gln Arg Lys Lys Arg Ala Leu Asp Thr 290 295
300 Asn Tyr Cys Phe Arg Asn Leu Glu Glu Asn Cys Cys
Val Arg Pro Leu 305 310 315
320 Tyr Ile Asp Phe Arg Gln Asp Leu Gly Trp Lys Trp Val His Glu Pro
325 330 335 Lys Gly Tyr
Tyr Ala Asn Phe Cys Ser Gly Pro Cys Pro Tyr Leu Arg 340
345 350 Ser Ala Asp Thr Thr His Ser Thr
Val Leu Gly Leu Tyr Asn Thr Leu 355 360
365 Asn Pro Glu Ala Ser Ala Ser Pro Cys Cys Val Pro Gln
Asp Leu Glu 370 375 380
Pro Leu Thr Ile Leu Tyr Tyr Val Gly Arg Thr Pro Lys Val Glu Gln 385
390 395 400 Leu Ser Asn Met
Val Val Lys Ser Cys Lys Cys Ser 405 410
1772085DNAHomo sapiens 177gtcctttcta gacagccccc tcctccaggc
tcagggacct gtctggctgt gagctcccag 60gaggtcccag gggtgtgacc tccctccctc
cctccctccc tcttcccttc accccaggcc 120agcccagggc cagctataaa gctggcccag
cctggctctc agcacaccca gctgcctgag 180accctccttc aacctcccta gaggacagcc
ccactctgcc tcctgctccc ccagggcagc 240accatgtggc ccctgtggct ctgctgggca
ctctgggtgc tgcccctggc tggccccggg 300gcggccctga ccgaggagca gctcctgggc
agcctgctgc ggcagctgca gctcagcgag 360gtgcccgtac tggacagggc cgacatggag
aagctggtca tccccgccca cgtgagggcc 420cagtatgtag tcctgctgcg gcgcagccac
ggggaccgct cccgcggaaa gaggttcagc 480cagagcttcc gagaggtggc cggcaggttc
ctggcgtcgg aggccgcgct gcacaggcac 540gggcggctgt ccccgcgcag cgcccaggcc
cgggtgaccg tcgagtggct gcgcgtccgc 600gacgacggct ccaaccgcac ctccctcatc
gactccaggc tggtgtccgt ccacgagagc 660ggctggaagg ccttcgacgt gaccgaggcc
gtgaacttct ggcagcagct gagccggccc 720cggcagccgc tgctgctaca ggtgtcggtg
cagagggagc atctgggccc gctggcgtcc 780ggcgcccaca agctggtccg ctttgcctcg
cagggggcgc cagccgggct tggggagccc 840cagctggagc tgcacaccct ggacctcagg
gactatggag ctcagggcga ctgtgaccct 900gaagcaccaa tgaccgaggg cacccgctgc
tgccgccagg agatgtacat tgacctgcag 960gggatgaagt gggccaagaa ctgggtgctg
gagcccccgg gcttcctggc ttacgagtgt 1020gtgggcacct gccagcagcc cccggaggcc
ctggccttca attggccatt tctggggccg 1080cgacagtgta tcgcctcgga gactgcctcg
ctgcccatga tcgtcagcat caaggaggga 1140ggcaggacca ggccccaggt ggtcagcctg
cccaacatga gggtgcagaa gtgcagctgt 1200gcctcggatg gggcgctcgt gccaaggagg
ctccagccat aggcgcctgg tgtatccatt 1260gagccctcta actgaacgtg tgcatagagg
tggtcttaat gtaggtctta actttatact 1320tagcaagtta ctccatccca atttagtgct
cctgtgtgac cttcgccctg tgtccttcca 1380tttcctgtct ttcccgtcca tcacccatcc
taagcactta cgtgagtaaa taatgcagct 1440cagatgctga gctctagtag gaaatgctgg
catgctgatt acaagataca gctgagcaat 1500gcacacattt tcagctggga gtttctgttc
tctggcaaat tcttcactga gtctggaaca 1560ataataccct atgattagaa ctggggaaac
agaactgaat tgctgtgtta tatgaggaat 1620taaaaccttc aaatctctat ttcccccaaa
tactgaccca ttctggactt ttgtaaacat 1680acctaggccc ctgttcccct gagagggtgc
taagaggaag gatgaagggc ttcaggctgg 1740gggcagtgga cagggaattg ggatacctgg
attctggttc tgacagggcc acaagctagg 1800atctctaaca aacgcagaag gctttggctc
gtcatttcct cttaaaaagg aggagctggg 1860cttcagctct aagaacttca ttgccctggg
gatcagacag cccctaccta cccctgccca 1920ctcctctgga gactgagcct tgcccgtgca
tatttaggtc atttcccaca ctgtcttaga 1980gaacttgtca ccagaaacca catgtatttg
catgtttttt gttaatttag ctaaagcaat 2040tgaatgtaga tactcagaag aaataaaaaa
tgatgtttca ctctg 2085178332PRTHomo sapiens 178Met Trp
Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1 5
10 15 Gly Pro Gly Ala Ala Leu Thr
Glu Glu Gln Leu Leu Gly Ser Leu Leu 20 25
30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp
Arg Ala Asp Met 35 40 45
Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu
50 55 60 Leu Arg Arg
Ser His Gly Asp Arg Ser Arg Gly Lys Arg Phe Ser Gln 65
70 75 80 Ser Phe Arg Glu Val Ala Gly
Arg Phe Leu Ala Ser Glu Ala Ala Leu 85
90 95 His Arg His Gly Arg Leu Ser Pro Arg Ser Ala
Gln Ala Arg Val Thr 100 105
110 Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser
Leu 115 120 125 Ile
Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe 130
135 140 Asp Val Thr Glu Ala Val
Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg 145 150
155 160 Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg
Glu His Leu Gly Pro 165 170
175 Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala
180 185 190 Pro Ala
Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu 195
200 205 Arg Asp Tyr Gly Ala Gln Gly
Asp Cys Asp Pro Glu Ala Pro Met Thr 210 215
220 Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile
Asp Leu Gln Gly 225 230 235
240 Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala
245 250 255 Tyr Glu Cys
Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe 260
265 270 Asn Trp Pro Phe Leu Gly Pro Arg
Gln Cys Ile Ala Ser Glu Thr Ala 275 280
285 Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg
Thr Arg Pro 290 295 300
Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala 305
310 315 320 Ser Asp Gly Ala
Leu Val Pro Arg Arg Leu Gln Pro 325 330
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