Patent application title: REAGENTS AND METHODS FOR MODULATING CONE PHOTORECEPTOR ACTIVITY
Inventors:
Jay Neitz (Seattle, WA, US)
Jay Neitz (Seattle, WA, US)
Maureen Neitz (Seattle, WA, US)
Maureen Neitz (Seattle, WA, US)
James A. Kuchenbecker (Seattle, WA, US)
Assignees:
Medical College of Wisconsin Research Foundation Inc.
University of Washington
IPC8 Class: AA61K4800FI
USPC Class:
514 44 R
Class name:
Publication date: 2012-07-05
Patent application number: 20120172419
Abstract:
The present invention provides reagents and methods for modulating cone
photoreceptor activity, and devices for assessment of cone photoreceptor
activity.Claims:
1. A method for cone cell gene therapy in a primate, comprising
administering to the eye of a primate in need of cone cell gene therapy a
recombinant gene delivery vector comprising (a) a promoter region,
wherein the promoter region is specific for retinal cone cells; and (b) a
gene encoding a therapeutic, wherein the gene is operatively linked to
the promoter region; wherein in vivo expression of the therapeutic in
cone cells of the primate serves to treat the primate in need of cone
cell gene therapy.
2. The method of claim 1, wherein the gene therapy serves to treat a cone cell disorder.
3. The method of claim 2, wherein the cone cell disorder is selected from the group consisting of color blindness, blue cone monochomacy, achromatopsia, incomplete achromatopsia, rod-cone degeneration, retinitis pigmentosa (RP), macular degeneration, cone dystrophy, blindness, Stargardt's Disease, and Leber's congenital amaurosis.
4. The method of 1 wherein the primate is of the Parvorder Catarrhini.
5. The method of claim 1 wherein the promoter comprises a sequence selected from the group consisting of the L opsin promoter (SEQ ID NO: 1), the M opsin promoter (SEQ ID NO: 2), and the S opsin promoter (SEQ ID NO: 3),
6. The method of claim 1, wherein the gene delivery vector further comprises an enhancer element upstream of the promoter, wherein the gene is operatively linked to the enhancer element.
7. The method of claim 6, the enhancer element is specific for primate retinal cone cells.
8. The method of claim 7, wherein the enhancer element comprises the nucleic acid sequence of SEQ ID NO: 51.
9. The method of claim 1, wherein the gene delivery vector further comprises an intron comprising a splice donor/acceptor region, wherein the intron is located downstream of the promoter region and is located upstream of the gene.
10. The method of claim 1, wherein the gene encodes a therapeutic protein comprising a polypeptide selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, and a polymorph of SEQ ID NO: 11 selected from the group consisting of: (i) Thr65Ile (ii) Ile111Val (iii) Ser116Tyr (iv) Leu153Met (v) Ile171Val (vi) Ala174Val (vii) Ile178Val (viii) Ser180Ala (ix) Ile230Thr (x) Ala233Ser (xi) Val236Met (xii) Ile274Val (xiii) Phe275Leu (xiv) Tyr277Phe (xv) Val279Phe (xvi) Thr285Ala (xvii) Pro298Ala; and (xviii) Tyr309Phe.
11. The method of claim 1, wherein the gene delivery vector comprises a recombinant adeno-associated virus (AAV) gene delivery vector.
12. The method of claim 11, wherein the AAV gene vector comprises rAAV2/5 vector.
13. The method of claim 1, wherein the method restores visual capacity in the primate.
14. The method of claim 1, wherein the primate suffers from color blindness, and the primate is able to visualize new colors as a result of the therapy.
15. The method of claim 14, wherein the promoter comprises a sequence selected from the group consisting of L opsin promoter (SEQ ID NO: 1), M opsin promoter (SEQ ID NO: 2), and S opsin promoter (SEQ ID NO: 3); and the gene encodes one or more polypeptides comprising a sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11; and a polymorph of SEQ ID NO: 11 selected from the group consisting of (i) Thr65Ile (ii) Ile111Val (iii) Ser116Tyr (iv) Leu153Met (v) Ile171Val (vi) Ala174Val (vii) Ile178Val (viii) Ser180Ala (ix) Ile230Thr (x) Ala233Ser (xi) Va1236Met (xii) Ile274Val (xiii) Phe275Leu (xiv) Tyr277Phe (xv) Va1279Phe (xvi) Thr285Ala (xvii) Pro298Ala; and (xviii) Tyr309Phe.
16. The method of claim 1, wherein the primate has a vision disorder in which its photoreceptors are healthy.
17. The method of claim 1, wherein the primate is an adult primate.
18. An isolated nucleic acid expression vector comprising: (a) a promoter region, wherein the promoter region is specific for primate retinal cone cells; and (b) a gene encoding a therapeutic, wherein the gene is operatively linked to the promoter region.
19. The isolated nucleic acid expression vector of claim 18, wherein the promoter comprises a nucleic acid selected from the group consisting of L opsin promoter (SEQ ID NO: 1), M opsin promoter (SEQ ID NO: 2), and S opsin promoter (SEQ ID NO: 3).
20. The isolated nucleic acid expression vector of claim 18, wherein the isolated nucleic acid expression vector further comprises an enhancer element upstream of the promoter, wherein the gene is operatively linked to the enhancer element.
21. The isolated nucleic acid expression vector of claim 20, wherein the enhancer element comprises a nucleic acid sequence according to SEQ ID NO: 51.
22. The isolated nucleic acid expression vector of claim 18, further comprising an intron comprising a splice donor/acceptor region, wherein the intron is located downstream of the promoter region and is located upstream of the gene.
23. The isolated nucleic acid expression vector of claim 18, wherein the gene encodes a therapeutic protein selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, and a polymorph of SEQ ID NO: 11 selected from the group consisting of: (i) Thr65Ile (ii) Ile111Val (iii) Ser116Tyr (iv) Leu153Met (v) Ile171Val (vi) Ala174Val (vii) Ile178Val (viii) Ser180Ala (ix) Ile230Thr (x) Ala233Ser (xi) Val236Met (xii) Ile274Val (xiii) Phe275Leu (xiv) Tyr277Phe (xv) Val1279Phe (xvi) Thr285Ala (xvii) Pro298Ala; and (xviii) Tyr309Phe.
24. The isolated nucleic acid expression vector of claim 18, wherein the vector comprises an AAV vector.
25. A formulation comprising packaged viral particles comprising the nucleic acid expression vectors of claim 18.
26. A recombinant host cells transfected or transduced with the nucleic acid expression vector of claim 18.
27. A wide field, color multi-focal electroretinogram (mf-ERG) comprising: (a) an electroretinogram (ERG) comprising (i) a recording electrode that is (A) designed for placement on at least one of a cornea and a sclera of at least one eye of a subject and (B) arranged to output at least one signal generated by the at least one eye; and (ii) a computing system communicatively coupled to the recording electrode, the computing system comprising (A) at least one processor and (B) data storage containing instructions executable by the at least one processor to carry out a set of functions, the set of functions including processing and saving the at least one signal generated by the at least one eye; (b) a retinal stimulator comprising matched light sources selected from the group consisting of red, green, blue, and ultraviolet light sources, wherein the matched light sources are connected to the ERG and in operation can be independently frequency modulated at rates between about 1 Hz and about 60 Hz, inclusive, wherein the stimulator in operation is capable of stimulating a retinal field of a subject throughout an operating radius of at least about 70 degrees; (c) one or more constant current integrated circuit chips arranged to drive the stimulator; and (d) a pulse-frequency modulator connected to the retinal stimulator, wherein in operation the pulse-frequency modulator is capable of controlling individual stimulator segments while keeping relative spectral content of the light constant.
28. The mf-ERG of claim 27, wherein the matched light sources are paired red and green light sources.
29. The mf-ERG of claim 27, wherein the matched light sources are triplets of red, green, and blue light sources.
30. The mf-ERG of claim 27, wherein the matched light sources are quartets of red, green, blue, and ultraviolet light sources.
31. The mf-ERG of claim 30, wherein the matched light sources comprise matched light emitting diodes (LEDs).
32. The mf-ERG of claim 27, wherein the retinal stimulator comprises a concave surface comprising a series of trapezoidal-shaped circuit boards placed edge-to-edge, wherein the concave surface positions the matched light sources so in operation they are held equidistantly from and pointing toward a single focal point where a subject's pupil can be positioned.
33. The mf-ERG of claim 32, wherein the concave surface comprises a geodesic dome.
34. The mf-ERG of claim 27, wherein the set of functions further comprises coding and decoding topographical regions on the recording electrode using a cyclic summation technique.
35. The mf-ERG of claim 27, wherein the ERG further comprises an amplifier; and wherein the computing system is communicatively coupled to the amplifier.
36. A method for determining a location of functioning opsin expression in a subject, comprising use of the mf-ERG of claim 27, wherein the recording electrode is placed on at least one of a cornea and a sclera of at least one eye of a subject; stimulation of the subject's retinal field with the retinal stimulator; and determining responses of different areas of the subject's retina to different stimulation frequencies to generate a map of retinal responses, wherein the map provides a location of functioning opsin expression in a subject.
37. (canceled)
Description:
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application Ser. No. 61/242587 filed Sep. 15, 2009, incorporated by reference herein in its entirety.
BACKGROUND
[0003] Classic visual deprivation experiments have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that treatment of congenital vision disorders would be ineffective unless administered to the very young.
SUMMARY OF THE INVENTION
[0004] In a first aspect, the present invention provides methods for cone cell gene therapy in a primate, comprising administering to the eye of a primate in need of cone cell gene therapy a recombinant gene delivery vector comprising:
[0005] (a) a promoter region, wherein the promoter region is specific for retinal cone cells; and
[0006] (b) a gene encoding a therapeutic, wherein the gene is operatively linked to the promoter region;
[0007] wherein in vivo expression of the therapeutic in cone cells of the primate serves to treat the primate in need of cone cell gene therapy.
[0008] The method of this aspect of the invention can be used, for example, to treat a cone cell disorder, including but not limited to color blindness, blue cone monochomacy, achromatopsia, incomplete achromatopsia, rod-cone degeneration, retinitis pigmentosa (RP), macular degeneration, cone dystrophy, blindness, Stargardt's Disease, and Leber's congenital amaurosis. In one embodiment, the methods restore visual capacity in the primate; in another embodiment, the primate is able to visualize new colors as a result of the therapy. In another embodiment, the primate has a vision disorder in which its photoreceptors are healthy. In a further embodiment, the primate is an adult primate.
[0009] In another aspect, the present invention provides isolated nucleic acid expression vector comprising:
[0010] (a) a promoter region, wherein the promoter region is specific for primate retinal cone cells; and
[0011] (b) a gene encoding a therapeutic, wherein the gene is operatively linked to the promoter region. In various embodiments, the vectors further comprise an enhancer element upstream of the promoter, wherein the gene is operatively linked to the enhancer element, and/or an intron comprising a splice donor/acceptor region, wherein the intron is located downstream of the promoter region and is located upstream of the gene. The vectors can be used, for example, in the methods of the invention.
[0012] In another aspect, the present invention provides color multi-focal electroretinogram (mf-ERG) comprising:
[0013] (a) an electroretinogram (ERG) comprising [0014] (i) a recording electrode that is (A) designed for placement on at least one of a cornea and a sclera of at least one eye of a subject and (B) arranged to output at least one signal generated by the at least one eye; and [0015] (ii) a computing system communicatively coupled to the recording electrode, the computing system comprising (A) at least one processor and [0016] (B) data storage containing instructions executable by the at least one processor to carry out a set of functions, the set of functions including processing and saving the at least one signal generated by the at least one eye;
[0017] (b) a retinal stimulator comprising matched light sources selected from the group consisting of red, green, blue, and ultraviolet light sources, wherein the matched light sources are connected to the ERG and in operation can be independently frequency modulated at rates between about 1 Hz and about 60 Hz, inclusive, wherein the stimulator in operation is capable of stimulating a retinal field of a subject throughout an operating radius of at least about 70 degrees;
[0018] (c) one or more constant current integrated circuit chips arranged to drive the stimulator; and
[0019] (d) a pulse-frequency modulator connected to the retinal stimulator, wherein in operation the pulse-frequency modulator is capable of controlling individual stimulator segments while keeping relative spectral content of the light constant. In various preferred embodiments, the matched light sources are paired red and green light sources;
[0020] triplets of red, green, and blue light sources; or quartets of red, green, blue, and ultraviolet light sources. In another preferred embodiment the retinal stimulator comprises a concave surface comprising a series of trapezoidal-shaped circuit boards placed edge-to-edge, wherein the concave surface positions the matched light sources so in operation they are held equidistantly from and pointing toward a single focal point where a subject's pupil can be positioned.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1. rAAV2/5 vector produced functional L-opsin in primate retina. a) Molecular map; TR=terminal repeats; LCR=locus control region; PP=proximal promoter; SD/SA=splice donor/acceptor; RHLOPS=recombinant human L opsin cDNA; PA1=polyadenylation signal. b) Red light Multi-focal electroretinogram (Mf-ERG) stimulus. c) mf-ERG 40 weeks after two injections (yellow circles) of a mixture of L-opsin- and green fluorescent protein (GFP)-coding viruses. Grey lines show borders of highest response; for comparison, inset=mfERG 16 weeks post-injection; there was no reliable signal from L-opsin, unchanged from baseline. High responses in far peripheral retina were measured reliably and may have originated from offshoot of one of the injections. d) Fluorescence photographs from a similar retinal area as c; grey lines from c were copied in d. e) Confocal microscopy revealed a mosaic pattern of GFP expression in 5-12% of cones. Because GFP-coding virus was diluted to 1/3 compared to L-opsin virus, an estimated 15-36% of cones in behaviourally tested animals express L-opsin. f) Mf-ERG from a behaviourally tested animal 70 weeks after 3 injections of L-opsin virus.
[0022] FIG. 2. Pre-therapy colour vision and possible treatment outcomes. a) Colour vision stimuli examples. b) Pre-therapy results, monkey 1. Hues tested are represented as dominant wavelengths (DWs) rather than u', v' coordinates. If a hue could not be reliably distinguished at even the highest saturation, the extrapolated threshold approached infinity. c) Pre-therapy results, monkey 2. d)-e), Possible experimental outcomes: Monkeys could have a relative increase in long-wavelength sensitivity, but remain dichromatic (dashed lines, d); theoretical colour spectrum appearances for a dichromat and a possible "spectral shift" are shown. Alternatively, dichromatic monkeys could become trichromatic. Results from a trichromatic female control monkey are plotted (dashed line, e; error bars=SEM and n varied from 7-11).
[0023] FIG. 3. Gene therapy produced trichromatic colour vision. a) Time course of thresholds for the blue-green confusion colour, DW =490 nm (circles), and a yellowish colour, DW=554 nm (squares). A logarithmic scale was used to fit high thresholds for DW=490 nm; significant improvement occurred after 20 weeks. Enclosed data points=untreated dichromatic monkey thresholds, DW=490 nm (triangle) and DW=554 nm (diamond). b)-c) Comparison of pre-therapy (open circles, solid line) and post-therapy thresholds (solid dots, dashed line). Enclosed data points are DW=490 nm thresholds when tested against a red-violet background (DW=-499 nm); pink triangles=trichromatic female control thresholds. Error bars=SEM; n varied from 7-11.
[0024] FIG. 4. a) The geodesic dome was created by placing trapezoidal-shaped circuit boards edge-to-edge. This structure holds the light emitting diodes (LEDs) so they converge on a single focal point. b) The circuit board takes the incoming control signals from the Retis-can mf-ERG and reroutes and modifies them to work with the new dome. The most frequent integrated circuit on the board are the constant current devices. c) The spectral composition of the red LED. d) The spectral composition of the green LED. e) The spectral sensitivity curves for the human M- (solid line) and L- (dashed line) cone photoreceptors. f) The activation of M-opsin (solid line) and the L-opsin (dashed line) in response to both the red and green LEDs.
[0025] FIG. 5. Circles and dashed line represent the red LED out-puts in microwatts as a function of intensity; triangles and solid line represent the green LED outputs. Each data point represents an average of 3 measurements. Error bars are three standard deviations (99.7% confidence interval). To measure linearity, r2 values were computed for both the red and green LEDs.
[0026] FIG. 6. The signal to noise ratio (SNR) for as a function of degrees of eccentricity for a typical (averaged) subject and for the highest subject recorded.
[0027] FIG. 7. a) Gerbil mf-ERG data in response to the L-cone isolating red stimulus. Locations of the retina that show a large amount of activity in response to stimulation by the red LEDs are indicated in red, while those areas that show the lowest amount of activation are indicated in blue (see scale). Gray lines show borders of the region where the mfERG response was highest. b) GFP fluorescence fundus image from the gerbil, scaled to the appropriate size, overlaid on the red-light mf-ERG data. The gray lines from (a) were copied into (b) to illustrate that areas of increased mf-ERG response corresponded to the same locations where robust GFP fluorescence was present. c) Red-light mf-ERG data from the squirrel monkey, which received two injections of the virus mixture, one superiorly and one inferiorly. d) A montage of GFP fluorescence images from the squirrel monkey, scaled to the appropriate size, overlaid on the mfERG data.
[0028] FIG. 8. The circles represent ERG response from LEDs that were moved on a linear path while the subject fixated forward. By 30 degrees, the signal is already less than half. In contrast, the triangles represent ERG response from LEDs that were fixed on a boom and rotated so that the LEDs always pointed at the pupil. Under this experimental protocol, -3 dB occurs first at 60 degrees.
DETAILED DESCRIPTION OF THE INVENTION
[0029] In a first aspect, the present invention provides methods for cone cell gene therapy in a primate, comprising administering to the eye of a primate in need of cone cell gene therapy a recombinant gene delivery vector comprising:
[0030] (a) a promoter region, wherein the promoter region is specific for retinal cone cells; and
[0031] (b) a gene encoding a therapeutic, wherein the gene is operatively linked to the promoter region;
[0032] wherein in vivo expression of the therapeutic in cone cells of the primate serves to treat the primate in need of cone cell gene therapy.
[0033] Cone cells are photoreceptor cells in the retina of the eye that function best in relatively bright light. The cone cells gradually become sparser towards the periphery of the retina. The methods of the present invention can be used for treatment of any condition that can be addressed, at least in part, by gene therapy of retinal cone photoreceptor cells. The inventors have demonstrated effective treatment of congenital vision disorders in adult primates, a result that is completely unexpected in the art.
[0034] In one preferred embodiment, the gene therapy serves to treat a cone cell disorder. As used herein, a "cone cell disorder" is any disorder impacting retinal cone cells, including but not limited to color blindness, blue cone monochomacy, achromatopsia, incomplete achromatopsia, rod-cone degeneration, retinitis pigmentosa (RP), macular degeneration, cone dystrophy, blindness, Stargardt's Disease, and Leber's congenital amaurosis.
[0035] The gene encoding a therapeutic to be expressed in the cone cells can comprise or consist of any gene or cDNA that encodes a polypeptide or RNA-based therapeutic (siRNA, antisense, ribozyme, shRNA, etc.) that can be used as a therapeutic for treating a cone cell disorder. In a preferred embodiment, the primate is of the Parvorder Catarrhini. As is known in the art, Catarrhini is one of the two subdivisions of the higher primates (the other being the New World monkeys), and includes Old World monkeys and the apes, which in turn are further divided into the lesser apes or gibbons and the great apes, consisting of the orangutans, gorillas, chimpanzees, bonobos, and humans. In a further preferred embodiment, the primate is a human.
[0036] A "promoter" is a DNA sequence that directs the binding of RNA polymerase and thereby promotes RNA synthesis, i.e., a minimal sequence sufficient to direct transcription. Any suitable promoter region can be used in the gene therapy vectors, so long as it specifically promotes expression of the gene in retinal cone cells. In a preferred embodiment, the promoter specifically promotes expression of the gene in primate retinal cone cells; more preferably in Catarrhini retinal cone cells; even more preferably in human retinal cone cells. As used herein, "specifically" means that the promoter predominately promotes expression of the gene in retinal cone cells compared to other cell types, such that at least 80%, and preferably 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97%, 98%, 99%, 99.5%, or more of expression of the gene after delivery of the vector to the eye will be in cone cells. Exemplary suitable promoter regions include the promoter region for any cone-specific gene, such as the L opsin promoter (SEQ ID NO:1), the M opsin promoter (SEQ ID NO:2), and the S opsin promoter (SEQ ID NO:3), or portions thereof suitable to promote expression in a cone-specific manner. Any suitable method for identifying promoter sequences capable of driving expression in primate cone cells can be used to identify such promoters, as will be understood by those of skill in the art based on the teachings herein.
[0037] In a preferred embodiment, the gene delivery vector further comprises an enhancer element upstream of the promoter, wherein the gene is operatively linked to the enhancer element. Enhancers are cis-acting elements that stimulate transcription of adjacent genes. Any suitable enhancer element can be used in the gene therapy vectors, so long as it enhances expression of the gene when used in combination with the promoter. In a preferred embodiment, the enhancer element is specific for retinal cone cells; more preferably, it is specific for primate retinal cone cells; more preferably in Catarrhini retinal cone cells; even more preferably in human retinal cone cells. As used herein, "specifically" means that the enhancer predominately enhances expression of the gene in retinal cone cells compared to other cell types, such that at least 80%, and preferably 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97%, 98%, 99%, 99.5%, or more of expression of the gene after delivery of the vector to the eye will be in cone cells. Exemplary suitable enhancer regions comprise or consist of the enhancer region for any cone-specific gene, such as the L/M minimal opsin enhancer (SEQ ID NO: 51),
[0038] L/M enhancer elements of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more nucleotides that comprise one or more copies of the L/M minimal opsin enhancer, and the full L/M opsin enhancer (SEQ ID NO:4), or other portions thereof suitable to promote expression in a cone-specific manner. Any suitable method for identifying enhancer sequences capable of driving expression in primate cone cells can be used to identify such enhancers, as will be understood by those of skill in the art based on the teachings herein.
[0039] The length of the promoter and enhancer regions can be of any suitable length for their intended purpose, and the spacing between the promoter and enhancer regions can be any suitable spacing to promote cone-specific expression of the gene product. In various preferred embodiments, the enhancer is located 0-1500; 0-1250; 0-1000; 0-750; 0-600; 0-500; 0-400; 0-300; 0-200; 0-100; 0-90; 0-80; 0-70; 0-60; 0-50; 0-40; 0-30; 0-20; or 0-10 nucleotides upstream of the promoter. The promoter can be any suitable distance upstream of the encoded gene.
[0040] In a further preferred embodiment that can be combined with any other embodiment in any aspect of the present invention, the enhancer comprises or consists of a sequence selected from the group consisting of the L/M minimal opsin enhancer (SEQ ID NO: 51), L/M enhancer elements of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more nucleotides that comprise one or more copies of the L/M minimal opsin enhancer, and the full L/M opsin enhancer (SEQ ID NO:4), or other portions thereof suitable to promote expression in a cone-specific manner, and the promoter comprises or consists of a sequence selected from the group consisting of L opsin promoter (SEQ ID NO: 1), the M opsin promoter (SEQ ID NO:2), and the S opsin promoter (SEQ ID NO:3).
[0041] In a further preferred embodiment, the gene delivery vector further comprises an intron comprising a splice donor/acceptor region, wherein the intron is located downstream of the promoter region and is located upstream of the gene. Any intron can be used, so long as it comprises a splice donor/acceptor region recognized in primate cone cells, so that the intron can be spliced out of the resulting mRNA product. In one embodiment, the intron comprises or consists of an SV40 intron according to SEQ ID NO:5. In various preferred embodiments, the 3' end of the intron is 0-20; 0-15; 0-10; 0-9; 0-8; 0-7; 0-6; or 0-5 nucleotides upstream of the gene, and its 5' end is 0-20; 0-15; 0-10; 0-9; 0-8; 0-7; 0-6; or 0-5 nucleotides downstream of the proximal promoter region.
[0042] The gene is operatively linked to the promoter region and the enhancer element, such that the promoter and enhancer elements are capable of driving expression of the gene or cDNA in cone cells of the subject.
[0043] The gene encoding a therapeutic to be expressed in the cone cells can be any gene or cDNA that encodes a polypeptide or RNA-based therapeutic (siRNA, antisense, ribozyme, shRNA, etc.) that can be used as a therapeutic for treating a cone cell disorder, or as a means to otherwise enhance vision, including but not limited to promoting tetrachromatic color vision. In various preferred embodiments, the gene encodes a therapeutic protein selected from the group consisting of
[0044] (a) SEQ ID NO: 7 (SEQ ID NO: 6) Homo sapiens opsin 1 (cone pigments), short-wave-sensitive (OPN1SW), mRNA NCBI Reference Sequence: NM_001708.2;
[0045] (b) SEQ ID NO: 9 (SEQ ID NO: 8) Homo sapiens opsin 1 (cone pigments), medium-wave-sensitive (OPN1MW), mRNA NCBI Reference Sequence: NM_000513.2;
[0046] (c) SEQ ID NO: 11 (SEQ ID NO: 10) Homo sapiens opsin 1 (cone pigments), long-wave-sensitive (OPN1LW), mRNA NCBI Reference Sequence: NM--020061.4;
[0047] (d) SEQ ID NO: 13 (SEQ ID NO: 12) ATP binding cassette retina gene (ABCR) gene (NM_000350);
[0048] (e) SEQ ID NO: 15 (SEQ ID NO: 14) retinal pigmented epithelium-specific 65 kD protein gene (RPE65) (NM--000329);
[0049] (f) SEQ ID NO: 17 (SEQ ID NO: 16) retinal binding protein 1 gene (RLBP1) (NM--000326);
[0050] (g) SEQ ID NO: 19 (SEQ ID NO: 18) peripherin/retinal degeneration slow gene, (NM--000322);
[0051] (h) SEQ ID NO: 21 (SEQ ID NO: 20) arrestin (SAG) (NM--000541);
[0052] (i) SEQ ID NO: 23 (SEQ ID NO: 22) alpha-transducin (GNAT1) (NM--000172);
[0053] (j) SEQ ID NO: 24 guanylate cyclase activator 1A (GUCA1A) (NP--000400.2);
[0054] (k) SEQ ID NO: 25 retina specific guanylate cyclase (GUCY2D), (NP--000171.1);
[0055] (l) SEQ ID NO: 26 & 27 alpha subunit of the cone cyclic nucleotide gated cation channel (CNGA3) (NP--001073347.1 or NP--001289.1);
[0056] (m) SEQ ID NO: 28 Human cone transducin alpha subunit (incomplete achromotopsia);
[0057] (n) SEQ ID NO: 29 cone cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha', protein (cone dystrophy type 4); [0058] (o) SEQ ID NO: 30 retinal cone rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma, protein (retinal cone dystrophy type 3A);
[0059] (p) SEQ ID NO: 31 cone rod homeobox, protein (Cone-rod dystrophy);
[0060] (q) SEQ ID NO: 32 cone photoreceptor cyclic nucleotide-gated channel beta subunit, protein (achromatopsia);
[0061] (r) SEQ ID NO: 33 cone photoreceptor cGMP-gated cation channel beta-subunit, protein (total color blindness, for example, among Pingelapese Islanders);
[0062] (s) SEQ ID NO: 35 (SEQ ID NO: 34) retinitis pigmentosa 1 (autosomal dominant) (RP 1);
[0063] (t) SEQ ID NO: 37 (SEQ ID NO: 36) retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP 1);
[0064] (u) SEQ ID NO: 39 (SEQ ID NO: 38) PRP8;
[0065] (v) SEQ ID NO: 41 (SEQ ID NO: 40) centrosomal protein 290 kDa (CEP290);
[0066] (w) SEQ ID NO: 43 (SEQ ID NO: 42) IMP (inosine 5'-monophosphate) dehydrogenase 1 (IMPDH1), transcript variant 1;
[0067] (x) SEQ ID NO: 45 (SEQ ID NO: 44) aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), transcript variant 1;
[0068] (y) SEQ ID NO: 47 (SEQ ID NO: 46) retinol dehydrogenase 12 (all-trans/9-cis/11-cis) (RDH12);
[0069] (z) SEQ ID NO: 49 (SEQ ID NO: 48) Leber congenital amaurosis 5 (LCA5), transcript variant 1; and
[0070] (aa) exemplary OPN1LW/OPN1MW2 polymorphs (compared to OPN1LW (L opsin) polypeptide sequence; the amino acid to the left of the number is the residue present in the L opsin sequence; the number is the reside number in L opsin, and the reside to the right of the number is the variation from L opsin. Polymorphs according to these embodiments may comprise one or more of the amino acid substitutions in Table 1 below:
TABLE-US-00001 TABLE 1 (i) Thr65Ile (ii) Ile111Val (iii) Ser116Tyr (iv) Leu153Met (v) Ile171Val (vi) Ala174Val (vii) Ile178Val (viii) Ser180Ala (ix) Ile230Thr (x) Ala233Ser (xi) Val236Met (xii) Ile274Val (xiii) Phe275Leu (xiv) Tyr277Phe (xv) Val279Phe (xvi) Thr285Ala (xvii) Pro298Ala (xviii) Tyr309Phe.
[0071] The proteins recited in (a)-(c) and (aa) are all involved in color vision. The exemplary polymorphs include ones at positions 65, 116, 180, 230, 233, 277, 285, and 309 that affect the spectra of the pigments in cone cells expressing them. Positions 274, 275, 277, 279, 285, 298 and 309 together distinguish L opsin from M opsin.
[0072] The proteins recited (d)-(z) are exemplary eye disease-associated gene, such as in retinitis pigmentosa (polypeptides "e"-"l", "s"-"y"), incomplete achromatopsia (polypeptide "m"), Stargardt's (polypeptide "d"); Leber congenital amaurosis (polypeptide "z"); cone dystrophy, such as cone dystrophy type 4 (polypeptide "n"); retinal cone dystrophy ; for example, retinal cone dystrophy type 3A (polypeptide "o") ; Cone-rod dystrophy (polypeptide "p"); achromatopsia (polypeptide "q'); and total color blindness, for example, among Pingelapese Islanders (polypeptide "r").
[0073] Exemplary nucleic acids encoding these polypeptides are shown by SEQ ID NO in parenthesis. Thus, in a further preferred embodiment, the genes comprise or consist of a nucleic acid sequence according to one or more of the nucleic acid sequences recited above. In a further preferred embodiment, the vector comprises the sequence shown in SEQ ID NO: 50
[0074] Any suitable gene therapy vector that can be used for cone cell delivery can be used in the methods of the present invention; the vector may comprise single or double stranded nucleic acid; preferably single stranded or double stranded DNA. In a preferred embodiment that can be combined with any of the above embodiments, the gene delivery vector comprises a recombinant adeno-associated virus (AAV) gene delivery vector. Prior to the present invention, rAAV vectors had not been shown capable of transducing primate cone cells. In this embodiment, the gene delivery vector is bounded on the 5' and 3' end by functional AAV inverted terminal repeat (ITR) sequences. By "functional AAV ITR sequences" is meant that the ITR sequences function as intended for the rescue, replication and packaging of the AAV virion. Hence, AAV ITRs for use in the vectors of the invention need not have a wild-type nucleotide sequence, and may be altered by the insertion, deletion or substitution of nucleotides or the AAV ITRs may be derived from any of several AAV serotypes. The rAAV vector may be derived from an adeno-associated virus serotype, including without limitation, AAV-1, AAV-2, AAV-3, AAV-4, AAV-5, AAV-6, AAV-7, AAV-8, etc. Preferred AAV vectors have the wild type REP and CAP genes deleted in whole or part, but retain functional flanking ITR sequences. In a further preferred embodiment, the AAV vector comprises rAAV2/5, a "pseudotyped" version of AAV2 created by using rep from AAV2 and cap from A AV5 or AAV2, A AV3, AAV4, AAV6, AAV7, AA V8 together with a plasmid containing a vector based on AAV2. Preferably, the rAAV is replication defective, in that the AAV vector cannot independently further replicate and package its genome. For example, when cone cells are transduced with rAAV virions, the gene is expressed in the transduced cone cells, however, due to the fact that the transduced cone cells lack AAV rep and cap genes and accessory function genes, the rAAV is not able to replicate.
[0075] Recombinant AAV (rAAV) virions encapsulating the vectors recited above for use in transducing cone cells may be produced using standard methodology. In one embodiment, an AAV expression vector according to the invention is introduced into a producer cell, followed by introduction of an AAV helper construct, where the helper construct includes AAV coding regions capable of being expressed in the producer cell and which complement AAV helper functions absent in the AAV vector. This is followed by introduction of helper virus and/or additional vectors into the producer cell, wherein the helper virus and/or additional vectors provide accessory functions capable of supporting efficient rAAV virus production. The producer cells are then cultured to produce rAAV. These steps are carried out using standard methodology. Replication-defective AAV virions encapsulating the recombinant AAV vectors of the instant invention are made by standard techniques known in the art using AAV packaging cells and packaging technology. Examples of these methods may be found, for example, in U.S. Pat. Nos. 5,436,146; 5,753,500, 6,040,183, 6,093,570 and 6,548,286, expressly incorporated by reference herein in their entirety. Further compositions and methods for packaging are described in Wang et al. (US 2002/0168342), also incorporated by reference herein in its entirety.
[0076] Any suitable method for producing viral particles for delivery can be used, including but not limited to those described in the examples that follow. Any concentration of viral particles suitable to effectively transducer cone cells can be administered to the eye. In one preferred embodiment, viral particles are delivered in a concentration of at least 1010 vector genome containing particles per mL; in various preferred embodiments, the viral particles are delivered in a concentration of at least 7.5×1010; 1011; 5×1011; 1012; 5×1012; 1013; 1.5×1013; 3×1013; 5×1013; 7.5×9×1013; or 9×1013 vectorgenome containing particles per mL. Similarly, any total number of viral particles suitable to provide appropriate transduction of retinal cone cells can be administered to the primate's eye. In various preferred embodiments, at least 1010; 5×1010; 1011; 5×1011; 1012; 1.5×1012; 3×1012; 5×1012; 7.5×1012; 1013; 1.5×1013; or 2.7×1013 viral particles are injected per eye. Any suitable number of administrations of the vector to the primate eye can be made. In one embodiment, the methods comprise a single administration; in other embodiments, multiple administrations are made over time as deemed appropriate by an attending clinician.
[0077] The viral stock for delivery to the primate eye can be treated as appropriate for delivery. The viral stock can be combined with pharmaceutically-acceptable carriers, diluents and reagents useful in preparing a formulation that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for primate use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solutions, dextrose solution, and 5% human serum albumin. Supplementary active compounds can also be incorporated into the formulations. Solutions or suspensions used for the formulations can include a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial compounds such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating compounds such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates; detergents such as Tween 20 to prevent aggregation; and compounds for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
[0078] In a further preferred embodiment that can be combined with any other embodiment, the methods of the invention restore visual capacity in the primate. As used herein, "restoring visual capacity" means that some benefit to vision is provided, including but not limited to a reduction or slowing of vision loss; improved visual acuity; decrease in abnormal sensitivity to bright lights; and/or an increase in one or more visual attributes, such as improved color perception (ie: monochromatic to dichromatic vision; dichromatic to trichromatic vision; trichromatic to tetrachromatic vision; etc.). The primate is preferably of the Parvorder Catarrhini, and more preferably is a human.
[0079] In a further preferred embodiment that can be combined with all of the above embodiments, the primate suffers from color blindness, and the primate is able to visualize new colors as a result of the therapy. In this embodiment, it is preferred that the enhancer (if present) comprises or consists of a sequence selected from the group consisting of the L/M minimal opsin enhancer (SEQ ID NO: 51), L/M enhancer elements of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more nucleotides that comprise one or more copies of the L/M minimal opsin enhancer, and the full L/M opsin enhancer (SEQ ID NO:4), or other portions thereof suitable to promote expression in a cone-specific manner, and the promoter comprises or consists of a sequence selected from the group consisting of L opsin promoter (SEQ ID NO: 1), the M opsin promoter (SEQ ID NO:2), and the S opsin promoter (SEQ ID NO:3), while the gene encodes one or more polypeptides comprising or consisting of a sequence selected from the group consisting of SEQ ID NO: 7 (OPN1SW), SEQ ID NO: 9 (OPN1MW), SEQ ID NO: 11 (OPN1LW), mRNA; and exemplary OPN1LW/OPN1MW2 polymorphs as described in Table 1 above. It is further preferred that the vector comprises a rAAV vector as described above.
[0080] The color blindness may be acquired or inherited, and can be full (monochromatic) or partial. In a preferred embodiment, the primate has partial color blindness selected from the group consisting of red-green and blue-yellow color blindness. The partial color blindness can comprise, for example, dichromacy or anomalous trichromasy. These methods result in the primate improved color perception (ie: monochromatic to dichromatic vision; dichromatic to trichromatic vision; trichromatic to tetrachromatic vision; etc.). The primate is preferably of the Parvorder Catarrhini, and more preferably is a human.
[0081] As described in detail below, the methods may be used to improve color perception in primates from dichromatic to trichromatic. Dichromats who are missing either the L- or the M-photopigment fail to distinguish from grey:colours near the so-called `spectral neutral point` located in the bluegreen region of color space (near dominant wavelength of 490 nm) and complementary colors near the `extra-spectral neutral point` in the red-violet region (near dominant wavelength of 499 nm), Co-expressing the L-opsin transgene within a subset of endogenous M-cones shifted their spectral sensitivity to respond to long wavelength light, thus producing two distinct cone types absorbing in the middle-to-long wavelengths, as required for trichromasy. These results demonstrate that gene therapy changed the spectral sensitivity of a subset of the cones, and the results further demonstrate the unexpected result that adult monkeys gained new color vision capacities because of the gene therapy.
[0082] In a further preferred embodiment of all of the above embodiments, the primate has a vision disorder in which its photoreceptors are healthy, such as color blindness. As used herein, "healthy" means that the cells being treated are functioning but simply do not provide for the desired color perception, in contrast to gene therapy in which the target cells are degenerating or dying. The studies reported herein are the first to use gene therapy in primates to address a vision disorder in which all photoreceptors are intact and healthy, making it possible to assess the full potential of gene therapy to restore visual capacities. The methods of the present invention thus will allow many opportunities for functions to be added or restored in the eye.
[0083] In a further preferred embodiment that can be combined with any of the other embodiments herein, the primate is an adult primate, such as an adult human (ie: at least 16 years of age; preferably at least 18 years of age or 21 years of age). Classic visual deprivation experiments have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that treatment of congenital vision disorders would be ineffective unless administered to the very young. The present study thus provides significantly unexpected results in curing a visual disorder in an adult primate.
[0084] Those of skill in the art will readily appreciate, based on the teachings herein, the variety of treatment modalities that can be accomplished using the methods of the invention. In one embodiment, the gene encodes ABCR and is administered to the eye of a primate with Stargardt disease. In other embodiments, the gene encodes:
[0085] one or more of polypeptides "e"- "1" and "s"- "y" in Table 1, and is administered to the eye of a primate with retinitis pigmentosa;
[0086] polypeptide "m" in Table 1, and is administered to the eye of a primate with incomplete achromatopsia;
[0087] polypeptide "z" in Table 1, and is administered to the eye of a primate with Leber congenital amaurosis;
[0088] polypeptide "n" in Table 1, and is administered to the eye of a primate with cone dystrophy, such as cone dystrophy type 4;
[0089] polypeptide "o" in Table 1, and is administered to the eye of a primate with retinal cone dystrophy, for example, retinal cone dystrophy type 3A;
[0090] polypeptide "p" in Table 1, and is administered to the eye of a primate with cone-rod dystrophy;
[0091] polypeptide "q" in Table 1, and is administered to the eye of a primate with achromatopsia; and/or
[0092] polypeptide "r" in Table 1, and is administered to the eye of a primate with total color blindness, for example, a native of the Pingelapese Islands.
[0093] Any suitable means for delivery of the gene therapy vector to the eye can be used, including but not limited to administering in a contact lens fluid, contact lens cleaning and rinsing solutions, eye drops, surgical irrigation solutions, ophthalmological devices, injection, iontophoresis, topical instillation on the eye, and topical instillation. The topical instillation can be administered, for example, in the form of a liquid solution, a paste, of a hydrogel. The topical instillation can be embedded, for example, in a foam matrix or supported in a reservoir. The injection into the primate eye can be, for example, an intracameral injection, an intracorneal injection, a subconjonctival injection, a subtenon injection, a subretinal injection, an intravitreal injection, and an injection into the anterior chamber.
[0094] The primate's progress in response to the treatment may be monitored by any suitable means. In embodiments where the methods are used to treat color blindness, monitoring or progress may comprise, for example, use of standard color vision tests, or the wide-field color multifocal electroretinogram (mf-ERG) system described below to detect spectral sensitivity shifts in the primate's vision. Thus, in another aspect, the present invention provides methods for use of the electroretinogram disclosed herein for monitoring changes in vision perception, such as color perception, of a primate undergoing gene therapy to treat a visual disorder. All embodiments of the methods disclosed above can be combined with all embodiments of the electroretinogram disclosed below.
[0095] In a second aspect, the present invention provides isolated nucleic acid expression vectors comprising:
[0096] (a) a promoter region, wherein the promoter region is specific for primate retinal cone cells; and
[0097] (b) a gene encoding a therapeutic, wherein the gene is operatively linked to the promoter region.
[0098] All terms in this second aspect have the same meaning as disclosed above for the first aspect of the invention. Similarly, all embodiments and combinations thereof disclosed above in the first aspect of the invention can be used in this second aspect of the invention. The inventors have demonstrated effective treatment of congenital vision disorders in adult primates using the recombinant vectors of the invention, a result that is completely unexpected in the art.
[0099] Any suitable promoter region can be used in the isolated nucleic acid expression vector, so long as it specifically promotes expression of the gene in retinal cone cells. In a preferred embodiment, the promoter specifically promotes expression of the gene in Catarrhini retinal cone cells; even more preferably in human retinal cone cells. Exemplary suitable promoter regions include the promoter region for any cone-specific gene, such as the L opsin promoter (SEQ ID NO: 1), the M opsin promoter (SEQ ID NO: 2), and the S opsin promoter (SEQ ID NO: 3), or portions thereof suitable to promote expression in a cone-specific manner.
[0100] In a preferred embodiment, the isolated nucleic acid expression vector further comprises an enhancer element upstream of the promoter, wherein the gene is operatively linked to the enhancer element. Any suitable enhancer element can be used in the gene therapy vectors, so long as it enhances expression of the gene when used in combination with the promoter. In a preferred embodiment, the enhancer element is specific for retinal cone cells; more preferably, it is specific for primate retinal cone cells; more preferably in Catarrhini retinal cone cells; even more preferably in human retinal cone cells. Exemplary suitable enhancer regions comprise or consist of the enhancer region for any cone-specific gene, such as the L/M minimal opsin enhancer (SEQ ID NO: 51), L/M enhancer elements of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more nucleotides that comprise one or more copies of the L/M minimal opsin enhancer, and the full L/M opsin enhancer (SEQ ID NO: 4), or other portions thereof suitable to promote expression in a cone-specific manner.
[0101] The length of the promoter and enhancer regions can be of any suitable length for their intended purpose, and the spacing between the promoter and enhancer regions can be any suitable spacing to promote cone-specific expression of the gene product. In various preferred embodiments, the enhancer is located 0-1500; 0-1250; 0-1000; 0-750; 0-600; 0-500; 0-400; 0-300; 0-200; 0-100; 0-90; 0-80; 0-70; 0-60; 0-50; 0-40; 0-30; 0-20; or 0-10 nucleotides upstream of the promoter. The promoter can be any suitable distance upstream of the encoded gene.
[0102] In a further preferred embodiment that can be combined with any other embodiment in any aspect of the present invention, the enhancer comprises or consists of a sequence selected from the group consisting of the L/M minimal opsin enhancer (SEQ ID NO: 51), L/M enhancer elements of 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more nucleotides that comprise one or more copies of the L/M minimal opsin enhancer, and the full L/M opsin enhancer (SEQ ID NO: 4), or other portions thereof suitable to promote expression in a cone-specific manner, and the promoter comprises or consists of a sequence selected from the group consisting of L opsin promoter (SEQ ID NO: 1), the M opsin promoter (SEQ ID NO: 2), and the S opsin promoter (SEQ ID NO: 3).
[0103] In a further preferred embodiment, the isolated nucleic acid expression vector further comprises an intron comprising a splice donor/acceptor region, wherein the intron is located downstream of the promoter region and is located upstream of the gene. Any intron can be used, so long as it comprises a splice donor/acceptor region recognized in primate cone cells, so that the intron can be spliced out of the resulting mRNA product. In one embodiment, the intron comprises or consists of an SV40 intron according to SEQ ID NO: 5. In various preferred embodiments, the 3' end of the intron is 0-20; 0-15; 0-10; 0-9; 0-8; 0-7; 0-6; or 0-5 nucleotides upstream of the gene, and its 5' end is 0-20; 0-15; 0-10; 0-9; 0-8; 0-7; 0-6; or 0-5 nucleotides downstream of the proximal promoter region.
[0104] The gene is operatively linked to the promoter region and the enhancer element, such that the promoter and enhancer elements are capable of driving expression of the gene or cDNA in cone cells of the subject.
[0105] The gene encoding a therapeutic to be expressed in the cone cells can be any gene or cDNA that encodes a polypeptide or RNA-based therapeutic (siRNA, antisense, ribozyme, shRNA, etc.) that can be used as a therapeutic for treating a cone cell disorder, or as a means to otherwise enhance vision, including but not limited to promoting tetrachromatic color vision. In various preferred embodiments, the gene encodes a therapeutic protein comprising or consisting of those disclosed above in the methods of the first aspect of the invention.
[0106] In a further preferred embodiment, the vector comprises the sequence shown in SEQ ID NO: 50, which details the vector used in at least some of the examples that follow.
[0107] In a further preferred embodiment that can be combined with any of the above embodiments, the gene delivery vector comprises a recombinant adeno-associated virus (AAV) gene delivery vector. In a further preferred embodiment, the AAV vector comprises rAAV2/5. Preferably, the rAAV is replication defective, in that the AAV vector cannot independently further replicate and package its genome. For example, when cone cells are transduced with rAAV virions, the gene is expressed in the transduced cone cells, however, due to the fact that the transduced cone cells lack AAV rep and cap genes and accessory function genes, the rAAV is not able to replicate.
[0108] In a third aspect, the present invention provides a formulation comprising packaged viral particles containing the nucleic acid expression vectors of the second aspect of the invention. In one preferred embodiment, viral particles are present in a concentration of at least 1010 vector genome containing particles per mL; in various preferred embodiments, the viral particles are delivered in a concentration of at least 7.5×1010; 1011; 5×1011; 1012; 5×1012; 1013; 1.5×1013; 3×1013; 5×1013; 7.5×9×1013; or 9×1013 vectorgenome containing particles per mL. The formulation may further comprise pharmaceutically-acceptable carriers, diluents and reagents as described above in the first aspect of the invention. The formulation may be in the form of a liquid solution, a paste, a hydrogel, or may be embedded within a substrate, including but not limited to a foam matrix or supported in a reservoir.
[0109] In a fourth aspect, the present invention provides recombinant host cells transfected or transduced with the nucleic acid expression vector of the second aspect of the invention. The cells may be of any type that can be transfected with the expression vector. In one embodiment where the expression vector is a rAAV vector, the cells comprise producer cells transduced with a replication incompetent rAAV expression vector according to the second aspect of the invention, form which viral particles can be obtained by introduction of an AAV helper construct as described above and as is well known in the art.
[0110] In a fifth aspect, the present invention provides a color multifocal electroretinogram system, comprising:
[0111] (a) an electroretinogram (ERG) comprising [0112] (i) a recording electrode that is (A) designed for placement on at least one of a cornea and a sclera of at least one eye of a subject and (B) arranged to output at least one signal generated by the at least one eye; and [0113] (ii) a computing system communicatively coupled to the recording electrode, the computing system comprising (A) at least one processor and [0114] (B) data storage containing instructions executable by the at least one processor to carry out a set of functions, the set of functions including processing and saving the at least one signal generated by the at least one eye;
[0115] (b) a retinal stimulator comprising matched light sources selected from the group consisting of red, green, blue, and ultraviolet light sources, wherein the matched light sources are connected to the ERG and in operation can be independently frequency modulated at rates between about 1 Hz and about 60 Hz, inclusive, wherein the stimulator in operation is capable of stimulating a retinal field of a subject throughout an operating radius of at least about 70 degrees;
[0116] (c) one or more constant current integrated circuit chips arranged to drive the stimulator; and
[0117] (d) a pulse-frequency modulator connected to the retinal stimulator, wherein in operation the pulse-frequency modulator is capable of controlling individual stimulator segments while keeping relative spectral content of the light constant.
[0118] The electroretinograms of the present invention can be used, for example, in characterizing the topography of expression of the different opsin transgenes in the eyes of living subjects treated with gene therapy, and thus can be used with the gene therapy methods of the invention disclosed above.
[0119] As used here, a "matched" light source is one that includes light stimulus of different wavelengths, wherein the number of pixels is approximately the same, or is the same, at each wavelength. One non-limiting example is a matched light source stimulus containing 1024 doublet pixels each containing a red (653 nm, half-bandwidth 22 nm) and a green (527 nm, half-bandwidth 33 nm) LED, with a resulting matched light source with 2,048 paired green and red LEDs.
[0120] In various preferred embodiments, the stimulator in operation is capable of stimulating a retinal field of a subject throughout an operating radius of at least about 80, 90, 100, 110, 120, 130, 140, 150, or more degrees.
[0121] In one preferred embodiment, the matched light sources are paired red and green light sources. In another preferred embodiment, the matched light sources are triplets of red, green, and blue light sources. In a further preferred embodiment, the matched light sources are quartets of red, green, blue, and ultraviolet light sources.
[0122] Any suitable matched light source can be used. In one preferred embodiment, the matched light sources comprise matched light emitting diodes (LEDs).
[0123] In another preferred embodiment, that can be combined with any of the embodiments herein, the retinal stimulator comprises a concave surface comprising a series of trapezoidal-shaped circuit boards placed edge-to-edge, wherein the concave surface positions the matched light sources so in operation they are held equidistantly from and pointing toward a single focal point where a subject's pupil can be positioned. This embodiment helps to limit SNR fall-off in peripheral retinal regions. Any suitable concave surface can be used; in a preferred embodiment, the concave surface comprises a geodesic dome.
[0124] In a further embodiment that can be combined with any of the above embodiments, the set of functions executable by the processor further comprises coding and decoding topographical regions on the recording electrode using a cyclic summation technique.
[0125] In a further preferred embodiment that can be combined with any of the embodiments herein, the ERG further comprises an amplifier; and wherein the computing system is communicatively coupled to the amplifier.
[0126] Further embodiments and details of the color multifocal electroretinogram system are provided in the Examples that follow.
[0127] In a further aspect, the present invention provides methods for determining a location of functioning opsin expression in a subject, comprising use of the mf-ERG of any embodiment or combination of embodiments of the fifth aspect of the invention, wherein the recording electrode is placed on at least one of a cornea and a sclera of at least one eye of a subject; stimulating the subject's retinal field with the retinal stimulator; and determining responses of different areas of the subject's retina to different stimulation frequencies to generate a map of retinal responses, wherein the map provides a location of functioning opsin expression in a subject. In one preferred embodiment, the subject has been treated according to the gene therapy methods for color blindness disclosed above according to any embodiment or combination of embodiments of the first aspect of the invention.
[0128] Unless the context clearly dictates otherwise, embodiments in one aspect of the invention may be used in other aspects of the invention, and can be combined with each other.
EXAMPLE 1
[0129] Red-green colour blindness, which results from the absence of either the long-(L) or middle-(M) wavelength-sensitive visual photopigments, is the most common single locus genetic disorder. Here, the possibility of curing colour blindness using gene therapy was explored in experiments on adult monkeys that had been colour blind since birth. A third type of cone pigment was added to dichromatic retinas, providing the receptoral basis for trichromatic colour vision. This opened a new avenue to explore the requirements for establishing the neural circuits for a new dimension of colour sensation. Classic visual deprivation experiments' have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that treatment of congenital vision disorders would be ineffective unless administered to the very young. Here, however, addition of a third opsin in adult red-green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour. Thus, trichromacy can arise from a single addition of a third cone class and it does not require an early developmental process. This provides a positive outlook for the potential of gene therapy to cure adult vision disorders.
[0130] Gene therapy was performed on adult squirrel monkeys (Saimiri sciureus) that were missing the L opsin gene. In this species, some females have trichromatic colour vision while males are red-green colour blind2. Serotype 2/5 recombinant adeno-associated virus (rAAV) containing a human L-opsin gene under control of the L/M opsin enhancer and promoter (FIG. 1a) was delivered to the photoreceptor layer via subretinal injections. Transcriptional regulatory elements were chosen to direct expression preferentially in M cones, but not short-(S) wavelength-sensitive cones or rods3. To provide the receptoral basis for trichromacy, animals received three 100 μL injections (containing a total of 2.7×1013 viral particles) in each eye which produced a relatively uniform, third submosaic of approximately 15-36% of M cones that coexpressed the transgene (FIGS. 1e, f).
[0131] Prior to treatment, monkeys were trained to perform a computer-based colour vision test, the Cambridge Colour Test4,5, which was modified for use with animals6 (FIG. 2a). Dichromats who are missing either the L- or M-photopigment fail to distinguish from grey: colours near the so-called "spectral neutral point" located in the blue-green region of colour space (near dominant wavelength (DW) 490 nm) and complementary colours near the "extra-spectral neutral point," in the red-violet region (near DW=-499 nm). While trichromats have four main hue percepts--blue, yellow, red, and green--dichromats have only two percepts, nominally blue and yellow. Before treatment, two dichromatic monkeys completed three colour vision tests consisting of 16 hues (FIG. 2b, c). Four-to-six months was required to test all 16 hues; thus, baseline results represent testing conducted for more than a year. As predicted, prior to treatment monkeys had low thresholds (averaging <0.03 units in u', v' colour space) for colours that represent blues and yellows to their eyes, but always failed to discriminate the blue-green (DW=490 nm) and red-violet hues (DW=-499 nm) with thresholds extrapolated from psychometric functions being orders of magnitude higher (FIGS. 2b, c). Results were highly repeatable, with no improvement between the first and third tests, making us confident that animals would not spontaneously improve in the absence of treatment. Co-expressing the L-opsin transgene within a subset of endogenous M-cones shifted their spectral sensitivity to respond to long wavelength light, thus producing two distinct cone types absorbing in the middle-to-long wavelengths, as required for trichromacy. The spectral sensitivity shift was readily detected using a custom-built wide-field colour multifocal electroretinogram (mf-ERG) system (FIGS. 1b, c, f) (see ref 7 for details). In preliminary experiments, validity of the colour mf-ERG was tested using an animal that had received a mixture of the L-opsin-coding virus plus an identical virus, except that a green fluorescent protein (GFP) gene replaced the L-opsin gene. As reported previously, faint GFP fluorescence was first detected at 9 weeks post-injection, and it continued to increase in area and intensity through 24 weeks8. While faint signs of GFP were first detectable at 9 weeks, L-opsin levels sufficient to produce suprathreshold mf-ERG signals were still not present at 16 weeks post-injection (FIG. 1c, inset). After GFP fluorescence became robust, the red light mf-ERG, which indicates responses from the introduced L-opsin, showed highly elevated response amplitudes in two areas (FIG. 1c) corresponding to locations of subretinal injections (FIG. 1d).
[0132] The two dichromatic monkeys who participated in behavioural tests of colour vision were treated with only L-opsin-coding virus. While the elongated pattern produced by two injections in FIGS. 1c and d allowed mf-ERG validation, the treatment goal was to produce a homogeneous region, as resulted from 3 injections shown in f, where the highest mf-ERG response covered about 80° of central retina, roughly the area for which humans have good red-green discrimination. These results demonstrate that gene therapy changed the spectral sensitivity of a subset of the cones. A priori, there were two possibilities for how a change in spectral sensitivity might change colour vision behaviour: 1) animals may have an increase in sensitivity to long-wavelength light, but if the neural circuitry for extracting colour information from the nascent "M+L cone" submosaic was absent, they would remain dichromatic, the hallmark of which is having two hues that are indistinguishable from grey (FIG. 2d). The spectral neutral point for individuals that have only S- and M-cones, (e.g. monkeys 1 and 2 pre-therapy), occurs near dominant wavelength (DW)=495 nm. At the limit, an increase in spectral sensitivity would shift the monkeys' neutral point toward that of individuals with only S and L cones, near DW=505 nm (dashed blue lines, FIG. 2d). 2) The second, more engaging possibility was that treatment would be sufficient to expand sensory capacity in monkeys, providing them with trichromatic vision. In this case, the animals' post-therapy results would appear similar to FIG. 2e, obtained from a trichromatic female control monkey.
[0133] Daily testing continued after treatment. After about 20 weeks post-injection (arrow, FIG. 3a), the trained monkeys' thresholds for blue-green and red-violet (DWs=490 and -499 nm, respectively, FIGS. 3b, c) improved, reducing to an average of 0.08 units in u', v' colour space, indicating that they gained trichromatic vision. This time point corresponded to the same period in which robust levels of transgene expression were reported in the squirrel monkey8. A trichromatic female monkey and untreated dichromatic monkeys were tested in parallel. As expected, the female had low thresholds for all colours, averaging <0.03 units in u', v' colour space, but the untreated dichromats always failed to discriminate DWs=490 nm (triangle, FIGS. 3a) and -499 nm, indicating a clear difference between treated and untreated monkeys.
[0134] Early experiments in which we obtained negative results served as "sham controls," demonstrating that acquiring a new dimension of colour vision requires a shift in spectral sensitivity that results from expression of an L pigment in a subset of M cones. Using similar subretinal injection procedures, we delivered fewer viral particles of an L-opsin-coding rAAV2/5 virus with an extra 146 base pair (bp) segment near the splice donor/acceptor site that had been carried over from the cloning vector and that was absent in the GFP-coding rAAV2/5 virus. The 146 bp segment contained an ATG and a duplicate mRNA start site that may have interfered with expression (see Full Methods online). Three monkeys received injections of this vector, containing an average of 1.7×1012 virus particles per eye, and no reliable changes in spectral sensitivity were measured using the ERG. One animal was also tested behaviourally and his colour vision was unchanged from baseline 1 year after injection. In subsequent experiments reported here, we removed the extra 146 bp segment and also increased the amount of viral particles delivered per eye by approximately 16-fold, to 2.7×1013. Negative results from earlier injections demonstrated that the subretinal injection procedure itself does not produce changes in the ERG or in colour vision.
[0135] The change in spectral sensitivity measured with the mf-ERG is necessary but not sufficient to produce a new colour vision capacity. For example, individuals with L but no M cones (termed deuteranopes) have a relatively enhanced sensitivity to red light but they are still as dichromatic as individuals with M but no L cones (protanopes), in that they are unable to distinguish particular "colours" from grey. To verify that the behavioural change observed in animals expressing the L pigment transgene was not purely a shift in spectral sensitivity (see FIG. 2d), monkey 1 was also tested on DWs=496 and 500 nm, and monkey 2 was tested on DWs 496 and 507 nm. Together, these DWs span the possible confusion points for deuteranopes and protanopes and for any intermediate dichromatic forms that could arise from expressing combinations of L and M pigments. As shown in FIGS. 3b and c, both monkeys' measured thresholds for these additional hues were similar to their thresholds for DW=490 nm, demonstrating they now lacked a spectral neutral point and have become truly trichromatic. Furthermore, treated monkeys were able to discriminate blue-green (DW=490 nm) when it was tested against a red-violet background (DW=-499 nm), instead of the grey background, indicating that the monkeys' newly-acquired "green" and "red" percepts were distinct from one another. The treated monkeys' improvement in colour vision has remained stable for over 2 years and we plan to continue testing the animals to evaluate long term treatment effects.
[0136] Classic experiments in which visual deprivation of one eye during development caused permanent vision loss1 led to the idea that inputs must be present during development for the formation of circuits to process them. From the clear change in behaviour associated with treatment, compared both between and within subjects, we conclude that adult monkeys gained new colour vision capacities because of gene therapy. These startling empirical results provide insight into the evolutionary question of what changes in the visual system are required for adding a new dimension of colour vision. Previously, it seemed possible that a transformation from dichromacy to trichromacy would require evolutionary/developmental changes, in addition to acquiring a third cone type. For example, L and M opsin-specific genetic regulatory elements might have been required to direct the opsins into distinct cone types9 that would be recognized by L and M cone-specific retinal circuitry10, and to account for cortical processing, multi-stage circuitry" might have evolved specifically for the purpose of trichromacy. However, our results demonstrate that trichromatic colour vision behaviour requires nothing more than a third cone type. As an alternative to the idea that the new dimension of colour vision arose by acquisition of a new L vs. M pathway, it is possible that it exploited the pre-existing blue-yellow circuitry. For example, if addition of the third cone class split the formerly S vs. M receptive fields into two types with differing spectral sensitivities, this would obviate the need for neural rewiring as part of the process of adopting new colour vision.
[0137] Some form of inherent plasticity in the mammalian visual system can be inferred from the acquisition of novel colour vision, as was also demonstrated in genetically engineered mice12; however, the point has been made that such plasticity need not imply that any rewiring of the neural circuitry has occurred13. Similarly, given the fact that new colour vision behaviour in adult squirrel monkeys corresponded to the same time interval as the appearance of robust levels of transgene expression, we conclude that rewiring of the visual system was not associated with the change from dichromatic to trichromatic vision.
[0138] Treated adult monkeys unquestionably respond to colours previously invisible to them. The internal experiences associated with the dramatic change in discrimination thresholds measured here cannot be determined; therefore, we cannot know whether the animals experience new internal sensations of "red" and "green." Nonetheless, we do know that evolution acts on behaviour, not on internalized experiences, and we suggest that gene therapy recapitulated what occurred during evolution of trichromasy in primates. These experiments demonstrate that a new colour vision capacity, as defined by new discrimination abilities, can be added by taking advantage of pre-existing neural circuitry and, internal experience aside, full colour vision could have evolved in the absence of any other change in the visual system except the addition of a third cone type.
[0139] Gene therapy trials are underway for Leber's congenital amaurosis14-16. Thus far, treatment has been administered to individuals who have suffered retinal degeneration from the disease. The experiments reported here are the first to use gene therapy in primates to address a vision disorder in which all photoreceptors are intact and healthy, making it possible to assess the full potential of gene therapy to restore visual capacities. Treatment allowing monkeys to see new colours in adulthood provides a striking counter-example to what occurs under conditions of monocular deprivation. For instance, it is impossible to restore vision in an adult who had grown up with a unilateral cataract. Future technologies will allow many opportunities for functions to be added or restored in the eye. While some changes may produce outcomes analogous to monocular deprivation, we predict that others, like gene therapy for red-green colour blindness, will provide vision where there was previously blindness.
METHODS SUMMARY FOR EXAMPLE 1
[0140] Viral vector. CHOPS2053 was a 2.1 kb fragment containing the locus control region (LCR) and proximal promoter (PP) upstream of the human X-chromosome opsin gene array9,17. These elements (also known as pR2.1) have been shown to target transgene expression to mammalian L/M cones3,18. RHLOPS was a 1.2 kb fragment containing recombinant human L opsin cDNA. A clone of the human L opsin cDNA19, known as hs7, was generously provided by J. Nathans. The QuickChange kit (Stratagene) was used to convert codon 180 so that it would encode a human L pigment maximally sensitive to 562 nm20. The virus was made using the genome from rAAV serotype 2 and the capsid from serotype 5, and the preparation had 9×1013 DNase-resistant vector genome containing particles per mL. To prevent vector aggregation, 0.014% Tween 20 was added to the final vector preparation. A total of 2.7×1013 viral particles was injected per eye.
[0141] An earlier version of the L-opsin coding rAAV2/5 used in previous unsuccessful experiments contained an extra 146 base pair segment between the splice donor/acceptor site and the translational start codon of the L-opsin gene that had been carried over from the cloning vector. Because we were concerned that this fragment may have interfered with transgene expression, a second version of L-opsin rAAV2/5 in which the extra 146 by had been removed was used in later experiments described here. In addition to modifying the vector, we also increased the amount of viral particles delivered per eye by approximately 16-fold, from 1.7×1012 to 2.7×1013. Thus, we cannot conclude from this set of experiments what exact titer of viral particles was required to produce the effects on color vision behaviour, or exactly what effects, if any, the extra 146 bp had on transgene expression in earlier unsuccessful attempts.
[0142] The single-stranded DNA genome of conventional rAAV vectors, including rAAV2/5 used here, is devoid of Rep coding sequences. Thus, the vector genome is stabilized predominantly in an episomal form; however, the potential for integration exists21. According to NIH guidelines, the viral vector used here is rated biosafety level 1 (BSL1), and animal biosafety level 1(ABSL1) meaning no special precautions were required in handling the virus or animals treated with the virus. Following treatment, squirrel monkeys had an increase in AAV antibody titers, ranging from 4-12 fold. Antibody titers remained unchanged in untreated control animals who were housed with treated animals.
[0143] Subretinal Injections. Subretinal injections were performed by a vitreo-retinal surgeon (T. B. C.) using a KDS model 210 syringe pump under a stereomicroscope. A 500 μL Hamilton Gastight (#1750TTL) Luer Lock syringe was connected to 88.9 cm of 30 gauge teflon tubing with male Luer Lock adapters at both ends (Hamilton 30TF double hub), which was then connected to a 30 gauge Becton Dickinson Yale regular bevel cannula (ref #511258) that was manually bent to produce a 135° angle 1.5 mm from the tip. All components were sterilized prior to use. The syringe and tubing were filled with sterile lactated Ringers solution to produce a dead volume of approximately 210 μL. Just prior to injection, 300 μL of rAAV was withdrawn using a rate of 100 μL/min.
[0144] Squirrel monkeys were anesthetized using intramuscular injections of ketamine (15 mg/kg) and xylazine (2 mg/kg); atropine (0.05 mg/kg) was also given to reduce airway secretions. The eye was dilated with 2-3 drops of tropicamide (1%) and treated with 1 drop each of betadine (5%), vigamox (0.5%), and proparacaine (1%). Subconjunctival injection of 0.1 mL of lidocaine (2%) was given and the anterior portion of the eye was exposed by performing a temporal canthotomy followed by limited conjuntival peritomy. Eyelids were held open with a speculum designed for premature infants. A temporal sclerotomy was made 1 mm posterior to the limbus with a 27 gauge needle, through which the injection cannula was inserted. Three subsequent 100 μL injections were made at different subretinal locations using an infusion rate of 1060 μL/min. Post-procedure, 0.05 mL each of decadron (10 mg/mL), kenalog (40 mg/mL), and cephazolin (100 mg/mL) were injected subconjunctivaly; 1 drop each of betadine (5%) and vigamox (0.5%) and a 0.6 cm strip of tobradex (0.3% tobramycin, 0.1% dexamethasone) ointment were applied topically; 10-20 mL of subcutaneous fluids (sterile lactated Ringers) were also given. Subsequent administration of steroids and analgesics were administered as needed post-procedure for potential inflammation or discomfort.
[0145] Confocal Microscopy. The animal in FIG. 1 c and d succumbed to respiratory illness, unrelated to gene therapy, approximately 2 years and 3 months post-injection. The retina was fixed in 4% paraformaldehyde in phosphate buffered saline (PBS), and rinsed in PBS with 10% and 30% sucrose. It was sequentially incubated with 10% Normal Donkey Serum, rabbit monoclonal antibody to M/L opsin (Chemicon AB5405), and a Cy3 (red) conjugated donkey anti-rabbit antibody (Jackson Immunoresearch). Confocal images were analyzed using ImageJ (rsbweb.nih.gov). In the middle panel of FIG. 1e, magenta dots mark cone locations, and the red anti-M/L-opsin antibody staining was removed to show GFP-expressing (green) cells more clearly.
[0146] Behavioural Colour Vision Assessment. A three-alternative forced-choice paradigm in which position and saturation of the stimulus was randomized between trials was used. Monkeys had to discriminate the location of a coloured patch of dots that varied in size and brightness, surrounded by similarly varying grey dots. When animals touched the coloured target, a positive tone sounded and a juice reward was given; the next stimulus appeared immediately. (The squirrel monkey shown in FIG. 2c is drinking a reward from a previous trial.) If the wrong position was chosen, a negative tone sounded, and a 2-3 sec "penalty time" occurred before the next trial.
[0147] For each hue, monkeys were tested on up to 11 different saturations ranging from 0.01 to 0.11 in u', v' colour space (CIE 1976) and a threshold was calculated, which was taken as the saturation required to reach a criterion of 57% correct, the value determined to be significantly greater than chance (33% correct, P=0.05); see ref 6 for full details.
REFERENCE FOR EXAMPLE 1
[0148] 1. Wiesel, T. N. & Hubel, D. H. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol. 26, 1003-1017 (1963). [0149] 2. Jacobs, G. H. A perspective on color vision in platyrrhine monkeys. Vision Res. 38, 3307-3313 (1998). [0150] 3. Li, Q., Timmers, A. M., Guy, J., Pang, J. & Hauswirth, W. W. Cone-specific expression using a human red opsin promoter in recombinant AAV. Vision Res. 48(2007). [0151] 4. Reffin, J. P., Astell, S. & Mollon, J. D. Trials of a computer-controlled colour vision test that preserves the advantages of pseudo-isochromatic plates. in Colour Vision Deficiencies X69-76 (Kluwer Academic Publishers, Dordrecht, 1991). [0152] 5. Regan, B. C., Reffin, J. P. & Mollon, J. D. Luminance noise and the rapid determination of discrimination ellipses in colour deficiency. Vision Res. 34, 1279-1299 (1994). [0153] 6. Mancuso, K., Neitz, M. & Neitz, J. An adaptation of the Cambridge Colour Test for use with animals. Vis. Neurosci. (2006). [0154] 7. Kuchenbecker, J., Sahay, M., Tait, D. M., Neitz, M. & Neitz, J. Topography of the long- to middle-wavelength sensitive cone ratio in the human retina assessed with a wide-field color multifocal electroretinogram. Vis. Neurosci. 25, 301-306 (2008). [0155] 8. Mancuso, K. et al. Recombinant adeno-associated virus targets passenger gene expression to cones in primate retina. J. Opt. Soc. Am. A Opt. Image Sci. Vis. 24, 1411-1416 (2007). [0156] 9. Nathans, J., Piantanida, T. P., Eddy, R. L., Shows, T. B. & Hogness, D. S. Molecular genetics of inherited variation in human color vision. Science 232, 203-210 (1986). [0157] 10. Shapley, R. Specificity of cone connections in the retina and color vision. Focus on "Specificity of cone inputs to macaque retinal ganglion cells". J. Neurophysiol. 95, 587-588 (2006). [0158] 11. DeValois, R. L. & DeValois, K. K. A multi-stage color model. Vision Res. 33, 1053-1065 (1993). [0159] 12. Jacobs, G. H., Williams, G. A., Cahill, H. & Nathans, J. Emergence of Novel Color Vision in Mice Engineered to Express a Human Cone Photopigment. Science 315, 1723-1725 (2007). [0160] 13. Makous, W. Comment on "Emergence of Novel Color Vision in Mice Engineered to Express a Human Cone Photopigment". Science 318, 196 (2007). [0161] 14. Maguire, A. M. et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358, 2240-2248 (2008). [0162] 15. Bainbridge, J. W. & Ali, R. R. Success in sight: The eyes have it! Ocular gene therapy trials for LCA look promising. Gene Ther. 15, 1191-1192 (2008). [0163] 16. Cideciyan, A. V. et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc. Natl. Acad. Sci. U. S. A. 105, 15112-15117 (2008). [0164] 17. Wang, Y. et al. A locus control region adjacent to the human red and green visual pigment genes. Neuron 9, 429-440 (1992). [0165] 18. Mauck, M. C., Mauncuso, K., Kuchenbecher, J., Connor, T. B., Hauswirth, W. W., Neitz, J., Neitz, M. . Longitudinal evaluation of expression of virally delivered transgenes in gerbil cone photoreceptors. Vis. Neurosci. 25, 273-282 (2008). [0166] 19. Nathans, J., Thomas, D. & Hogness, D. S. Molecular genetics of human color vision: the genes encoding blue, green, and red pigments. Science 232, 193-202 (1986). [0167] 20. Neitz, M., Neitz, J. & Jacobs, G. H. Spectral tuning of pigments underlying red-green color vision. Science 252, 971-974 (1991). [0168] 21. Buning, H., Perabo, L., Coutelle, O., Quadt-Humme, S. & Hallek, M. Recent developments in adeno-associated virus vector technology. J. Gene Med. 10, 717-733 (2008).
EXAMPLE 2
Description and Validation of New LED-Based, Wide-Field, Color mf-ERG
[0169] The electroretinogram (ERG) is an electrophysiologic recording technique used to measure electrical activity of the entire retina. The electrochemical potential of retinal cells change in response to light, which in turn induces voltage on an electrode placed on the cornea and/or sclera. The first ERGs were recorded by a Swedish physiologist working in the mid-1800's in amphibian retina. Since this time the technique has been widely incorporated in clinical practice as a diagnostic tool. Marriage of physiology to engineering has led to a variety of stimuli and analysis paradigms which can tease out specific cellular responses or region specific information. The latter has been motivated by the fact that the topographical organization of the retina plays an important role in disease with different diseases being characterized by different affected retinal areas. Early attempts to evaluate the function of specific retinal regions using the ERG illuminated only a small patch of retina, however, such "focal ERGs" have the drawback that light reflected from the focal area onto other retinal regions produces an ERG response that cannot be uncoupled from that produced by the region of interest. The other problem is that obtaining any type of a topographical map of retinal function using the mono-focal approach is prohibited by the time required to obtain ERGs serially from many different retinal regions. Both problems have been solved with the development of the multifocal- (mf-) ERG, pioneered by Erich Sutter in the early 1990s (Sutter, 1991). Mf-ERGs perform a series of individual focal ERG experiments simultaneously by taking advantage of either (1) correlation techniques or (2) frequency encoding. In this way, a complete topographical map of electrical responses over a large retinal region is obtained in a relatively short period of time.
[0170] The typical ERG apparatus for mf-ERGs stimulates a hexagonal patch of retina with a 20 degree radius and uses video display. More recently a display that employs white light emitting diodes (LEDs) was designed for use with a frequency encoding method for obtaining mf-ERGs. Having a stimulus that could reach further into the periphery would be useful in the early detection of retinal diseases that progress from peripheral to central retina. Additionally, individuals with normal trichromatic color vision express three distinct photopigments, or opsins, in separate classes of cone photoreceptor: short- (S-), middle- (M-), and long- (L-) wavelength sensitive. The S-cones are maximally sensitive to short wavelengths of light near 420 nm; M-cones have their maximal response near 530 nm; and the L-cones are most sensitive near 560 nm. Thus, an mf-ERG stimulus containing LEDs of different wavelengths would have applications in characterizing the topography of expression of the different opsin transgenes in the eyes of living subjects treated with gene therapy.
[0171] In particular, in gene therapy treatments administering recombinant adeno-associated virus (rAAV) carrying a human L-opsin gene M-opsin gene or S-opsin gene to primates that have two cone types to produce trichromatic color vision. As such, a non-invasive objective method is needed to determine the locations of functioning opsin expression in vivo.
[0172] Here we describe a wide-field color mf-ERG capable of stimulating a radius greater than 70 degrees. The wide field mf-ERG has a colored LED-based stimulus that incorporates a new design capable of maintaining viable signal-to-noise ratio (SNR) out into the far peripheral retina.
mf-ERG and Stimulus Panel
[0173] An LEDs as a light source was chosen because new advancements in LED technology allow for a large number of focused photons to be emitted from a point source. Additionally, LEDs are available in a variety of single peak narrow-bandwidth packages. The stimulus contained 1024 doublet pixels each containing a red (653 nm, half-bandwidth 22 nm, FIG. 2.1c) and a green (527 nm, half-bandwidth 33 nm, FIG. 2.1d) LED. Thus, the new display had 2,048 paired green and red LEDs. LEDs have inherent manufacturing variations in their breakdown resistance. Since the amount of current is proportional to the number of photons per unit time, applying a constant voltage across the LEDs would result in varying photon output. To circumvent these issues and ensure repeatability and linearity, constant current integrated circuit chips (Allegro A6276) were used to drive the LEDs (FIG. 2.1b). These devices are designed to maintain constant current despite fluctuations in anode voltage. To prevent variation in peak wavelength over varied intensities, a pulse frequency modulation (PFM) signal was used (Swanson, Ueno, Smith, & Pokorny, 1987).
[0174] Using red and green LEDs, it is possible to isolate responses of L- or M-cones using silent substitution. Integrating the spectral composition of the green LED with the spectral sensitivity curves of the human M- and L- photopigments (FIG. 2.1e) yields that approximately equal quanta are caught by both photopigments (FIG. 2.1f). In contrast, the red LED is six times more effective at stimulating the L photopigment than it is the M (FIG. 2.1f). Isolation of responses that are due to transduction from an introduced L-opsin transgene, M-opsin transgene or S-opsin transgene are straightforward in primates because red, blue or green LEDs can be chosen that are much more effective for the L-opsin M-opsin or S-opsin transgene respectively than for the endogenous pigments of the untreated dichromatic primates. In the case of Squirrel monkeys, they have S-cones maximally sensitive near 430 nm, and they can express any of several variants of middle-to-long wavelength opsin including L or M. The monkey used in validation experiments had M-cones sensitive near 532 nm, in addition to his S-cones. Thus, following the administration of the L-opsin transgene via subretinal injection, the mf-ERGs of squirrel monkey were predicted to show elevations in mf-ERG amplitude to red light in regions corresponding areas of the retina transduced, and distal areas would show progressively lower amplitudes to the L-cone isolating stimulus.
[0175] Resolution of the stimulator was 1024 LED over a larger stimulating area of about 150 degrees of visual field. Sensitivity of the measurement can be increased by summing more retinal responses per unit area and by using ultra-bright LEDs. Other new techniques that were used to prevent peripheral SNR fall-off included the use of trapezoidal shaped printed circuit boards that when placed edge-to-edge created a geodesic dome (FIG. 2.1a). The advantage of this design was that LEDs were held equidistantly from and pointing toward a single focal point where the subject's pupil was positioned. Any variation in directionality caused by imperfect sphericity was corrected by aiming each LED individually. In the typical usage, LEDs from areas of the dome shaped stimulator were summed so that there were 37 individual segments, which together subtended the 150° of visual angle, thus allowing a wide-field functional map of an area covering almost the entire retina to be produced.
[0176] There are two mathematical methodologies available to code and decode the topographical regions on the recording electrode: One is a cross-correlation technique called m-sequence and the other is a frequency encoding technique called cyclic summation. Cyclic summation is preferred in our application because it has been empirically shown to provide higher signal-to-noise ratio than m-sequence (Lindenberg, Horn, & Korth, 2003). Also, cyclic summation cannot be done using any kind of conventional CRT or LCD video display. Cyclic summation requires independent control of every segment of the display. Conventional video displays update the entire screen with every video frame typically at 60 Hz. In cyclic summation, each segment being analyzed is updating at a slightly different frequency. Typically, the "center frequency" is 30 Hz but each segment fractionally differenent from 30 Hz, i.e., 30.00 Hz, 30.10 Hz, 30.20 . . . etc. In the analysis, responses to different areas of the retina to different segment frequencies are used to generate a map of retinal responses which are read out as electrophysiological "activity." For example, after gene therapy using an L opsin gene in a primate retina containing only M and S cones, areas of retina that express the newly introduced L opsin will have higher electrical activity in response to the red LED light relative to the green light than areas of the retina not expressing the transgene. This allows the effectiveness of the gene therapy in terms of areas responding their time course to be monitored with an objective measure.
[0177] In practice, we define the following parameters; fc=center frequency, T=total time, Q=number of segments, and n=0. . . (Q-1). The number of cycles per segment is given by
cycles n = f c T - [ Q - 1 2 + n ] . ( 2.1 ) ##EQU00001##
Then, fn represents the frequencies at which each segment is encoded into the stimulus is
f n = cycles n T . ( 2.2 ) ##EQU00002##
Finally, by windowing and summing the recorded retinal waveform, defined as w(t), region specific signal, Activityn, can be extracted in equation 2.3,
Activity n = n = 0 ( Q - 1 ) m = 0 ( cycles n - 1 ) w ( m f n ( m + 1 ) f n ) . ( 2.3 ) ##EQU00003##
For our purposes, fc=30 Hz, T=40 seconds, and Q=37. In the retina, an additional advantage of the cyclic summation method are that the intensity and temporal frequency of the LEDs can be specified to isolate cone photoreceptor responses and silence rod photoreceptor responses.
Repeatability, Linearity, and SNR
[0178] Measurements for repeatability and linearity were made using a UDT S370 Optometer (UDT Instruments, San Diego, Calif.). LED outputs were measured in microwatts (uW) at seven different intensity settings, in random order. Three complete sets of data were taken on three separate days. All measurements were taken after the instrument became equilibrated with the ambient room temperature, which reflects normal operation of the instrument.
[0179] Signal-to-noise ratio was measured using a human subject by first placing an opaque material in front of the stimulus and running successive mf-ERGs. Voltages received during the blocked trials were taken as the noise of the instrument. Signal was then measured by performing mf-ERGs on four human subjects with normal trichromatic color vision. To compare SNR as a function of eccentricity, signal and noise were broken into different eccentric rings. Best subject and the average of all subjects were calculated for each ring. Tests involving human subjects were done in accordance with the principles embodied in the Declaration of Helsinki
Viral Vector and Subretinal Injections
[0180] To validate whether the instrument operated as expected, a mixture of two recombinant adeno-associated viruses was injected sub-retinally in a gerbil (Meriones unguiculatus) and a squirrel monkey (Saimiri sciureus). One virus, rAAV.CHOPS2053.GFP, carried a gene for green fluorescent protein (GFP) and the other virus, rAAV.CHOPS2053.RHLOPS, coded for human L-opsin. The L-opsin virus was identical to the GFP virus except that a Not I restriction fragment containing the coding sequence for green fluorescent protein was replaced with a 1.2 kb Not I restriction fragment containing recombinant human L opsin cDNA. The opsin gene encoded a human L pigment that is predicted from the deduced amino acid sequence to be maximally sensitive to 562 nm light. In order to provide a method for visualizing transduced cone photoreceptors using immunohistochemistry in future experiments, the sequence of the human L opsin transgene was changed so that the last 12 amino acids matched the known epitope for the monoclonal antibody OS-2. This antibody was previously shown to specifically label S or UV cones in mammalian and primate retina. The C-terminal 12 amino acids of human S opsin were demonstrated to be the epitope. The substitution of the C-terminal 12 amino acids of S-opsin into L-opsin is not predicted to change the spectral sensitivity of the L-opsin trans-gene product.
[0181] Subretinal injections were performed. Briefly, gerbils were anesthetized using a combination of Ketamine (50 mg/kg) and Xylazine (2 mg/kg), and it received two 5 uL subretinal injections of a 1:1 (volume:volume) mixture of rAAV.CHOPS2053.GFP and rAAV.CHOPS2053.RHLOPS that were placed in the superior retinal area. A color mf-ERG was then performed on this animal at 6 months post-injection. Squirrel monkeys was anesthetized using 15 mg/kg ketamine and 2 mg/kg xylazine, and they received two 100 uL subretinal injections of a virus mixture containing 110 uL of rAAV.CHOPS2053.GFP and 220 uL of rAAV.CHOPS2053.RHLOPS. Both injections were positioned near the fovea, with the first injection placed superiorly, and the second injection placed in the inferotemporal region of the retina. A color mf-ERG was performed on this animal about 42 weeks, or 10.5 months post-injection. All of these procedures were conducted in accordance with the experimental animal care and usage guidelines of the United States National Institutes of Health.
Fundus Exams
[0182] Both the gerbil and squirrel monkey had fundus images taken at multiple time points post-injection to observe expression of the GFP transgene over time. Fundus images were obtained using the fluorescein angiography mode of the RetCam II digital imaging system (Massie Laboratories, Pleasanton, Calif. For the gerbil, images were taken with a lens designed for detecting retinopathy in premature infants, which provides a 130° field of view, and for the monkey, a high magnification 30° lens was used. Thus, multiple fundus images from the squirrel monkey were pieced together into a montage, in order to show a comparable retinal area.
Results
[0183] Measures of repeatability, linearity, and signal-to-noise ratio (SNR) were performed to evaluate the wide-field color ERG system. More properly, given n=2 . . . 8, m=1/2n, and t=[0, ˜3.5, 7] days, then intensity, Im(t), is said to be repeatable if
s = 3 1 2 t = 1 3 ( I m ( t ) - I m ( t ) _ ) 2 ≦ ( 2.4 ) ##EQU00004##
where ε is defined as
ε=0.05max(photonm). (2.5)
The instrument was said to be linear if Pearson's R2 was greater than 0.95. And finally, signal (in SNR) was is calculated by averaging response from four subjects, and noise was taken as the residual signal while an opaque material blocked stimulus.
[0184] Repeatability and linearity are demonstrated in FIG. 2.2. Each data point is an average of optometer measurements for the particular intensity setting taken on three separate days; error bars are the standard deviations with a 99.7% confidence interval. Pearson's R correlation was calculated and the coefficient of determination (R2) values is shown. The red LEDs shared 0.9987 total variance and the green LEDs shared 0.9996 total variance demonstrating system is linear and repeatable over time. SNR values are shown in Table 2.1. The SNR was high for the inner segments of the stimulus panel; it decreased in more peripheral regions but remained high enough to allow measurements into the far periphery.
[0185] Because the GFP-coding virus and the L-opsin-coding virus were injected together at the same locations, fluorescence fundus images could be registered with mf-ERG data from the same animal in order to validate the redesigned wide-field color mf-ERG system. Areas of high GFP expression corresponded well to areas of high mf-ERG voltage in response to the L-cone isolating red stimulus (FIG. 2.3). Animals were insensitive to the red 653 nm wave-length light prior to injection, verifying that the signal measured in animals post-injection is true signal coming from the introduced L-opsin transgene product. In the squirrel monkey, the red-light mf-ERG data showed high voltage in the regions that corresponded to the fluorescence fundus images.
[0186] To evaluate whether the concave surface of the newly developed stimulator produces ERG amplitudes that are relatively constant with retinal eccentricity an experiment was performed in which flicker ERG responses were measured under two different conditions. In FIG. 2.4, the circles represent ERG responses from an LED traveling down a linear path while the subject fixated forward. On the same graph, triangles represent ERG responses from an LED traveling on a rotating boom while the subject fixated forward. The boom held the LEDs perpendicular to the cornea. Results from this experiment demonstrate the increase in signal given by the convex stimulator, compared to a traditional flat-panel LCD screen or CRT monitor. The curved stimulus design, in addition to the use of ultra-bright LEDs as the light source, increased the SNR sufficiently high in the far periphery to ensure viable signals were recorded from cone photoreceptors.
[0187] In the conventional mf-ERG, the signal amplitudes are greatly reduced in the periphery because the illumination from a flat screen falls off roughly as the cosine with increasing eccentricity. In our design, the redesigned stimulus had concave structure holding the LEDs such that the inner surface pointed perpendicular to the stimulated retinal area. In addition, similar to traditional mf-ERG stimulators, the number of LEDs in each segment was increased with eccentricity to compensate for the decrease in cone density.
[0188] If 40% of cones express the transgene the increase in red sensitivity should be that expected from a spectral ERG in which 20% of the total ERG contribution is from L opsin while 80% is from M opsin. This is consistent with the observed red sensitivity in both monkeys and gerbils.
[0189] This is the first time that measurements from cones in the far peripheral retina have been achieved. Results from these experiments indicate that the wide-field color mf-ERG system is a valid technique for measuring the topography of opsin expression in living subjects, and it will serve as an important tool for evaluating success of gene therapy in humans.
REFERENCES FOR EXAMPLE 2
[0190] Sutter, E. E. (1991). The Fast m-Transform: A Fast Computation of Cross-Correlations with Binary m-Sequences. SIAM Journal on Computing, 20(4), 686-694. [0191] Swanson, W. H., Ueno, T., Smith, V. C., & Pokorny, J. (1987). Temporal modulation sensitivity and pulse-detection thresholds for chromatic and luminance perturbations. Journal of the Optical Society of America A--Optics, Image Science and Vision, 4(10), 13. [0192] Lindenberg, T., Horn, F. K., & Korth, M. (2003). Cyclic summation versus m-sequence technique in the multifocal ERG. Graefes Archive of Clinical Experimental Ophthalmology., 241(6), 505-510.
Sequence CWU
1
511494DNAArtificial SequenceSynthetic 1ggatccggtt ccaggcctcg gccctaaata
gtctccctgg gctttcaaga gaaccacatg 60agaaaggagg attcgggctc tgagcagttt
caccacccac cccccagtct gcaaatcctg 120acccgtgggt ccacctgccc caaaggcgga
cgcaggacag tagaagggaa cagagaacac 180ataaacacag agagggccac agcggctccc
acagtcaccg ccaccttcct ggcggggatg 240ggtggggcgt ctgagtttgg ttcccagcaa
atccctctga gccgcccttg cgggctcgcc 300tcaggagcag gggagcaaga ggtgggagga
ggaggtctaa gtcccaggcc caattaagag 360atcaggtagt gtagggtttg ggagctttta
aggtgaagag gcccgggctg atcccacagg 420ccagtataaa gcgccgtgac cctcaggtga
tgcgccaggg ccggctgccg tcggggacag 480ggctttccat agcc
4942494DNAArtificial SequenceSynthetic
2ttatttagta gaaacggggt ttcaccatgt tagtcaggct ggtcgggaac tcctgacctc
60aggagatcta cccgccttgg cctcccaaag tgctgggatt acaggcgtgt gccactgtgc
120ccagccactt ttttttagac agagtcttgg tctgttgccc aggctagagt tcagtggcgc
180catctcagct cactgcaacc tccgcctccc agattcaagc gattctcctg cctcgacctc
240ccagtagctg ggattacagg tttccagcaa atccctctga gccgcccccg ggggctcgcc
300tcaggagcaa ggaagcaagg ggtgggagga ggaggtctaa gtcccaggcc caattaagag
360atcagatggt gtaggatttg ggagctttta aggtgaagag gcccgggctg atcccactgg
420ccggtataaa gcaccgtgac cctcaggtga cgcaccaggg ccggctgccg tcggggacag
480ggctttccat agcc
4943568DNAArtificial SequenceSynthetic 3ctaggcattg tcaagttgcc taagtcctgt
tccatcaagg ctgtttactg atgtgcttcc 60agggcactcc ccactcccag ccctttcctg
cagcccaggg ctggttccta gcctctcagc 120agacttaaga tgggcacctt ccacaaaggg
gcagatgagt tgaggaaaac ttaactgata 180cagttgtgcc agaagccaaa ataagaggcg
tgccctttct atagccccat taaaagaaca 240aaaaagtgga agcatcttca gtgaatatgg
gtcagcacct cccagacctc agggagtcca 300cttctgttca tcccagcacc cagcattgca
tatccagatt atttgagccc aatctcttat 360cctctgaaga acacaatcgg ctttggggcc
acaaaaggtt taggtagtgg tttagggatt 420tctaatccca aactttgtcc ttgggaggtt
taggattagt attgatcatt cacagagccc 480aagtgttttt agaggagggg ttttgtgggg
tgggaggatc acctataaga ggactcagag 540gggggtgtgg ggcatccatg agaaaaat
56841555DNAArtificial SequenceSynthetic
4ccagggtgag attatgaggc tgagctgaga atatcaagac tgtaccgagt agggggcctt
60ggcaagtgtg gagagcccgg cagctggggc agagggcgga gtacggtgtg cgtttacgga
120cctcttcaaa cgaggtagga aggtcagaag tcaaaaaggg aacaaatgat gtttaaccac
180acaaaaatga aaatccaatg gttggatatc cattccaaat acacaaaggc aacggataag
240tgatccgggc caggcacaga aggccatgca cccgtaggat tgcactcaga gctcccaaat
300gcataggaat agaagggtgg gtgcaggagg ctgaggggtg gggaaagggc atgggtgttt
360catgaggaca gagcttccgt ttcatgcaat gaaaagagtt tggagacgga tggtggtgac
420tggactatac acttacacac ggtagcgatg gtacactttg tattatgtat attttaccac
480gatcttttta aagtgtcaaa ggcaaatggc caaatggttc cttgtcctat agctgtagca
540gccatcggct gttagtgaca aagcccctga gtcaagatga cagcagcccc cataactcct
600aatcggctct cccgcgtgga gtcatttagg agtagtcgca ttagagacaa gtccaacatc
660taatcttcca ccctggccag ggccccagct ggcagcgagg gtgggagact ccgggcagag
720cagagggcgc tgacattggg gcccggcctg gcttgggtcc ctctggcctt tccccagggg
780ccctctttcc ttggggcttt cttgggccgc cactgctccc gctcctctcc ccccatccca
840ccccctcacc ccctcgttct tcatatcctt ctctagtgct ccctccactt tcatccaccc
900ttctgcaaga gtgtgggacc acaaatgagt tttcacctgg cctggggaca cacgtgcccc
960cacaggtgct gagtgacttt ctaggacagt aatctgcttt aggctaaaat gggacttgat
1020cttctgttag ccctaatcat caattagcag agccggtgaa ggtgcagaac ctaccgcctt
1080tccaggcctc ctcccacctc tgccacctcc actctccttc ctgggatgtg ggggctggca
1140cacgtgtggc ccagggcatt ggtgggattg cactgagctg ggtcattagc gtaatcctgg
1200acaagggcag acagggcgag cggagggcca gctccggggc tcaggcaagg ctgggggctt
1260cccccagaca ccccactcct cctctgctgg acccccactt catagggcac ttcgtgttct
1320caaagggctt ccaaatagca tggtggcctt ggatgcccag ggaagcctca gagttgctta
1380tctccctcta gacagaaggg gaatctcggt caagagggag aggtcgccct gttcaaggcc
1440acccagccag ctcatggcgg taatgggaca aggctggcca gccatcccac cctcagaagg
1500gacccggtgg ggcaggtgat ctcagaggag gctcacttct gggtctcaca ttctt
15555189DNAArtificial SequenceSynthetic 5gatccggtac tcgaggaact gaaaaaccag
aaagttaact ggtaagttta gtctttttgt 60cttttatttc aggtcccgga tccggtggtg
gtgcaaatca aagaactgct cctcagtgga 120tgttgccttt acttctaggc ctgtacggaa
gtgttacttc tgctctaaaa gctgcggaat 180tgtacccgc
18961114DNAHomo sapiens 6atgagaaaaa
tgtcggagga agagttttat ctgttcaaaa atatctcttc agtggggccg 60tgggatgggc
ctcagtacca cattgcccct gtctgggcct tctacctcca ggcagctttc 120atgggcactg
tcttccttat agggttccca ctcaatgcca tggtgctggt ggccacactg 180cgctacaaaa
agttgcggca gcccctcaac tacattctgg tcaacgtgtc cttcggaggc 240ttcctcctct
gcatcttctc tgtcttccct gtcttcgtcg ccagctgtaa cggatacttc 300gtcttcggtc
gccatgtttg tgctttggag ggcttcctgg gcactgtagc aggtctggtt 360acaggatggt
cactggcctt cctggccttt gagcgctaca ttgtcatctg taagcccttc 420ggcaacttcc
gcttcagctc caagcatgca ctgacggtgg tcctggctac ctggaccatt 480ggtattggcg
tctccatccc acccttcttt ggctggagcc ggttcatccc tgagggcctg 540cagtgttcct
gtggccctga ctggtacacc gtgggcacca aataccgcag cgagtcctat 600acgtggttcc
tcttcatctt ctgcttcatt gtgcctctct ccctcatctg cttctcctac 660actcagctgc
tgagggccct gaaagctgtt gcagctcagc agcaggagtc agctacgacc 720cagaaggctg
aacgggaggt gagccgcatg gtggttgtga tggtaggatc cttctgtgtc 780tgctacgtgc
cctacgcggc cttcgccatg tacatggtca acaaccgtaa ccatgggctg 840gacttacggc
ttgtcaccat tccttcattc ttctccaaga gtgcttgcat ctacaatccc 900atcatctact
gcttcatgaa taagcagttc caagcttgca tcatgaagat ggtgtgtggg 960aaggccatga
cagatgaatc cgacacatgc agctcccaga aaacagaagt ttctactgtc 1020tcgtctaccc
aagttggccc caactgagga cccaatattg gcctgtttgc aacagctaga 1080attaaatttt
acttttaaaa aaaaaaaaaa aaaa 11147348PRTHomo
sapiens 7Met Arg Lys Met Ser Glu Glu Glu Phe Tyr Leu Phe Lys Asn Ile Ser1
5 10 15Ser Val Gly Pro
Trp Asp Gly Pro Gln Tyr His Ile Ala Pro Val Trp 20
25 30Ala Phe Tyr Leu Gln Ala Ala Phe Met Gly Thr
Val Phe Leu Ile Gly 35 40 45Phe
Pro Leu Asn Ala Met Val Leu Val Ala Thr Leu Arg Tyr Lys Lys 50
55 60Leu Arg Gln Pro Leu Asn Tyr Ile Leu Val
Asn Val Ser Phe Gly Gly65 70 75
80Phe Leu Leu Cys Ile Phe Ser Val Phe Pro Val Phe Val Ala Ser
Cys 85 90 95Asn Gly Tyr
Phe Val Phe Gly Arg His Val Cys Ala Leu Glu Gly Phe 100
105 110Leu Gly Thr Val Ala Gly Leu Val Thr Gly
Trp Ser Leu Ala Phe Leu 115 120
125Ala Phe Glu Arg Tyr Ile Val Ile Cys Lys Pro Phe Gly Asn Phe Arg 130
135 140Phe Ser Ser Lys His Ala Leu Thr
Val Val Leu Ala Thr Trp Thr Ile145 150
155 160Gly Ile Gly Val Ser Ile Pro Pro Phe Phe Gly Trp
Ser Arg Phe Ile 165 170
175Pro Glu Gly Leu Gln Cys Ser Cys Gly Pro Asp Trp Tyr Thr Val Gly
180 185 190Thr Lys Tyr Arg Ser Glu
Ser Tyr Thr Trp Phe Leu Phe Ile Phe Cys 195 200
205Phe Ile Val Pro Leu Ser Leu Ile Cys Phe Ser Tyr Thr Gln
Leu Leu 210 215 220Arg Ala Leu Lys Ala
Val Ala Ala Gln Gln Gln Glu Ser Ala Thr Thr225 230
235 240Gln Lys Ala Glu Arg Glu Val Ser Arg Met
Val Val Val Met Val Gly 245 250
255Ser Phe Cys Val Cys Tyr Val Pro Tyr Ala Ala Phe Ala Met Tyr Met
260 265 270Val Asn Asn Arg Asn
His Gly Leu Asp Leu Arg Leu Val Thr Ile Pro 275
280 285Ser Phe Phe Ser Lys Ser Ala Cys Ile Tyr Asn Pro
Ile Ile Tyr Cys 290 295 300Phe Met Asn
Lys Gln Phe Gln Ala Cys Ile Met Lys Met Val Cys Gly305
310 315 320Lys Ala Met Thr Asp Glu Ser
Asp Thr Cys Ser Ser Gln Lys Thr Glu 325
330 335Val Ser Thr Val Ser Ser Thr Gln Val Gly Pro Asn
340 34581998DNAHomo sapiens 8cccactggcc
ggtataaagc accgtgaccc tcaggtgacg caccagggcc ggctgccgtc 60ggggacaggg
ctttccatag ccatggccca gcagtggagc ctccaaaggc tcgcaggccg 120ccatccgcag
gacagctatg aggacagcac ccagtccagc atcttcacct acaccaacag 180caactccacc
agaggcccct tcgaaggccc gaattaccac atcgctccca gatgggtgta 240ccacctcacc
agtgtctgga tgatctttgt ggtcattgca tccgtcttca caaatgggct 300tgtgctggcg
gccaccatga agttcaagaa gctgcgccac ccgctgaact ggatcctggt 360gaacctggcg
gtcgctgacc tggcagagac cgtcatcgcc agcactatca gcgttgtgaa 420ccaggtctat
ggctacttcg tgctgggcca ccctatgtgt gtcctggagg gctacaccgt 480ctccctgtgt
gggatcacag gtctctggtc tctggccatc atttcctggg agagatggat 540ggtggtctgc
aagccctttg gcaatgtgag atttgatgcc aagctggcca tcgtgggcat 600tgccttctcc
tggatctggg ctgctgtgtg gacagccccg cccatctttg gttggagcag 660gtactggccc
cacggcctga agacttcatg cggcccagac gtgttcagcg gcagctcgta 720ccccggggtg
cagtcttaca tgattgtcct catggtcacc tgctgcatca ccccactcag 780catcatcgtg
ctctgctacc tccaagtgtg gctggccatc cgagcggtgg caaagcagca 840gaaagagtct
gaatccaccc agaaggcaga gaaggaagtg acgcgcatgg tggtggtgat 900ggtcctggca
ttctgcttct gctggggacc atacgccttc ttcgcatgct ttgctgctgc 960caaccctggc
taccccttcc accctttgat ggctgccctg ccggccttct ttgccaaaag 1020tgccactatc
tacaaccccg ttatctatgt ctttatgaac cggcagtttc gaaactgcat 1080cttgcagctt
ttcgggaaga aggttgacga tggctctgaa ctctccagcg cctccaaaac 1140ggaggtctca
tctgtgtcct cggtatcgcc tgcatgaggt ctgcctccta cccatcccgc 1200ccaccggggc
tttggccacc tctcctttcc ccctccttct ccatccctgt aaaataaatg 1260taatttatct
ttgccaaaac caacaaagtc acagaggctt tcactgcagt gtgggaccac 1320ctgagcctct
gcgtgtgcag gcactgggtc tcgagagggt gcaaggggga taaagaggag 1380agagcgcttc
atagacttta agttttcccg agcctcatgt ctaccgatgg cgtgaaagga 1440tcctggcaaa
acagaagtgt gaggcaggtg ggcgtctata tccatttcac caggctggtg 1500gttacataat
cggcaagcaa gagctgtgga ggggcttgct ggatgccctc agcacccagg 1560aggagggagg
gagctagcaa gctaaggcag gtggccctcc tggcccctta aggtccatct 1620gctggaggcc
cagagtcctt ggagtacagt ctacacctgg aggggaccca ttcctgccag 1680tctgtggcag
ggatggcgcg ccacctctgc caggccagga ccccaagccc gatcagcatc 1740agcatggtgc
aggtgcacag gcgtgagctg atcagtgacg aggggcaggc acacaaggtg 1800gagacaaaga
ccaagaggac ggttgccagt gagaggcgcg gactcaggaa cttgaacaac 1860atctgcgggg
gacggctttg gaggtgctcc gctgcctcca gttgggtgac ttgctgtagc 1920atctccagct
tggatattcg gctcttgaag gtctccgtga tctcctgcag gagacgaaaa 1980tgcacgcacc
agaagtca 19989364PRTHomo
sapiens 9Met Ala Gln Gln Trp Ser Leu Gln Arg Leu Ala Gly Arg His Pro Gln1
5 10 15Asp Ser Tyr Glu
Asp Ser Thr Gln Ser Ser Ile Phe Thr Tyr Thr Asn 20
25 30Ser Asn Ser Thr Arg Gly Pro Phe Glu Gly Pro
Asn Tyr His Ile Ala 35 40 45Pro
Arg Trp Val Tyr His Leu Thr Ser Val Trp Met Ile Phe Val Val 50
55 60Ile Ala Ser Val Phe Thr Asn Gly Leu Val
Leu Ala Ala Thr Met Lys65 70 75
80Phe Lys Lys Leu Arg His Pro Leu Asn Trp Ile Leu Val Asn Leu
Ala 85 90 95Val Ala Asp
Leu Ala Glu Thr Val Ile Ala Ser Thr Ile Ser Val Val 100
105 110Asn Gln Val Tyr Gly Tyr Phe Val Leu Gly
His Pro Met Cys Val Leu 115 120
125Glu Gly Tyr Thr Val Ser Leu Cys Gly Ile Thr Gly Leu Trp Ser Leu 130
135 140Ala Ile Ile Ser Trp Glu Arg Trp
Met Val Val Cys Lys Pro Phe Gly145 150
155 160Asn Val Arg Phe Asp Ala Lys Leu Ala Ile Val Gly
Ile Ala Phe Ser 165 170
175Trp Ile Trp Ala Ala Val Trp Thr Ala Pro Pro Ile Phe Gly Trp Ser
180 185 190Arg Tyr Trp Pro His Gly
Leu Lys Thr Ser Cys Gly Pro Asp Val Phe 195 200
205Ser Gly Ser Ser Tyr Pro Gly Val Gln Ser Tyr Met Ile Val
Leu Met 210 215 220Val Thr Cys Cys Ile
Thr Pro Leu Ser Ile Ile Val Leu Cys Tyr Leu225 230
235 240Gln Val Trp Leu Ala Ile Arg Ala Val Ala
Lys Gln Gln Lys Glu Ser 245 250
255Glu Ser Thr Gln Lys Ala Glu Lys Glu Val Thr Arg Met Val Val Val
260 265 270Met Val Leu Ala Phe
Cys Phe Cys Trp Gly Pro Tyr Ala Phe Phe Ala 275
280 285Cys Phe Ala Ala Ala Asn Pro Gly Tyr Pro Phe His
Pro Leu Met Ala 290 295 300Ala Leu Pro
Ala Phe Phe Ala Lys Ser Ala Thr Ile Tyr Asn Pro Val305
310 315 320Ile Tyr Val Phe Met Asn Arg
Gln Phe Arg Asn Cys Ile Leu Gln Leu 325
330 335Phe Gly Lys Lys Val Asp Asp Gly Ser Glu Leu Ser
Ser Ala Ser Lys 340 345 350Thr
Glu Val Ser Ser Val Ser Ser Val Ser Pro Ala 355
360101234DNAHomo sapiens 10cggctgccgt cggggacagg gctttccata gccatggccc
agcagtggag cctccaaagg 60ctcgcaggcc gccatccgca ggacagctat gaggacagca
cccagtccag catcttcacc 120tacaccaaca gcaactccac cagaggcccc ttcgaaggcc
cgaattacca catcgctccc 180agatgggtgt accacctcac cagtgtctgg atgatctttg
tggtcactgc atccgtcttc 240acaaatgggc ttgtgctggc ggccaccatg aagttcaaga
agctgcgcca cccgctgaac 300tggatcctgg tgaacctggc ggtcgctgac ctagcagaga
ccgtcatcgc cagcactatc 360agcattgtga accaggtctc tggctacttc gtgctgggcc
accctatgtg tgtcctggag 420ggctacaccg tctccctgtg tgggatcaca ggtctctggt
ctctggccat catttcctgg 480gagaggtggc tggtggtgtg caagcccttt ggcaatgtga
gatttgatgc caagctggcc 540atcgtgggca ttgccttctc ctggatctgg tctgctgtgt
ggacagcccc gcccatcttt 600ggttggagca ggtactggcc ccacggcctg aagacttcat
gcggcccaga cgtgttcagc 660ggcagctcgt accccggggt gcagtcttac atgattgtcc
tcatggtcac ctgctgcatc 720atcccactcg ctatcatcat gctctgctac ctccaagtgt
ggctggccat ccgagcggtg 780gcaaagcagc agaaagagtc tgaatccacc cagaaggcag
agaaggaagt gacgcgcatg 840gtggtggtga tgatctttgc gtactgcgtc tgctggggac
cctacacctt cttcgcatgc 900tttgctgctg ccaaccctgg ttacgccttc caccctttga
tggctgccct gccggcctac 960tttgccaaaa gtgccactat ctacaacccc gttatctatg
tctttatgaa ccggcagttt 1020cgaaactgca tcttgcagct tttcgggaag aaggttgacg
atggctctga actctccagc 1080gcctccaaaa cggaggtctc atctgtgtcc tcggtatcgc
ctgcatgagg tctgcctcct 1140acccatcccg cccaccgggg ctttggccac ctctcctttc
cccctccttc tccatccctg 1200taaaataaat gtaatttatc tttgccaaaa ccaa
123411364PRTHomo sapiens 11Met Ala Gln Gln Trp Ser
Leu Gln Arg Leu Ala Gly Arg His Pro Gln1 5
10 15Asp Ser Tyr Glu Asp Ser Thr Gln Ser Ser Ile Phe
Thr Tyr Thr Asn 20 25 30Ser
Asn Ser Thr Arg Gly Pro Phe Glu Gly Pro Asn Tyr His Ile Ala 35
40 45Pro Arg Trp Val Tyr His Leu Thr Ser
Val Trp Met Ile Phe Val Val 50 55
60Thr Ala Ser Val Phe Thr Asn Gly Leu Val Leu Ala Ala Thr Met Lys65
70 75 80Phe Lys Lys Leu Arg
His Pro Leu Asn Trp Ile Leu Val Asn Leu Ala 85
90 95Val Ala Asp Leu Ala Glu Thr Val Ile Ala Ser
Thr Ile Ser Ile Val 100 105
110Asn Gln Val Ser Gly Tyr Phe Val Leu Gly His Pro Met Cys Val Leu
115 120 125Glu Gly Tyr Thr Val Ser Leu
Cys Gly Ile Thr Gly Leu Trp Ser Leu 130 135
140Ala Ile Ile Ser Trp Glu Arg Trp Leu Val Val Cys Lys Pro Phe
Gly145 150 155 160Asn Val
Arg Phe Asp Ala Lys Leu Ala Ile Val Gly Ile Ala Phe Ser
165 170 175Trp Ile Trp Ser Ala Val Trp
Thr Ala Pro Pro Ile Phe Gly Trp Ser 180 185
190Arg Tyr Trp Pro His Gly Leu Lys Thr Ser Cys Gly Pro Asp
Val Phe 195 200 205Ser Gly Ser Ser
Tyr Pro Gly Val Gln Ser Tyr Met Ile Val Leu Met 210
215 220Val Thr Cys Cys Ile Ile Pro Leu Ala Ile Ile Met
Leu Cys Tyr Leu225 230 235
240Gln Val Trp Leu Ala Ile Arg Ala Val Ala Lys Gln Gln Lys Glu Ser
245 250 255Glu Ser Thr Gln Lys
Ala Glu Lys Glu Val Thr Arg Met Val Val Val 260
265 270Met Ile Phe Ala Tyr Cys Val Cys Trp Gly Pro Tyr
Thr Phe Phe Ala 275 280 285Cys Phe
Ala Ala Ala Asn Pro Gly Tyr Ala Phe His Pro Leu Met Ala 290
295 300Ala Leu Pro Ala Tyr Phe Ala Lys Ser Ala Thr
Ile Tyr Asn Pro Val305 310 315
320Ile Tyr Val Phe Met Asn Arg Gln Phe Arg Asn Cys Ile Leu Gln Leu
325 330 335Phe Gly Lys Lys
Val Asp Asp Gly Ser Glu Leu Ser Ser Ala Ser Lys 340
345 350Thr Glu Val Ser Ser Val Ser Ser Val Ser Pro
Ala 355 360127326DNAHomo sapiens 12aggacacagc
gtccggagcc agaggcgctc ttaacggcgt ttatgtcctt tgctgtctga 60ggggcctcag
ctctgaccaa tctggtcttc gtgtggtcat tagcatgggc ttcgtgagac 120agatacagct
tttgctctgg aagaactgga ccctgcggaa aaggcaaaag attcgctttg 180tggtggaact
cgtgtggcct ttatctttat ttctggtctt gatctggtta aggaatgcca 240acccgctcta
cagccatcat gaatgccatt tccccaacaa ggcgatgccc tcagcaggaa 300tgctgccgtg
gctccagggg atcttctgca atgtgaacaa tccctgtttt caaagcccca 360ccccaggaga
atctcctgga attgtgtcaa actataacaa ctccatcttg gcaagggtat 420atcgagattt
tcaagaactc ctcatgaatg caccagagag ccagcacctt ggccgtattt 480ggacagagct
acacatcttg tcccaattca tggacaccct ccggactcac ccggagagaa 540ttgcaggaag
aggaatacga ataagggata tcttgaaaga tgaagaaaca ctgacactat 600ttctcattaa
aaacatcggc ctgtctgact cagtggtcta ccttctgatc aactctcaag 660tccgtccaga
gcagttcgct catggagtcc cggacctggc gctgaaggac atcgcctgca 720gcgaggccct
cctggagcgc ttcatcatct tcagccagag acgcggggca aagacggtgc 780gctatgccct
gtgctccctc tcccagggca ccctacagtg gatagaagac actctgtatg 840ccaacgtgga
cttcttcaag ctcttccgtg tgcttcccac actcctagac agccgttctc 900aaggtatcaa
tctgagatct tggggaggaa tattatctga tatgtcacca agaattcaag 960agtttatcca
tcggccgagt atgcaggact tgctgtgggt gaccaggccc ctcatgcaga 1020atggtggtcc
agagaccttt acaaagctga tgggcatcct gtctgacctc ctgtgtggct 1080accccgaggg
aggtggctct cgggtgctct ccttcaactg gtatgaagac aataactata 1140aggcctttct
ggggattgac tccacaagga aggatcctat ctattcttat gacagaagaa 1200caacatcctt
ttgtaatgca ttgatccaga gcctggagtc aaatccttta accaaaatcg 1260cttggagggc
ggcaaagcct ttgctgatgg gaaaaatcct gtacactcct gattcacctg 1320cagcacgaag
gatactgaag aatgccaact caacttttga agaactggaa cacgttagga 1380agttggtcaa
agcctgggaa gaagtagggc cccagatctg gtacttcttt gacaacagca 1440cacagatgaa
catgatcaga gataccctgg ggaacccaac agtaaaagac tttttgaata 1500ggcagcttgg
tgaagaaggt attactgctg aagccatcct aaacttcctc tacaagggcc 1560ctcgggaaag
ccaggctgac gacatggcca acttcgactg gagggacata tttaacatca 1620ctgatcgcac
cctccgcctg gtcaatcaat acctggagtg cttggtcctg gataagtttg 1680aaagctacaa
tgatgaaact cagctcaccc aacgtgccct ctctctactg gaggaaaaca 1740tgttctgggc
cggagtggta ttccctgaca tgtatccctg gaccagctct ctaccacccc 1800acgtgaagta
taagatccga atggacatag acgtggtgga gaaaaccaat aagattaaag 1860acaggtattg
ggattctggt cccagagctg atcccgtgga agatttccgg tacatctggg 1920gcgggtttgc
ctatctgcag gacatggttg aacaggggat cacaaggagc caggtgcagg 1980cggaggctcc
agttggaatc tacctccagc agatgcccta cccctgcttc gtggacgatt 2040ctttcatgat
catcctgaac cgctgtttcc ctatcttcat ggtgctggca tggatctact 2100ctgtctccat
gactgtgaag agcatcgtct tggagaagga gttgcgactg aaggagacct 2160tgaaaaatca
gggtgtctcc aatgcagtga tttggtgtac ctggttcctg gacagcttct 2220ccatcatgtc
gatgagcatc ttcctcctga cgatattcat catgcatgga agaatcctac 2280attacagcga
cccattcatc ctcttcctgt tcttgttggc tttctccact gccaccatca 2340tgctgtgctt
tctgctcagc accttcttct ccaaggccag tctggcagca gcctgtagtg 2400gtgtcatcta
tttcaccctc tacctgccac acatcctgtg cttcgcctgg caggaccgca 2460tgaccgctga
gctgaagaag gctgtgagct tactgtctcc ggtggcattt ggatttggca 2520ctgagtacct
ggttcgcttt gaagagcaag gcctggggct gcagtggagc aacatcggga 2580acagtcccac
ggaaggggac gaattcagct tcctgctgtc catgcagatg atgctccttg 2640atgctgctgt
ctatggctta ctcgcttggt accttgatca ggtgtttcca ggagactatg 2700gaaccccact
tccttggtac tttcttctac aagagtcgta ttggcttggc ggtgaagggt 2760gttcaaccag
agaagaaaga gccctggaaa agaccgagcc cctaacagag gaaacggagg 2820atccagagca
cccagaagga atacacgact ccttctttga acgtgagcat ccagggtggg 2880ttcctggggt
atgcgtgaag aatctggtaa agatttttga gccctgtggc cggccagctg 2940tggaccgtct
gaacatcacc ttctacgaga accagatcac cgcattcctg ggccacaatg 3000gagctgggaa
aaccaccacc ttgtccatcc tgacgggtct gttgccacca acctctggga 3060ctgtgctcgt
tgggggaagg gacattgaaa ccagcctgga tgcagtccgg cagagccttg 3120gcatgtgtcc
acagcacaac atcctgttcc accacctcac ggtggctgag cacatgctgt 3180tctatgccca
gctgaaagga aagtcccagg aggaggccca gctggagatg gaagccatgt 3240tggaggacac
aggcctccac cacaagcgga atgaagaggc tcaggaccta tcaggtggca 3300tgcagagaaa
gctgtcggtt gccattgcct ttgtgggaga tgccaaggtg gtgattctgg 3360acgaacccac
ctctggggtg gacccttact cgagacgctc aatctgggat ctgctcctga 3420agtatcgctc
aggcagaacc atcatcatgt ccactcacca catggacgag gccgacctcc 3480ttggggaccg
cattgccatc attgcccagg gaaggctcta ctgctcaggc accccactct 3540tcctgaagaa
ctgctttggc acaggcttgt acttaacctt ggtgcgcaag atgaaaaaca 3600tccagagcca
aaggaaaggc agtgagggga cctgcagctg ctcgtctaag ggtttctcca 3660ccacgtgtcc
agcccacgtc gatgacctaa ctccagaaca agtcctggat ggggatgtaa 3720atgagctgat
ggatgtagtt ctccaccatg ttccagaggc aaagctggtg gagtgcattg 3780gtcaagaact
tatcttcctt cttccaaata agaacttcaa gcacagagca tatgccagcc 3840ttttcagaga
gctggaggag acgctggctg accttggtct cagcagtttt ggaatttctg 3900acactcccct
ggaagagatt tttctgaagg tcacggagga ttctgattca ggacctctgt 3960ttgcgggtgg
cgctcagcag aaaagagaaa acgtcaaccc ccgacacccc tgcttgggtc 4020ccagagagaa
ggctggacag acaccccagg actccaatgt ctgctcccca ggggcgccgg 4080ctgctcaccc
agagggccag cctcccccag agccagagtg cccaggcccg cagctcaaca 4140cggggacaca
gctggtcctc cagcatgtgc aggcgctgct ggtcaagaga ttccaacaca 4200ccatccgcag
ccacaaggac ttcctggcgc agatcgtgct cccggctacc tttgtgtttt 4260tggctctgat
gctttctatt gttatccctc cttttggcga ataccccgct ttgacccttc 4320acccctggat
atatgggcag cagtacacct tcttcagcat ggatgaacca ggcagtgagc 4380agttcacggt
acttgcagac gtcctcctga ataagccagg ctttggcaac cgctgcctga 4440aggaagggtg
gcttccggag tacccctgtg gcaactcaac accctggaag actccttctg 4500tgtccccaaa
catcacccag ctgttccaga agcagaaatg gacacaggtc aacccttcac 4560catcctgcag
gtgcagcacc agggagaagc tcaccatgct gccagagtgc cccgagggtg 4620ccgggggcct
cccgcccccc cagagaacac agcgcagcac ggaaattcta caagacctga 4680cggacaggaa
catctccgac ttcttggtaa aaacgtatcc tgctcttata agaagcagct 4740taaagagcaa
attctgggtc aatgaacaga ggtatggagg aatttccatt ggaggaaagc 4800tcccagtcgt
ccccatcacg ggggaagcac ttgttgggtt tttaagcgac cttggccgga 4860tcatgaatgt
gagcgggggc cctatcacta gagaggcctc taaagaaata cctgatttcc 4920ttaaacatct
agaaactgaa gacaacatta aggtgtggtt taataacaaa ggctggcatg 4980ccctggtcag
ctttctcaat gtggcccaca acgccatctt acgggccagc ctgcctaagg 5040acaggagccc
cgaggagtat ggaatcaccg tcattagcca acccctgaac ctgaccaagg 5100agcagctctc
agagattaca gtgctgacca cttcagtgga tgctgtggtt gccatctgcg 5160tgattttctc
catgtccttc gtcccagcca gctttgtcct ttatttgatc caggagcggg 5220tgaacaaatc
caagcacctc cagtttatca gtggagtgag ccccaccacc tactgggtga 5280ccaacttcct
ctgggacatc atgaattatt ccgtgagtgc tgggctggtg gtgggcatct 5340tcatcgggtt
tcagaagaaa gcctacactt ctccagaaaa ccttcctgcc cttgtggcac 5400tgctcctgct
gtatggatgg gcggtcattc ccatgatgta cccagcatcc ttcctgtttg 5460atgtccccag
cacagcctat gtggctttat cttgtgctaa tctgttcatc ggcatcaaca 5520gcagtgctat
taccttcatc ttggaattat ttgagaataa ccggacgctg ctcaggttca 5580acgccgtgct
gaggaagctg ctcattgtct tcccccactt ctgcctgggc cggggcctca 5640ttgaccttgc
actgagccag gctgtgacag atgtctatgc ccggtttggt gaggagcact 5700ctgcaaatcc
gttccactgg gacctgattg ggaagaacct gtttgccatg gtggtggaag 5760gggtggtgta
cttcctcctg accctgctgg tccagcgcca cttcttcctc tcccaatgga 5820ttgccgagcc
cactaaggag cccattgttg atgaagatga tgatgtggct gaagaaagac 5880aaagaattat
tactggtgga aataaaactg acatcttaag gctacatgaa ctaaccaaga 5940tttatccagg
cacctccagc ccagcagtgg acaggctgtg tgtcggagtt cgccctggag 6000agtgctttgg
cctcctggga gtgaatggtg ccggcaaaac aaccacattc aagatgctca 6060ctggggacac
cacagtgacc tcaggggatg ccaccgtagc aggcaagagt attttaacca 6120atatttctga
agtccatcaa aatatgggct actgtcctca gtttgatgca attgatgagc 6180tgctcacagg
acgagaacat ctttaccttt atgcccggct tcgaggtgta ccagcagaag 6240aaatcgaaaa
ggttgcaaac tggagtatta agagcctggg cctgactgtc tacgccgact 6300gcctggctgg
cacgtacagt gggggcaaca agcggaaact ctccacagcc atcgcactca 6360ttggctgccc
accgctggtg ctgctggatg agcccaccac agggatggac ccccaggcac 6420gccgcatgct
gtggaacgtc atcgtgagca tcatcagaga agggagggct gtggtcctca 6480catcccacag
catggaagaa tgtgaggcac tgtgtacccg gctggccatc atggtaaagg 6540gcgcctttcg
atgtatgggc accattcagc atctcaagtc caaatttgga gatggctata 6600tcgtcacaat
gaagatcaaa tccccgaagg acgacctgct tcctgacctg aaccctgtgg 6660agcagttctt
ccaggggaac ttcccaggca gtgtgcagag ggagaggcac tacaacatgc 6720tccagttcca
ggtctcctcc tcctccctgg cgaggatctt ccagctcctc ctctcccaca 6780aggacagcct
gctcatcgag gagtactcag tcacacagac cacactggac caggtgtttg 6840taaattttgc
taaacagcag actgaaagtc atgacctccc tctgcaccct cgagctgctg 6900gagccagtcg
acaagcccag gactgatctt tcacaccgct cgttcctgca gccagaaagg 6960aactctgggc
agctggaggc gcaggagcct gtgcccatat ggtcatccaa atggactggc 7020cagcgtaaat
gaccccactg cagcagaaaa caaacacacg aggagcatgc agcgaattca 7080gaaagaggtc
tttcagaagg aaaccgaaac tgacttgctc acctggaaca cctgatggtg 7140aaaccaaaca
aatacaaaat ccttctccag accccagaac tagaaacccc gggccatccc 7200actagcagct
ttggcctcca tattgctctc atttcaagca gatctgcttt tctgcatgtt 7260tgtctgtgtg
tctgcgttgt gtgtgatttt catggaaaaa taaaatgcaa atgcactcat 7320cacaaa
7326132273PRTHomo
sapiens 13Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp
Thr1 5 10 15Leu Arg Lys
Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro 20
25 30Leu Ser Leu Phe Leu Val Leu Ile Trp Leu
Arg Asn Ala Asn Pro Leu 35 40
45Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala 50
55 60Gly Met Leu Pro Trp Leu Gln Gly Ile
Phe Cys Asn Val Asn Asn Pro65 70 75
80Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val
Ser Asn 85 90 95Tyr Asn
Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu 100
105 110Leu Met Asn Ala Pro Glu Ser Gln His
Leu Gly Arg Ile Trp Thr Glu 115 120
125Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu
130 135 140Arg Ile Ala Gly Arg Gly Ile
Arg Ile Arg Asp Ile Leu Lys Asp Glu145 150
155 160Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly
Leu Ser Asp Ser 165 170
175Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala
180 185 190His Gly Val Pro Asp Leu
Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala 195 200
205Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala
Lys Thr 210 215 220Val Arg Tyr Ala Leu
Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile225 230
235 240Glu Asp Thr Leu Tyr Ala Asn Val Asp Phe
Phe Lys Leu Phe Arg Val 245 250
255Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln Gly Ile Asn Leu Arg Ser
260 265 270Trp Gly Gly Ile Leu
Ser Asp Met Ser Pro Arg Ile Gln Glu Phe Ile 275
280 285His Arg Pro Ser Met Gln Asp Leu Leu Trp Val Thr
Arg Pro Leu Met 290 295 300Gln Asn Gly
Gly Pro Glu Thr Phe Thr Lys Leu Met Gly Ile Leu Ser305
310 315 320Asp Leu Leu Cys Gly Tyr Pro
Glu Gly Gly Gly Ser Arg Val Leu Ser 325
330 335Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys Ala Phe
Leu Gly Ile Asp 340 345 350Ser
Thr Arg Lys Asp Pro Ile Tyr Ser Tyr Asp Arg Arg Thr Thr Ser 355
360 365Phe Cys Asn Ala Leu Ile Gln Ser Leu
Glu Ser Asn Pro Leu Thr Lys 370 375
380Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu Met Gly Lys Ile Leu Tyr385
390 395 400Thr Pro Asp Ser
Pro Ala Ala Arg Arg Ile Leu Lys Asn Ala Asn Ser 405
410 415Thr Phe Glu Glu Leu Glu His Val Arg Lys
Leu Val Lys Ala Trp Glu 420 425
430Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe Asp Asn Ser Thr Gln Met
435 440 445Asn Met Ile Arg Asp Thr Leu
Gly Asn Pro Thr Val Lys Asp Phe Leu 450 455
460Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr Ala Glu Ala Ile Leu
Asn465 470 475 480Phe Leu
Tyr Lys Gly Pro Arg Glu Ser Gln Ala Asp Asp Met Ala Asn
485 490 495Phe Asp Trp Arg Asp Ile Phe
Asn Ile Thr Asp Arg Thr Leu Arg Leu 500 505
510Val Asn Gln Tyr Leu Glu Cys Leu Val Leu Asp Lys Phe Glu
Ser Tyr 515 520 525Asn Asp Glu Thr
Gln Leu Thr Gln Arg Ala Leu Ser Leu Leu Glu Glu 530
535 540Asn Met Phe Trp Ala Gly Val Val Phe Pro Asp Met
Tyr Pro Trp Thr545 550 555
560Ser Ser Leu Pro Pro His Val Lys Tyr Lys Ile Arg Met Asp Ile Asp
565 570 575Val Val Glu Lys Thr
Asn Lys Ile Lys Asp Arg Tyr Trp Asp Ser Gly 580
585 590Pro Arg Ala Asp Pro Val Glu Asp Phe Arg Tyr Ile
Trp Gly Gly Phe 595 600 605Ala Tyr
Leu Gln Asp Met Val Glu Gln Gly Ile Thr Arg Ser Gln Val 610
615 620Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu Gln
Gln Met Pro Tyr Pro625 630 635
640Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro
645 650 655Ile Phe Met Val
Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys 660
665 670Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys
Glu Thr Leu Lys Asn 675 680 685Gln
Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser 690
695 700Phe Ser Ile Met Ser Met Ser Ile Phe Leu
Leu Thr Ile Phe Ile Met705 710 715
720His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu
Phe 725 730 735Leu Leu Ala
Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser 740
745 750Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala
Ala Cys Ser Gly Val Ile 755 760
765Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp 770
775 780Arg Met Thr Ala Glu Leu Lys Lys
Ala Val Ser Leu Leu Ser Pro Val785 790
795 800Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe
Glu Glu Gln Gly 805 810
815Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp
820 825 830Glu Phe Ser Phe Leu Leu
Ser Met Gln Met Met Leu Leu Asp Ala Ala 835 840
845Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Phe Pro
Gly Asp 850 855 860Tyr Gly Thr Pro Leu
Pro Trp Tyr Phe Leu Leu Gln Glu Ser Tyr Trp865 870
875 880Leu Gly Gly Glu Gly Cys Ser Thr Arg Glu
Glu Arg Ala Leu Glu Lys 885 890
895Thr Glu Pro Leu Thr Glu Glu Thr Glu Asp Pro Glu His Pro Glu Gly
900 905 910Ile His Asp Ser Phe
Phe Glu Arg Glu His Pro Gly Trp Val Pro Gly 915
920 925Val Cys Val Lys Asn Leu Val Lys Ile Phe Glu Pro
Cys Gly Arg Pro 930 935 940Ala Val Asp
Arg Leu Asn Ile Thr Phe Tyr Glu Asn Gln Ile Thr Ala945
950 955 960Phe Leu Gly His Asn Gly Ala
Gly Lys Thr Thr Thr Leu Ser Ile Leu 965
970 975Thr Gly Leu Leu Pro Pro Thr Ser Gly Thr Val Leu
Val Gly Gly Arg 980 985 990Asp
Ile Glu Thr Ser Leu Asp Ala Val Arg Gln Ser Leu Gly Met Cys 995
1000 1005Pro Gln His Asn Ile Leu Phe His
His Leu Thr Val Ala Glu His 1010 1015
1020Met Leu Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln Glu Glu Ala
1025 1030 1035Gln Leu Glu Met Glu Ala
Met Leu Glu Asp Thr Gly Leu His His 1040 1045
1050Lys Arg Asn Glu Glu Ala Gln Asp Leu Ser Gly Gly Met Gln
Arg 1055 1060 1065Lys Leu Ser Val Ala
Ile Ala Phe Val Gly Asp Ala Lys Val Val 1070 1075
1080Ile Leu Asp Glu Pro Thr Ser Gly Val Asp Pro Tyr Ser
Arg Arg 1085 1090 1095Ser Ile Trp Asp
Leu Leu Leu Lys Tyr Arg Ser Gly Arg Thr Ile 1100
1105 1110Ile Met Ser Thr His His Met Asp Glu Ala Asp
Leu Leu Gly Asp 1115 1120 1125Arg Ile
Ala Ile Ile Ala Gln Gly Arg Leu Tyr Cys Ser Gly Thr 1130
1135 1140Pro Leu Phe Leu Lys Asn Cys Phe Gly Thr
Gly Leu Tyr Leu Thr 1145 1150 1155Leu
Val Arg Lys Met Lys Asn Ile Gln Ser Gln Arg Lys Gly Ser 1160
1165 1170Glu Gly Thr Cys Ser Cys Ser Ser Lys
Gly Phe Ser Thr Thr Cys 1175 1180
1185Pro Ala His Val Asp Asp Leu Thr Pro Glu Gln Val Leu Asp Gly
1190 1195 1200Asp Val Asn Glu Leu Met
Asp Val Val Leu His His Val Pro Glu 1205 1210
1215Ala Lys Leu Val Glu Cys Ile Gly Gln Glu Leu Ile Phe Leu
Leu 1220 1225 1230Pro Asn Lys Asn Phe
Lys His Arg Ala Tyr Ala Ser Leu Phe Arg 1235 1240
1245Glu Leu Glu Glu Thr Leu Ala Asp Leu Gly Leu Ser Ser
Phe Gly 1250 1255 1260Ile Ser Asp Thr
Pro Leu Glu Glu Ile Phe Leu Lys Val Thr Glu 1265
1270 1275Asp Ser Asp Ser Gly Pro Leu Phe Ala Gly Gly
Ala Gln Gln Lys 1280 1285 1290Arg Glu
Asn Val Asn Pro Arg His Pro Cys Leu Gly Pro Arg Glu 1295
1300 1305Lys Ala Gly Gln Thr Pro Gln Asp Ser Asn
Val Cys Ser Pro Gly 1310 1315 1320Ala
Pro Ala Ala His Pro Glu Gly Gln Pro Pro Pro Glu Pro Glu 1325
1330 1335Cys Pro Gly Pro Gln Leu Asn Thr Gly
Thr Gln Leu Val Leu Gln 1340 1345
1350His Val Gln Ala Leu Leu Val Lys Arg Phe Gln His Thr Ile Arg
1355 1360 1365Ser His Lys Asp Phe Leu
Ala Gln Ile Val Leu Pro Ala Thr Phe 1370 1375
1380Val Phe Leu Ala Leu Met Leu Ser Ile Val Ile Pro Pro Phe
Gly 1385 1390 1395Glu Tyr Pro Ala Leu
Thr Leu His Pro Trp Ile Tyr Gly Gln Gln 1400 1405
1410Tyr Thr Phe Phe Ser Met Asp Glu Pro Gly Ser Glu Gln
Phe Thr 1415 1420 1425Val Leu Ala Asp
Val Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg 1430
1435 1440Cys Leu Lys Glu Gly Trp Leu Pro Glu Tyr Pro
Cys Gly Asn Ser 1445 1450 1455Thr Pro
Trp Lys Thr Pro Ser Val Ser Pro Asn Ile Thr Gln Leu 1460
1465 1470Phe Gln Lys Gln Lys Trp Thr Gln Val Asn
Pro Ser Pro Ser Cys 1475 1480 1485Arg
Cys Ser Thr Arg Glu Lys Leu Thr Met Leu Pro Glu Cys Pro 1490
1495 1500Glu Gly Ala Gly Gly Leu Pro Pro Pro
Gln Arg Thr Gln Arg Ser 1505 1510
1515Thr Glu Ile Leu Gln Asp Leu Thr Asp Arg Asn Ile Ser Asp Phe
1520 1525 1530Leu Val Lys Thr Tyr Pro
Ala Leu Ile Arg Ser Ser Leu Lys Ser 1535 1540
1545Lys Phe Trp Val Asn Glu Gln Arg Tyr Gly Gly Ile Ser Ile
Gly 1550 1555 1560Gly Lys Leu Pro Val
Val Pro Ile Thr Gly Glu Ala Leu Val Gly 1565 1570
1575Phe Leu Ser Asp Leu Gly Arg Ile Met Asn Val Ser Gly
Gly Pro 1580 1585 1590Ile Thr Arg Glu
Ala Ser Lys Glu Ile Pro Asp Phe Leu Lys His 1595
1600 1605Leu Glu Thr Glu Asp Asn Ile Lys Val Trp Phe
Asn Asn Lys Gly 1610 1615 1620Trp His
Ala Leu Val Ser Phe Leu Asn Val Ala His Asn Ala Ile 1625
1630 1635Leu Arg Ala Ser Leu Pro Lys Asp Arg Ser
Pro Glu Glu Tyr Gly 1640 1645 1650Ile
Thr Val Ile Ser Gln Pro Leu Asn Leu Thr Lys Glu Gln Leu 1655
1660 1665Ser Glu Ile Thr Val Leu Thr Thr Ser
Val Asp Ala Val Val Ala 1670 1675
1680Ile Cys Val Ile Phe Ser Met Ser Phe Val Pro Ala Ser Phe Val
1685 1690 1695Leu Tyr Leu Ile Gln Glu
Arg Val Asn Lys Ser Lys His Leu Gln 1700 1705
1710Phe Ile Ser Gly Val Ser Pro Thr Thr Tyr Trp Val Thr Asn
Phe 1715 1720 1725Leu Trp Asp Ile Met
Asn Tyr Ser Val Ser Ala Gly Leu Val Val 1730 1735
1740Gly Ile Phe Ile Gly Phe Gln Lys Lys Ala Tyr Thr Ser
Pro Glu 1745 1750 1755Asn Leu Pro Ala
Leu Val Ala Leu Leu Leu Leu Tyr Gly Trp Ala 1760
1765 1770Val Ile Pro Met Met Tyr Pro Ala Ser Phe Leu
Phe Asp Val Pro 1775 1780 1785Ser Thr
Ala Tyr Val Ala Leu Ser Cys Ala Asn Leu Phe Ile Gly 1790
1795 1800Ile Asn Ser Ser Ala Ile Thr Phe Ile Leu
Glu Leu Phe Glu Asn 1805 1810 1815Asn
Arg Thr Leu Leu Arg Phe Asn Ala Val Leu Arg Lys Leu Leu 1820
1825 1830Ile Val Phe Pro His Phe Cys Leu Gly
Arg Gly Leu Ile Asp Leu 1835 1840
1845Ala Leu Ser Gln Ala Val Thr Asp Val Tyr Ala Arg Phe Gly Glu
1850 1855 1860Glu His Ser Ala Asn Pro
Phe His Trp Asp Leu Ile Gly Lys Asn 1865 1870
1875Leu Phe Ala Met Val Val Glu Gly Val Val Tyr Phe Leu Leu
Thr 1880 1885 1890Leu Leu Val Gln Arg
His Phe Phe Leu Ser Gln Trp Ile Ala Glu 1895 1900
1905Pro Thr Lys Glu Pro Ile Val Asp Glu Asp Asp Asp Val
Ala Glu 1910 1915 1920Glu Arg Gln Arg
Ile Ile Thr Gly Gly Asn Lys Thr Asp Ile Leu 1925
1930 1935Arg Leu His Glu Leu Thr Lys Ile Tyr Pro Gly
Thr Ser Ser Pro 1940 1945 1950Ala Val
Asp Arg Leu Cys Val Gly Val Arg Pro Gly Glu Cys Phe 1955
1960 1965Gly Leu Leu Gly Val Asn Gly Ala Gly Lys
Thr Thr Thr Phe Lys 1970 1975 1980Met
Leu Thr Gly Asp Thr Thr Val Thr Ser Gly Asp Ala Thr Val 1985
1990 1995Ala Gly Lys Ser Ile Leu Thr Asn Ile
Ser Glu Val His Gln Asn 2000 2005
2010Met Gly Tyr Cys Pro Gln Phe Asp Ala Ile Asp Glu Leu Leu Thr
2015 2020 2025Gly Arg Glu His Leu Tyr
Leu Tyr Ala Arg Leu Arg Gly Val Pro 2030 2035
2040Ala Glu Glu Ile Glu Lys Val Ala Asn Trp Ser Ile Lys Ser
Leu 2045 2050 2055Gly Leu Thr Val Tyr
Ala Asp Cys Leu Ala Gly Thr Tyr Ser Gly 2060 2065
2070Gly Asn Lys Arg Lys Leu Ser Thr Ala Ile Ala Leu Ile
Gly Cys 2075 2080 2085Pro Pro Leu Val
Leu Leu Asp Glu Pro Thr Thr Gly Met Asp Pro 2090
2095 2100Gln Ala Arg Arg Met Leu Trp Asn Val Ile Val
Ser Ile Ile Arg 2105 2110 2115Glu Gly
Arg Ala Val Val Leu Thr Ser His Ser Met Glu Glu Cys 2120
2125 2130Glu Ala Leu Cys Thr Arg Leu Ala Ile Met
Val Lys Gly Ala Phe 2135 2140 2145Arg
Cys Met Gly Thr Ile Gln His Leu Lys Ser Lys Phe Gly Asp 2150
2155 2160Gly Tyr Ile Val Thr Met Lys Ile Lys
Ser Pro Lys Asp Asp Leu 2165 2170
2175Leu Pro Asp Leu Asn Pro Val Glu Gln Phe Phe Gln Gly Asn Phe
2180 2185 2190Pro Gly Ser Val Gln Arg
Glu Arg His Tyr Asn Met Leu Gln Phe 2195 2200
2205Gln Val Ser Ser Ser Ser Leu Ala Arg Ile Phe Gln Leu Leu
Leu 2210 2215 2220Ser His Lys Asp Ser
Leu Leu Ile Glu Glu Tyr Ser Val Thr Gln 2225 2230
2235Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala Lys Gln
Gln Thr 2240 2245 2250Glu Ser His Asp
Leu Pro Leu His Pro Arg Ala Ala Gly Ala Ser 2255
2260 2265Arg Gln Ala Gln Asp 2270142608DNAHomo
sapiens 14tccttcttca ttctgcagtt ggtgccagaa ctctggatcc tgaactggaa
gaaaatgtct 60atccaggttg agcatcctgc tggtggttac aagaaactgt ttgaaactgt
ggaggaactg 120tcctcgccgc tcacagctca tgtaacaggc aggatccccc tctggctcac
cggcagtctc 180cttcgatgtg ggccaggact ctttgaagtt ggatctgagc cattttacca
cctgtttgat 240gggcaagccc tcctgcacaa gtttgacttt aaagaaggac atgtcacata
ccacagaagg 300ttcatccgca ctgatgctta cgtacgggca atgactgaga aaaggatcgt
cataacagaa 360tttggcacct gtgctttccc agatccctgc aagaatatat tttccaggtt
tttttcttac 420tttcgaggag tagaggttac tgacaatgcc cttgttaatg tctacccagt
gggggaagat 480tactacgctt gcacagagac caactttatt acaaagatta atccagagac
cttggagaca 540attaagcagg ttgatctttg caactatgtc tctgtcaatg gggccactgc
tcacccccac 600attgaaaatg atggaaccgt ttacaatatt ggtaattgct ttggaaaaaa
tttttcaatt 660gcctacaaca ttgtaaagat cccaccactg caagcagaca aggaagatcc
aataagcaag 720tcagagatcg ttgtacaatt cccctgcagt gaccgattca agccatctta
cgttcatagt 780tttggtctga ctcccaacta tatcgttttt gtggagacac cagtcaaaat
taacctgttc 840aagttccttt cttcatggag tctttgggga gccaactaca tggattgttt
tgagtccaat 900gaaaccatgg gggtttggct tcatattgct gacaaaaaaa ggaaaaagta
cctcaataat 960aaatacagaa cttctccttt caacctcttc catcacatca acacctatga
agacaatggg 1020tttctgattg tggatctctg ctgctggaaa ggatttgagt ttgtttataa
ttacttatat 1080ttagccaatt tacgtgagaa ctgggaagag gtgaaaaaaa atgccagaaa
ggctccccaa 1140cctgaagtta ggagatatgt acttcctttg aatattgaca aggctgacac
aggcaagaat 1200ttagtcacgc tccccaatac aactgccact gcaattctgt gcagtgacga
gactatctgg 1260ctggagcctg aagttctctt ttcagggcct cgtcaagcat ttgagtttcc
tcaaatcaat 1320taccagaagt attgtgggaa accttacaca tatgcgtatg gacttggctt
gaatcacttt 1380gttccagata ggctctgtaa gctgaatgtc aaaactaaag aaacttgggt
ttggcaagag 1440cctgattcat acccatcaga acccatcttt gtttctcacc cagatgcctt
ggaagaagat 1500gatggtgtag ttctgagtgt ggtggtgagc ccaggagcag gacaaaagcc
tgcttatctc 1560ctgattctga atgccaagga cttaagtgaa gttgcccggg ctgaagtgga
gattaacatc 1620cctgtcacct ttcatggact gttcaaaaaa tcttgagcat actccagcaa
gatatgtttt 1680tggtagcaaa actgagaaaa tcagcttcag gtctgcaatc aaattctgtt
caattttagc 1740ctgctatatg tcatggtttt aacttgcaga tgcgcacaat tttgcaatgt
tttacagaaa 1800gcactgagtt gagcaagcaa ttcctttatt taaaaaaaaa agtacgtatt
tagataatca 1860tacttcctct gtgagacagg ccataactga aaaactctta aatatttagc
aatcaaatag 1920gaaatgaatg tggacttact aaatggcttt taattcctat tataagagca
tattttaggt 1980acctatctgc tccaattata tttttaacat ttaaaaacca aagtcctcta
cacttgattt 2040atattatatg tggctttgct gagtcaagga agtatcatgc aataaggctt
aattactaaa 2100tgtcaaacca aactttttct caaaccaggg actatcatct aagattaatt
acagtaatta 2160ttttgcgtat acgtaactgc tcaaagatta tgaatcttat gaatgttaac
ctttccgttt 2220attacaagca agtactatta tttctgattt tataataaga aaatctgtgt
ttaatcaact 2280gaggcctctc aaccaaataa catctcagag attaagttat atattaaaag
cttatgtaac 2340ataaaagcaa gtacatatag tagtgactat atttaaaaaa acagcataaa
atgcttaaaa 2400atgtaatatt tactaaaatc agattatggg ataatgttgc aggattatac
tttattgcat 2460cttttttgtt taattgtatt taagcattgt gcaatcactt gggaaaaata
ttaaattatt 2520aacattgagg tattaataca ttttaagcct tttgttttta aatttctttt
cttccagaga 2580ttgtttaaaa ataaatattg acaaaaat
260815533PRTHomo sapiens 15Met Ser Ile Gln Val Glu His Pro Ala
Gly Gly Tyr Lys Lys Leu Phe1 5 10
15Glu Thr Val Glu Glu Leu Ser Ser Pro Leu Thr Ala His Val Thr
Gly 20 25 30Arg Ile Pro Leu
Trp Leu Thr Gly Ser Leu Leu Arg Cys Gly Pro Gly 35
40 45Leu Phe Glu Val Gly Ser Glu Pro Phe Tyr His Leu
Phe Asp Gly Gln 50 55 60Ala Leu Leu
His Lys Phe Asp Phe Lys Glu Gly His Val Thr Tyr His65 70
75 80Arg Arg Phe Ile Arg Thr Asp Ala
Tyr Val Arg Ala Met Thr Glu Lys 85 90
95Arg Ile Val Ile Thr Glu Phe Gly Thr Cys Ala Phe Pro Asp
Pro Cys 100 105 110Lys Asn Ile
Phe Ser Arg Phe Phe Ser Tyr Phe Arg Gly Val Glu Val 115
120 125Thr Asp Asn Ala Leu Val Asn Val Tyr Pro Val
Gly Glu Asp Tyr Tyr 130 135 140Ala Cys
Thr Glu Thr Asn Phe Ile Thr Lys Ile Asn Pro Glu Thr Leu145
150 155 160Glu Thr Ile Lys Gln Val Asp
Leu Cys Asn Tyr Val Ser Val Asn Gly 165
170 175Ala Thr Ala His Pro His Ile Glu Asn Asp Gly Thr
Val Tyr Asn Ile 180 185 190Gly
Asn Cys Phe Gly Lys Asn Phe Ser Ile Ala Tyr Asn Ile Val Lys 195
200 205Ile Pro Pro Leu Gln Ala Asp Lys Glu
Asp Pro Ile Ser Lys Ser Glu 210 215
220Ile Val Val Gln Phe Pro Cys Ser Asp Arg Phe Lys Pro Ser Tyr Val225
230 235 240His Ser Phe Gly
Leu Thr Pro Asn Tyr Ile Val Phe Val Glu Thr Pro 245
250 255Val Lys Ile Asn Leu Phe Lys Phe Leu Ser
Ser Trp Ser Leu Trp Gly 260 265
270Ala Asn Tyr Met Asp Cys Phe Glu Ser Asn Glu Thr Met Gly Val Trp
275 280 285Leu His Ile Ala Asp Lys Lys
Arg Lys Lys Tyr Leu Asn Asn Lys Tyr 290 295
300Arg Thr Ser Pro Phe Asn Leu Phe His His Ile Asn Thr Tyr Glu
Asp305 310 315 320Asn Gly
Phe Leu Ile Val Asp Leu Cys Cys Trp Lys Gly Phe Glu Phe
325 330 335Val Tyr Asn Tyr Leu Tyr Leu
Ala Asn Leu Arg Glu Asn Trp Glu Glu 340 345
350Val Lys Lys Asn Ala Arg Lys Ala Pro Gln Pro Glu Val Arg
Arg Tyr 355 360 365Val Leu Pro Leu
Asn Ile Asp Lys Ala Asp Thr Gly Lys Asn Leu Val 370
375 380Thr Leu Pro Asn Thr Thr Ala Thr Ala Ile Leu Cys
Ser Asp Glu Thr385 390 395
400Ile Trp Leu Glu Pro Glu Val Leu Phe Ser Gly Pro Arg Gln Ala Phe
405 410 415Glu Phe Pro Gln Ile
Asn Tyr Gln Lys Tyr Cys Gly Lys Pro Tyr Thr 420
425 430Tyr Ala Tyr Gly Leu Gly Leu Asn His Phe Val Pro
Asp Arg Leu Cys 435 440 445Lys Leu
Asn Val Lys Thr Lys Glu Thr Trp Val Trp Gln Glu Pro Asp 450
455 460Ser Tyr Pro Ser Glu Pro Ile Phe Val Ser His
Pro Asp Ala Leu Glu465 470 475
480Glu Asp Asp Gly Val Val Leu Ser Val Val Val Ser Pro Gly Ala Gly
485 490 495Gln Lys Pro Ala
Tyr Leu Leu Ile Leu Asn Ala Lys Asp Leu Ser Glu 500
505 510Val Ala Arg Ala Glu Val Glu Ile Asn Ile Pro
Val Thr Phe His Gly 515 520 525Leu
Phe Lys Lys Ser 530161752DNAHomo sapiens 16gagcccgatt taacggaaac
tgtgggcggt gagaagttcc ttatgacaca ctaatcccaa 60cctgctgacc ggaccacgcc
tccagcggag ggaacctcta gagctccagg acattcaggt 120accaggtagc cccaaggagg
agctgccgac ctggcaggga acaaccaaga ctggggttaa 180atctcacagc ctgcaagtgg
aagagaagaa cttgaaccca ggtccaactt ttgcgccaca 240gcaggctgcc tcttggtcct
gacaggaagt cacaacttgg ccctgacttc ctatcctagg 300gaaggggccg gctggagagg
ccaggacaga gaaagcagat cccttctttt tccaaggact 360ctgtgtcttc cataggcaac
atgtcagaag gggtgggcac gttccgcatg gtacctgaag 420aggaacagga gctccgtgcc
caactggagc agctcacaac caaggaccat ggacctgtct 480ttggcccgtg cagccagctg
ccccgccaca ccttgcagaa ggccaaggat gagctgaacg 540agagagagga gacccgggag
gaggcagtgc gagagctgca ggagatggtg caggcgcagg 600cggcctcggg ggaggagctg
gcggtggccg tggcggagag ggtgcaagag aaggacagcg 660gcttcttcct gcgcttcatc
cgcgcacgga agttcaacgt gggccgtgcc tatgagctgc 720tcagaggcta tgtgaatttc
cggctgcagt accctgagct ctttgacagc ctgtccccag 780aggctgtccg ctgcaccatt
gaagctggct accctggtgt cctctctagt cgggacaagt 840atggccgagt ggtcatgctc
ttcaacattg agaactggca aagtcaagaa atcacctttg 900atgagatctt gcaggcatat
tgcttcatcc tggagaagct gctggagaat gaggaaactc 960aaatcaatgg cttctgcatc
attgagaact tcaagggctt taccatgcag caggctgcta 1020gtctccggac ttcagatctc
aggaagatgg tggacatgct ccaggattcc ttcccagccc 1080ggttcaaagc catccacttc
atccaccagc catggtactt caccacgacc tacaatgtgg 1140tcaagccctt cttgaagagc
aagctgcttg agagggtctt tgtccacggg gatgaccttt 1200ctggtttcta ccaggagatc
gatgagaaca tcctgccctc tgacttcggg ggcacgctgc 1260ccaagtatga tggcaaggcc
gttgctgagc agctctttgg cccccaggcc caagctgaga 1320acacagcctt ctgaaaacat
ctcctgccag ctgaactgta gttagaatct ctgggcctct 1380cctcaactgt cctggaccca
aggctaggaa agggctgctt gagatgactg tggtcccccc 1440ttagactccc taagcccgag
tgagctcagg tgtcaccctg ttctcaagtt gggggatggg 1500taataaagga gggggaattc
ccttgaacaa gaagaactgg ggatagttat atttccacct 1560gcccttgaag ctttaagaca
gtgatttttg tgtaaggttg tatttcaaag actcgaattc 1620attttctcag tcatttcctt
tgtaacagag ttttacgact tagagtctgt gaaaacaggc 1680aaggagcccg ggttaaaata
tccccctatt cgcccccaaa atgcaataaa agaagataaa 1740agagagagga ta
175217317PRTHomo sapiens
17Met Ser Glu Gly Val Gly Thr Phe Arg Met Val Pro Glu Glu Glu Gln1
5 10 15Glu Leu Arg Ala Gln Leu
Glu Gln Leu Thr Thr Lys Asp His Gly Pro 20 25
30Val Phe Gly Pro Cys Ser Gln Leu Pro Arg His Thr Leu
Gln Lys Ala 35 40 45Lys Asp Glu
Leu Asn Glu Arg Glu Glu Thr Arg Glu Glu Ala Val Arg 50
55 60Glu Leu Gln Glu Met Val Gln Ala Gln Ala Ala Ser
Gly Glu Glu Leu65 70 75
80Ala Val Ala Val Ala Glu Arg Val Gln Glu Lys Asp Ser Gly Phe Phe
85 90 95Leu Arg Phe Ile Arg Ala
Arg Lys Phe Asn Val Gly Arg Ala Tyr Glu 100
105 110Leu Leu Arg Gly Tyr Val Asn Phe Arg Leu Gln Tyr
Pro Glu Leu Phe 115 120 125Asp Ser
Leu Ser Pro Glu Ala Val Arg Cys Thr Ile Glu Ala Gly Tyr 130
135 140Pro Gly Val Leu Ser Ser Arg Asp Lys Tyr Gly
Arg Val Val Met Leu145 150 155
160Phe Asn Ile Glu Asn Trp Gln Ser Gln Glu Ile Thr Phe Asp Glu Ile
165 170 175Leu Gln Ala Tyr
Cys Phe Ile Leu Glu Lys Leu Leu Glu Asn Glu Glu 180
185 190Thr Gln Ile Asn Gly Phe Cys Ile Ile Glu Asn
Phe Lys Gly Phe Thr 195 200 205Met
Gln Gln Ala Ala Ser Leu Arg Thr Ser Asp Leu Arg Lys Met Val 210
215 220Asp Met Leu Gln Asp Ser Phe Pro Ala Arg
Phe Lys Ala Ile His Phe225 230 235
240Ile His Gln Pro Trp Tyr Phe Thr Thr Thr Tyr Asn Val Val Lys
Pro 245 250 255Phe Leu Lys
Ser Lys Leu Leu Glu Arg Val Phe Val His Gly Asp Asp 260
265 270Leu Ser Gly Phe Tyr Gln Glu Ile Asp Glu
Asn Ile Leu Pro Ser Asp 275 280
285Phe Gly Gly Thr Leu Pro Lys Tyr Asp Gly Lys Ala Val Ala Glu Gln 290
295 300Leu Phe Gly Pro Gln Ala Gln Ala
Glu Asn Thr Ala Phe305 310
315183027DNAHomo sapiens 18cagcgttcag gctgcccctt cttggctggg aagggcgctg
aagaaacaac gcccaggacc 60aggactatcc cctgctcaag ctgtgattcc gagacccctg
ccaccactac tgcattcacg 120gggatcccag gctagtggga ctcgacatgg gtagccccca
gggcagctcc ctacagcttg 180ggccatctgc acttttccca aggccctaag tctccgcctc
tgggctcgtt aaggtttggg 240gtgggagctg tgctgtggga agcaacccgg actacacttg
gcaagcatgg cgctactgaa 300agtcaagttt gaccagaaga agcgggtcaa gttggcccaa
gggctctggc tcatgaactg 360gttctccgtg ttggctggca tcatcatctt cagcctagga
ctgttcctga agattgaact 420ccgaaagagg agcgatgtga tgaataattc tgagagccat
tttgtgccca actcattgat 480agggatgggg gtgctatcct gtgtcttcaa ctcgctggct
gggaagatct gctacgacgc 540cctggaccca gccaagtatg ccagatggaa gccctggctg
aagccgtacc tggctatctg 600tgttctcttc aacatcatcc tcttccttgt ggctctctgc
tgctttctgc ttcggggctc 660gctggagaac accctgggcc aagggctcaa gaacggcatg
aagtactacc gggacacaga 720cacccctggc aggtgtttca tgaagaagac catcgacatg
ctgcagatcg agttcaaatg 780ctgcggcaac aacggttttc gggactggtt tgagattcag
tggatcagca atcgctacct 840ggacttttcc tccaaagaag tcaaagatcg aatcaagagc
aacgtggatg ggcggtacct 900ggtggacggc gtccctttca gctgctgcaa tcctagctcg
ccacggccct gcatccagta 960tcagatcacc aacaactcag cacactacag ttacgaccac
cagacggagg agctcaacct 1020gtgggtgcgt ggctgcaggg ctgccctgct gagctactac
agcagcctca tgaactccat 1080gggtgtcgtc acgctcctca tttggctctt cgaggtgacc
attacaattg ggctgcgcta 1140cctacagacg tcgctggatg gtgtgtccaa ccccgaggaa
tctgagagcg agagccaggg 1200ctggctgctg gagaggagcg tgccggagac ctggaaggcc
tttctggaga gtgtgaagaa 1260gctgggcaag ggcaaccagg tggaagccga gggcgcagac
gcaggccagg ccccagaggc 1320tggctgaggg ccctggggcc cctcccctcc cgaacactga
gaaatagtgc actccaagaa 1380acgtggatct ccccctcatc caactccgaa agtctgaatc
tcccaaggag ggcaccatct 1440tacagagact ctccctgacg gtggaattta agtttagggt
ccctaaaagc atttgacaca 1500cagttgttga atgactgacc caaaatgtga atgaagctaa
tgtgaatgtg agtgaagctc 1560ccttcaggcc cgctgcccta ggatatgccc tcctggtgac
tcgggggctg tctcagacga 1620ctagcccagg acccatcttt ctcacacgga tttagtccca
ccctatggcc actggccgta 1680tctgagggct gctccccttt tagaatttac ctcttatgag
ctccatgttg cttcactcta 1740tccaaagtgt cacttggtgc ataagcacag aaatctgaaa
aatggccatg ttgtcttttt 1800tttttttttt taatgccaag attgacaggt tggccgtttg
cttaatgcca gaagttgggg 1860gaaagttacg cttttctaag aataatggac tcttaaggca
ttgagggctc taaacaggat 1920tctttaatca tggagcaaga gaatttcaag gcaggggatt
ttatccccca ccaaaaacac 1980agtgaaaggc ctgcttttgt gtcccattca catgccctcg
gtcactgagt ctggagtgaa 2040ccacgggttg aggaagtcag gctgttggcg tgtcccagca
ccacaccacc cctaaagtgc 2100caggtgatct cctgtggctc atcggtggaa gcagtggggt
aggctgctgc cctgctgtgg 2160aagaggagca acaatcagac atgagtccac cctttggaga
ccaggcctca gctcttggtg 2220ggcccaggga cacccacaca ggtggccatc acagccccat
ggacaacact aattgtccac 2280agcaaagggc aaggaatcct ctgggagctt cttccgtttc
ttccccccag atacccatct 2340tgaaaaacac tatttctgga atgcttctgc atcaaaggag
attctttgag atagcccatc 2400ttcctgagct agcaaataca ggagttttca ctttctttag
gaaagagaag ctttcagggg 2460aaggagagaa tgattttgct gacttcccaa gccctggtga
ccagaccaag gcagggccca 2520gcataattcc tccagttgga tgaacattca agagagctcg
ttcctacctg gctggagacc 2580gaggccagaa ggcaaaaacc agaaagggaa cagtccataa
cttacctctg cttctgaccg 2640atggtgtttg ggaataggtt actttggact gagtttgggt
tctctgctgt cctaagaact 2700tcagtgtaga gaaaataaga cttctggtgc tgctggggta
tgttctgggc ttaattcccc 2760caagcagaag accagatcca agatgtttgg acaccctgtc
agacgttggt cccaagttta 2820attagatttc tgaatctcgt tgaggccaag gaatgatcca
tactgaaaaa atgctgagcc 2880agccatcttt ggcaaaggtc cctgagctct tgctatctct
caagagtgct gagaaccacg 2940gtgaaagtgc tgctctaggc ccacaagtgt aactatgctg
ttaacagctg tcaatagata 3000attaaaattc atactgtatg aaaatca
302719346PRTHomo sapiens 19Met Ala Leu Leu Lys Val
Lys Phe Asp Gln Lys Lys Arg Val Lys Leu1 5
10 15Ala Gln Gly Leu Trp Leu Met Asn Trp Phe Ser Val
Leu Ala Gly Ile 20 25 30Ile
Ile Phe Ser Leu Gly Leu Phe Leu Lys Ile Glu Leu Arg Lys Arg 35
40 45Ser Asp Val Met Asn Asn Ser Glu Ser
His Phe Val Pro Asn Ser Leu 50 55
60Ile Gly Met Gly Val Leu Ser Cys Val Phe Asn Ser Leu Ala Gly Lys65
70 75 80Ile Cys Tyr Asp Ala
Leu Asp Pro Ala Lys Tyr Ala Arg Trp Lys Pro 85
90 95Trp Leu Lys Pro Tyr Leu Ala Ile Cys Val Leu
Phe Asn Ile Ile Leu 100 105
110Phe Leu Val Ala Leu Cys Cys Phe Leu Leu Arg Gly Ser Leu Glu Asn
115 120 125Thr Leu Gly Gln Gly Leu Lys
Asn Gly Met Lys Tyr Tyr Arg Asp Thr 130 135
140Asp Thr Pro Gly Arg Cys Phe Met Lys Lys Thr Ile Asp Met Leu
Gln145 150 155 160Ile Glu
Phe Lys Cys Cys Gly Asn Asn Gly Phe Arg Asp Trp Phe Glu
165 170 175Ile Gln Trp Ile Ser Asn Arg
Tyr Leu Asp Phe Ser Ser Lys Glu Val 180 185
190Lys Asp Arg Ile Lys Ser Asn Val Asp Gly Arg Tyr Leu Val
Asp Gly 195 200 205Val Pro Phe Ser
Cys Cys Asn Pro Ser Ser Pro Arg Pro Cys Ile Gln 210
215 220Tyr Gln Ile Thr Asn Asn Ser Ala His Tyr Ser Tyr
Asp His Gln Thr225 230 235
240Glu Glu Leu Asn Leu Trp Val Arg Gly Cys Arg Ala Ala Leu Leu Ser
245 250 255Tyr Tyr Ser Ser Leu
Met Asn Ser Met Gly Val Val Thr Leu Leu Ile 260
265 270Trp Leu Phe Glu Val Thr Ile Thr Ile Gly Leu Arg
Tyr Leu Gln Thr 275 280 285Ser Leu
Asp Gly Val Ser Asn Pro Glu Glu Ser Glu Ser Glu Ser Gln 290
295 300Gly Trp Leu Leu Glu Arg Ser Val Pro Glu Thr
Trp Lys Ala Phe Leu305 310 315
320Glu Ser Val Lys Lys Leu Gly Lys Gly Asn Gln Val Glu Ala Glu Gly
325 330 335Ala Asp Ala Gly
Gln Ala Pro Glu Ala Gly 340 345201767DNAHomo
sapiens 20gtcagctggg tgactcatac atctgtgaga ccctccgtat ggagaccggg
gcggggggtg 60ttgcttaatg cttagaactg ctgaaactac cagttcactg tctcagcact
aatccaactc 120tgctccttaa gtgggatttg gcttttagac attgagacct ggatgctggg
catcctcgct 180agatccccta caaattcccc acatacgtag gccaggagcc tcagcggtgc
cccttcaggc 240tcatctggca agacggtacc agcttgctca gaacaggggc tggctattca
tcatctcaga 300gcatagagac cctctccttg ccacccggcc cttcccacct ggttggtgac
aaatcacaag 360gtggtagaag ttgccaggga cagataacat ggcagccagc gggaagacca
gcaagtccga 420accgaaccat gttatcttca agaagatctc ccgggacaaa tcggtgacca
tctacctggg 480gaacagagac tacatagacc atgtcagcca agtccagcct gtggatggtg
tcgtgttggt 540tgatcctgat cttgtgaagg gaaagaaagt gtatgtcact ctgacctgcg
ccttccgcta 600tggccaagag gacattgacg tgatcggctt gaccttccgc agggacctgt
acttctcccg 660ggtccaggtg tatcctcctg tgggggccgc gagcaccccc acaaaactgc
aagagagcct 720gcttaaaaag ctggggagca acacgtaccc ctttctcctg acgtttcctg
actacttgcc 780ctgttcagtg atgttgcagc cagctccaca agattcaggg aagtcctgtg
gggttgactt 840tgaggtcaaa gcattcgcca cagacagcac cgatgccgaa gaggacaaaa
tccccaagaa 900gagctccgtg cgattactga tccgcaaagt acagcatgcc ccacttgaga
tgggtcccca 960gccccgagct gaggcggcct ggcagttctt catgtctgac aagcccctgc
accttgcggt 1020ctctctcaac aaagagatct atttccatgg ggagcccatc cctgtgaccg
tgactgtcac 1080caataacaca gagaagaccg tgaagaagat taaagcattc gtggaacagg
tggccaatgt 1140ggttctctac tcgagtgatt attacgtcaa gcccgtggct atggaggaag
cgcaagaaaa 1200agtgccacca aacagcactt tgaccaagac gctgacgctg ctgcccttgc
tggctaacaa 1260tcgagaaagg agaggcattg ccctggatgg gaaaatcaag cacgaggaca
caaaccttgc 1320ctccagcacc atcattaagg agggcataga ccggaccgtc ctgggaatcc
tggtgtctta 1380ccagatcaag gtgaagctca cagtgtcagg ctttctggga gagctcacct
ccagtgaagt 1440cgccactgag gtcccattcc gcctcatgca ccctcagcct gaggacccag
ctaaggaaag 1500ttatcaggat gcaaatttag tttttgagga gtttgctcgc cataatctga
aagatgcagg 1560agaagctgag gaggggaaga gagacaagaa tgacgttgat gagtgaagat
gtcggctcag 1620gatgccggaa aatgacctgt agttaccagt gcaacgagca aagccccaca
gtttagtcct 1680ttggagttat gctgcgtatg aaaggatgag tcttcttccg agaaataaag
cttgtttgtt 1740ctcccctgga aaaaaaaaaa aaaaaaa
176721405PRTHomo sapiens 21Met Ala Ala Ser Gly Lys Thr Ser Lys
Ser Glu Pro Asn His Val Ile1 5 10
15Phe Lys Lys Ile Ser Arg Asp Lys Ser Val Thr Ile Tyr Leu Gly
Asn 20 25 30Arg Asp Tyr Ile
Asp His Val Ser Gln Val Gln Pro Val Asp Gly Val 35
40 45Val Leu Val Asp Pro Asp Leu Val Lys Gly Lys Lys
Val Tyr Val Thr 50 55 60Leu Thr Cys
Ala Phe Arg Tyr Gly Gln Glu Asp Ile Asp Val Ile Gly65 70
75 80Leu Thr Phe Arg Arg Asp Leu Tyr
Phe Ser Arg Val Gln Val Tyr Pro 85 90
95Pro Val Gly Ala Ala Ser Thr Pro Thr Lys Leu Gln Glu Ser
Leu Leu 100 105 110Lys Lys Leu
Gly Ser Asn Thr Tyr Pro Phe Leu Leu Thr Phe Pro Asp 115
120 125Tyr Leu Pro Cys Ser Val Met Leu Gln Pro Ala
Pro Gln Asp Ser Gly 130 135 140Lys Ser
Cys Gly Val Asp Phe Glu Val Lys Ala Phe Ala Thr Asp Ser145
150 155 160Thr Asp Ala Glu Glu Asp Lys
Ile Pro Lys Lys Ser Ser Val Arg Leu 165
170 175Leu Ile Arg Lys Val Gln His Ala Pro Leu Glu Met
Gly Pro Gln Pro 180 185 190Arg
Ala Glu Ala Ala Trp Gln Phe Phe Met Ser Asp Lys Pro Leu His 195
200 205Leu Ala Val Ser Leu Asn Lys Glu Ile
Tyr Phe His Gly Glu Pro Ile 210 215
220Pro Val Thr Val Thr Val Thr Asn Asn Thr Glu Lys Thr Val Lys Lys225
230 235 240Ile Lys Ala Phe
Val Glu Gln Val Ala Asn Val Val Leu Tyr Ser Ser 245
250 255Asp Tyr Tyr Val Lys Pro Val Ala Met Glu
Glu Ala Gln Glu Lys Val 260 265
270Pro Pro Asn Ser Thr Leu Thr Lys Thr Leu Thr Leu Leu Pro Leu Leu
275 280 285Ala Asn Asn Arg Glu Arg Arg
Gly Ile Ala Leu Asp Gly Lys Ile Lys 290 295
300His Glu Asp Thr Asn Leu Ala Ser Ser Thr Ile Ile Lys Glu Gly
Ile305 310 315 320Asp Arg
Thr Val Leu Gly Ile Leu Val Ser Tyr Gln Ile Lys Val Lys
325 330 335Leu Thr Val Ser Gly Phe Leu
Gly Glu Leu Thr Ser Ser Glu Val Ala 340 345
350Thr Glu Val Pro Phe Arg Leu Met His Pro Gln Pro Glu Asp
Pro Ala 355 360 365Lys Glu Ser Tyr
Gln Asp Ala Asn Leu Val Phe Glu Glu Phe Ala Arg 370
375 380His Asn Leu Lys Asp Ala Gly Glu Ala Glu Glu Gly
Lys Arg Asp Lys385 390 395
400Asn Asp Val Asp Glu 405222483DNAHomo sapiens
22agttgattgc aggtcctcct ggggccagaa gggtgcctgg gaggccaggt tctggggatc
60ccctccatcc agaagaacca cctgctcact ctgtcccttc gcctgctgct gggaccatgg
120gggctggggc cagtgctgag gagaagcact ccagggagct ggaaaagaag ctgaaagagg
180acgctgagaa ggatgctcga accgtgaagc tgctgcttct gggtgccggt gagtccggga
240agagcaccat cgtcaagcag atgaagatta tccaccagga cgggtactcg ctggaagagt
300gcctcgagtt tatcgccatc atctacggca acacgttgca gtccatcctg gccatcgtac
360gcgccatgac cacactcaac atccagtacg gagactctgc acgccaggac gacgcccgga
420agctgatgca catggcagac actatcgagg agggcacgat gcccaaggag atgtcggaca
480tcatccagcg gctgtggaag gactccggta tccaggcctg ttttgagcgc gcctcggagt
540accagctcaa cgactcggcg ggctactacc tctccgacct ggagcgcctg gtaaccccgg
600gctacgtgcc caccgagcag gacgtgctgc gctcgcgagt caagaccact ggcatcatcg
660agacgcagtt ctccttcaag gatctcaact tccggatgtt cgatgtgggc gggcagcgct
720cggagcgcaa gaagtggatc cactgcttcg agggcgtgac ctgcatcatc ttcatcgcgg
780cgctgagcgc ctacgacatg gtgctagtgg aggacgacga agtgaaccgc atgcacgaga
840gcctgcacct gttcaacagc atctgcaacc accgctactt cgccacgacg tccatcgtgc
900tcttccttaa caagaaggac gtcttcttcg agaagatcaa gaaggcgcac ctcagcatct
960gtttcccgga ctacgatgga cccaacacct acgaggacgc cggcaactac atcaaggtgc
1020agttcctcga gctcaacatg cggcgcgacg tgaaggagat ctattcccac atgacgtgcg
1080ccaccgacac gcagaacgtc aaatttgtct tcgacgctgt caccgacatc atcatcaagg
1140agaacctcaa agactgtggc ctcttctgag gccagggcct gtgctgcagt cggggacaag
1200gagcttccgt ctggcaaggc cggggcacaa tttgcactcc cctcagctag acgcacagac
1260tcagcaataa acctttgcat caggctccag ctgtcctttc ttggtggagg acttaattat
1320cacaagtcat gggcatttat taagtgccca gtgctgggtt gggcatgaag tgggaagatg
1380gcccctccca ggaagaagta cctggcctga caaggtgggg cactcttggg ggtatgggac
1440caactcatgg cttttcacgg gagttgagga gagaggagct gtggaaaata ttcactggga
1500cagtcttgga tcaagaggga gttttgaggt ggaggctcat tctggcaggg accgtagtgt
1560ctaccagccc cagaaacatg ggcttatggc cacaggagtt cagtggagca agagcagggg
1620aggagagacg tggacaggtg cccaaagcca gtcggagggc ctgggctttc tcagaaggtg
1680atggagagtc ttggaagccc tcgaggcagg aacataattg cagggctggg attagggtga
1740gggaagtgag gcacactcac cttgggtgca acatttaagg cgatgccaaa aaatttagta
1800accaaggtaa ataatattag gataatattt ttaaaaatca aatgaatgca aaaccccaca
1860atgaatgaaa tatcaaaatc caacagagga tcaaacagag gcatgctaag atatattggg
1920gcttgaagca aagggaaaac tatttgttgc tatatgtttg tagggatttt ttgccagttt
1980taaaaataca tgtatcataa agtttactat ctcagccact tgccggtgta tagtttggtg
2040gtgttaagta cattcataat gttgtacaac caccgcaact gttcatctcc agaactcctt
2100tcctcttgta aaactgtaac tctgtaccca tgaaaaaata accccccatt cctgccttcc
2160cccggctcct ggcatccacc attctacttt ccatctctat gaatgtgact gctctaagtg
2220cctcagatgt gtgggtccat gaagtctttg tctttttgca actggcttat ttcacttagc
2280atcatgtctt caaggtttat tcatgtgtag catatggcag aatctccttc ctttttaagg
2340ttgaataata ttccattgta tatattccac actttgttta tttattcatc tattgatgaa
2400tggttacatc tgccttttgg ctattgtgaa taatgctgct atgaacatgg gtgtacaaat
2460ctctcaaaaa aaaaaaaaaa aaa
248323350PRTHomo sapiens 23Met Gly Ala Gly Ala Ser Ala Glu Glu Lys His
Ser Arg Glu Leu Glu1 5 10
15Lys Lys Leu Lys Glu Asp Ala Glu Lys Asp Ala Arg Thr Val Lys Leu
20 25 30Leu Leu Leu Gly Ala Gly Glu
Ser Gly Lys Ser Thr Ile Val Lys Gln 35 40
45Met Lys Ile Ile His Gln Asp Gly Tyr Ser Leu Glu Glu Cys Leu
Glu 50 55 60Phe Ile Ala Ile Ile Tyr
Gly Asn Thr Leu Gln Ser Ile Leu Ala Ile65 70
75 80Val Arg Ala Met Thr Thr Leu Asn Ile Gln Tyr
Gly Asp Ser Ala Arg 85 90
95Gln Asp Asp Ala Arg Lys Leu Met His Met Ala Asp Thr Ile Glu Glu
100 105 110Gly Thr Met Pro Lys Glu
Met Ser Asp Ile Ile Gln Arg Leu Trp Lys 115 120
125Asp Ser Gly Ile Gln Ala Cys Phe Glu Arg Ala Ser Glu Tyr
Gln Leu 130 135 140Asn Asp Ser Ala Gly
Tyr Tyr Leu Ser Asp Leu Glu Arg Leu Val Thr145 150
155 160Pro Gly Tyr Val Pro Thr Glu Gln Asp Val
Leu Arg Ser Arg Val Lys 165 170
175Thr Thr Gly Ile Ile Glu Thr Gln Phe Ser Phe Lys Asp Leu Asn Phe
180 185 190Arg Met Phe Asp Val
Gly Gly Gln Arg Ser Glu Arg Lys Lys Trp Ile 195
200 205His Cys Phe Glu Gly Val Thr Cys Ile Ile Phe Ile
Ala Ala Leu Ser 210 215 220Ala Tyr Asp
Met Val Leu Val Glu Asp Asp Glu Val Asn Arg Met His225
230 235 240Glu Ser Leu His Leu Phe Asn
Ser Ile Cys Asn His Arg Tyr Phe Ala 245
250 255Thr Thr Ser Ile Val Leu Phe Leu Asn Lys Lys Asp
Val Phe Phe Glu 260 265 270Lys
Ile Lys Lys Ala His Leu Ser Ile Cys Phe Pro Asp Tyr Asp Gly 275
280 285Pro Asn Thr Tyr Glu Asp Ala Gly Asn
Tyr Ile Lys Val Gln Phe Leu 290 295
300Glu Leu Asn Met Arg Arg Asp Val Lys Glu Ile Tyr Ser His Met Thr305
310 315 320Cys Ala Thr Asp
Thr Gln Asn Val Lys Phe Val Phe Asp Ala Val Thr 325
330 335Asp Ile Ile Ile Lys Glu Asn Leu Lys Asp
Cys Gly Leu Phe 340 345
35024201PRTHomo sapiens 24Met Gly Asn Val Met Glu Gly Lys Ser Val Glu Glu
Leu Ser Ser Thr1 5 10
15Glu Cys His Gln Trp Tyr Lys Lys Phe Met Thr Glu Cys Pro Ser Gly
20 25 30Gln Leu Thr Leu Tyr Glu Phe
Arg Gln Phe Phe Gly Leu Lys Asn Leu 35 40
45Ser Pro Ser Ala Ser Gln Tyr Val Glu Gln Met Phe Glu Thr Phe
Asp 50 55 60Phe Asn Lys Asp Gly Tyr
Ile Asp Phe Met Glu Tyr Val Ala Ala Leu65 70
75 80Ser Leu Val Leu Lys Gly Lys Val Glu Gln Lys
Leu Arg Trp Tyr Phe 85 90
95Lys Leu Tyr Asp Val Asp Gly Asn Gly Cys Ile Asp Arg Asp Glu Leu
100 105 110Leu Thr Ile Ile Gln Ala
Ile Arg Ala Ile Asn Pro Cys Ser Asp Thr 115 120
125Thr Met Thr Ala Glu Glu Phe Thr Asp Thr Val Phe Ser Lys
Ile Asp 130 135 140Val Asn Gly Asp Gly
Glu Leu Ser Leu Glu Glu Phe Ile Glu Gly Val145 150
155 160Gln Lys Asp Gln Met Leu Leu Asp Thr Leu
Thr Arg Ser Leu Asp Leu 165 170
175Thr Arg Ile Val Arg Arg Leu Gln Asn Gly Glu Gln Asp Glu Glu Gly
180 185 190Ala Asp Glu Ala Ala
Glu Ala Ala Gly 195 200251103PRTHomo sapiens 25Met
Thr Ala Cys Ala Arg Arg Ala Gly Gly Leu Pro Asp Pro Gly Leu1
5 10 15Cys Gly Pro Ala Trp Trp Ala
Pro Ser Leu Pro Arg Leu Pro Arg Ala 20 25
30Leu Pro Arg Leu Pro Leu Leu Leu Leu Leu Leu Leu Leu Gln
Pro Pro 35 40 45Ala Leu Ser Ala
Val Phe Thr Val Gly Val Leu Gly Pro Trp Ala Cys 50 55
60Asp Pro Ile Phe Ser Arg Ala Arg Pro Asp Leu Ala Ala
Arg Leu Ala65 70 75
80Ala Ala Arg Leu Asn Arg Asp Pro Gly Leu Ala Gly Gly Pro Arg Phe
85 90 95Glu Val Ala Leu Leu Pro
Glu Pro Cys Arg Thr Pro Gly Ser Leu Gly 100
105 110Ala Val Ser Ser Ala Leu Ala Arg Val Ser Gly Leu
Val Gly Pro Val 115 120 125Asn Pro
Ala Ala Cys Arg Pro Ala Glu Leu Leu Ala Glu Glu Ala Gly 130
135 140Ile Ala Leu Val Pro Trp Gly Cys Pro Trp Thr
Gln Ala Glu Gly Thr145 150 155
160Thr Ala Pro Ala Val Thr Pro Ala Ala Asp Ala Leu Tyr Ala Leu Leu
165 170 175Arg Ala Phe Gly
Trp Ala Arg Val Ala Leu Val Thr Ala Pro Gln Asp 180
185 190Leu Trp Val Glu Ala Gly Arg Ser Leu Ser Thr
Ala Leu Arg Ala Arg 195 200 205Gly
Leu Pro Val Ala Ser Val Thr Ser Met Glu Pro Leu Asp Leu Ser 210
215 220Gly Ala Arg Glu Ala Leu Arg Lys Val Arg
Asp Gly Pro Arg Val Thr225 230 235
240Ala Val Ile Met Val Met His Ser Val Leu Leu Gly Gly Glu Glu
Gln 245 250 255Arg Tyr Leu
Leu Glu Ala Ala Glu Glu Leu Gly Leu Thr Asp Gly Ser 260
265 270Leu Val Phe Leu Pro Phe Asp Thr Ile His
Tyr Ala Leu Ser Pro Gly 275 280
285Pro Glu Ala Leu Ala Ala Leu Ala Asn Ser Ser Gln Leu Arg Arg Ala 290
295 300His Asp Ala Val Leu Thr Leu Thr
Arg His Cys Pro Ser Glu Gly Ser305 310
315 320Val Leu Asp Ser Leu Arg Arg Ala Gln Glu Arg Arg
Glu Leu Pro Ser 325 330
335Asp Leu Asn Leu Gln Gln Val Ser Pro Leu Phe Gly Thr Ile Tyr Asp
340 345 350Ala Val Phe Leu Leu Ala
Arg Gly Val Ala Glu Ala Arg Ala Ala Ala 355 360
365Gly Gly Arg Trp Val Ser Gly Ala Ala Val Ala Arg His Ile
Arg Asp 370 375 380Ala Gln Val Pro Gly
Phe Cys Gly Asp Leu Gly Gly Asp Glu Glu Pro385 390
395 400Pro Phe Val Leu Leu Asp Thr Asp Ala Ala
Gly Asp Arg Leu Phe Ala 405 410
415Thr Tyr Met Leu Asp Pro Ala Arg Gly Ser Phe Leu Ser Ala Gly Thr
420 425 430Arg Met His Phe Pro
Arg Gly Gly Ser Ala Pro Gly Pro Asp Pro Ser 435
440 445Cys Trp Phe Asp Pro Asn Asn Ile Cys Gly Gly Gly
Leu Glu Pro Gly 450 455 460Leu Val Phe
Leu Gly Phe Leu Leu Val Val Gly Met Gly Leu Ala Gly465
470 475 480Ala Phe Leu Ala His Tyr Val
Arg His Arg Leu Leu His Met Gln Met 485
490 495Val Ser Gly Pro Asn Lys Ile Ile Leu Thr Val Asp
Asp Ile Thr Phe 500 505 510Leu
His Pro His Gly Gly Thr Ser Arg Lys Val Ala Gln Gly Ser Arg 515
520 525Ser Ser Leu Gly Ala Arg Ser Met Ser
Asp Ile Arg Ser Gly Pro Ser 530 535
540Gln His Leu Asp Ser Pro Asn Ile Gly Val Tyr Glu Gly Asp Arg Val545
550 555 560Trp Leu Lys Lys
Phe Pro Gly Asp Gln His Ile Ala Ile Arg Pro Ala 565
570 575Thr Lys Thr Ala Phe Ser Lys Leu Gln Glu
Leu Arg His Glu Asn Val 580 585
590Ala Leu Tyr Leu Gly Leu Phe Leu Ala Arg Gly Ala Glu Gly Pro Ala
595 600 605Ala Leu Trp Glu Gly Asn Leu
Ala Val Val Ser Glu His Cys Thr Arg 610 615
620Gly Ser Leu Gln Asp Leu Leu Ala Gln Arg Glu Ile Lys Leu Asp
Trp625 630 635 640Met Phe
Lys Ser Ser Leu Leu Leu Asp Leu Ile Lys Gly Ile Arg Tyr
645 650 655Leu His His Arg Gly Val Ala
His Gly Arg Leu Lys Ser Arg Asn Cys 660 665
670Ile Val Asp Gly Arg Phe Val Leu Lys Ile Thr Asp His Gly
His Gly 675 680 685Arg Leu Leu Glu
Ala Gln Lys Val Leu Pro Glu Pro Pro Arg Ala Glu 690
695 700Asp Gln Leu Trp Thr Ala Pro Glu Leu Leu Arg Asp
Pro Ala Leu Glu705 710 715
720Arg Arg Gly Thr Leu Ala Gly Asp Val Phe Ser Leu Ala Ile Ile Met
725 730 735Gln Glu Val Val Cys
Arg Ser Ala Pro Tyr Ala Met Leu Glu Leu Thr 740
745 750Pro Glu Glu Val Val Gln Arg Val Arg Ser Pro Pro
Pro Leu Cys Arg 755 760 765Pro Leu
Val Ser Met Asp Gln Ala Pro Val Glu Cys Ile Leu Leu Met 770
775 780Lys Gln Cys Trp Ala Glu Gln Pro Glu Leu Arg
Pro Ser Met Asp His785 790 795
800Thr Phe Asp Leu Phe Lys Asn Ile Asn Lys Gly Arg Lys Thr Asn Ile
805 810 815Ile Asp Ser Met
Leu Arg Met Leu Glu Gln Tyr Ser Ser Asn Leu Glu 820
825 830Asp Leu Ile Arg Glu Arg Thr Glu Glu Leu Glu
Leu Glu Lys Gln Lys 835 840 845Thr
Asp Arg Leu Leu Thr Gln Met Leu Pro Pro Ser Val Ala Glu Ala 850
855 860Leu Lys Thr Gly Thr Pro Val Glu Pro Glu
Tyr Phe Glu Gln Val Thr865 870 875
880Leu Tyr Phe Ser Asp Ile Val Gly Phe Thr Thr Ile Ser Ala Met
Ser 885 890 895Glu Pro Ile
Glu Val Val Asp Leu Leu Asn Asp Leu Tyr Thr Leu Phe 900
905 910Asp Ala Ile Ile Gly Ser His Asp Val Tyr
Lys Val Glu Thr Ile Gly 915 920
925Asp Ala Tyr Met Val Ala Ser Gly Leu Pro Gln Arg Asn Gly Gln Arg 930
935 940His Ala Ala Glu Ile Ala Asn Met
Ser Leu Asp Ile Leu Ser Ala Val945 950
955 960Gly Thr Phe Arg Met Arg His Met Pro Glu Val Pro
Val Arg Ile Arg 965 970
975Ile Gly Leu His Ser Gly Pro Cys Val Ala Gly Val Val Gly Leu Thr
980 985 990Met Pro Arg Tyr Cys Leu
Phe Gly Asp Thr Val Asn Thr Ala Ser Arg 995 1000
1005Met Glu Ser Thr Gly Leu Pro Tyr Arg Ile His Val
Asn Leu Ser 1010 1015 1020Thr Val Gly
Ile Leu Arg Ala Leu Asp Ser Gly Tyr Gln Val Glu 1025
1030 1035Leu Arg Gly Arg Thr Glu Leu Lys Gly Lys Gly
Ala Glu Asp Thr 1040 1045 1050Phe Trp
Leu Val Gly Arg Arg Gly Phe Asn Lys Pro Ile Pro Lys 1055
1060 1065Pro Pro Asp Leu Gln Pro Gly Ser Ser Asn
His Gly Ile Ser Leu 1070 1075 1080Gln
Glu Ile Pro Pro Glu Arg Arg Arg Lys Leu Glu Lys Ala Arg 1085
1090 1095Pro Gly Gln Phe Ser
110026676PRTHomo sapiens 26Met Ala Lys Ile Asn Thr Gln Tyr Ser His Pro
Ser Arg Thr His Leu1 5 10
15Lys Val Lys Thr Ser Asp Arg Asp Leu Asn Arg Ala Glu Asn Gly Leu
20 25 30Ser Arg Ala His Ser Ser Ser
Glu Glu Thr Ser Ser Val Leu Gln Pro 35 40
45Gly Ile Ala Met Glu Thr Arg Gly Leu Ala Asp Ser Gly Gln Gly
Ser 50 55 60Phe Thr Gly Gln Gly Ile
Ala Arg Leu Ser Arg Leu Ile Phe Leu Leu65 70
75 80Arg Arg Trp Ala Ala Arg His Val His His Gln
Asp Gln Gly Pro Asp 85 90
95Ser Phe Pro Asp Arg Phe Arg Gly Ala Glu Leu Lys Glu Val Ser Ser
100 105 110Gln Glu Ser Asn Ala Gln
Ala Asn Val Gly Ser Gln Glu Pro Ala Asp 115 120
125Arg Gly Arg Arg Lys Lys Thr Lys Lys Lys Asp Ala Ile Val
Val Asp 130 135 140Pro Ser Ser Asn Leu
Tyr Tyr Arg Trp Leu Thr Ala Ile Ala Leu Pro145 150
155 160Val Phe Tyr Asn Trp Tyr Leu Leu Ile Cys
Arg Ala Cys Phe Asp Glu 165 170
175Leu Gln Ser Glu Tyr Leu Met Leu Trp Leu Val Leu Asp Tyr Ser Ala
180 185 190Asp Val Leu Tyr Val
Leu Asp Val Leu Val Arg Ala Arg Thr Gly Phe 195
200 205Leu Glu Gln Gly Leu Met Val Ser Asp Thr Asn Arg
Leu Trp Gln His 210 215 220Tyr Lys Thr
Thr Thr Gln Phe Lys Leu Asp Val Leu Ser Leu Val Pro225
230 235 240Thr Asp Leu Ala Tyr Leu Lys
Val Gly Thr Asn Tyr Pro Glu Val Arg 245
250 255Phe Asn Arg Leu Leu Lys Phe Ser Arg Leu Phe Glu
Phe Phe Asp Arg 260 265 270Thr
Glu Thr Arg Thr Asn Tyr Pro Asn Met Phe Arg Ile Gly Asn Leu 275
280 285Val Leu Tyr Ile Leu Ile Ile Ile His
Trp Asn Ala Cys Ile Tyr Phe 290 295
300Ala Ile Ser Lys Phe Ile Gly Phe Gly Thr Asp Ser Trp Val Tyr Pro305
310 315 320Asn Ile Ser Ile
Pro Glu His Gly Arg Leu Ser Arg Lys Tyr Ile Tyr 325
330 335Ser Leu Tyr Trp Ser Thr Leu Thr Leu Thr
Thr Ile Gly Glu Thr Pro 340 345
350Pro Pro Val Lys Asp Glu Glu Tyr Leu Phe Val Val Val Asp Phe Leu
355 360 365Val Gly Val Leu Ile Phe Ala
Thr Ile Val Gly Asn Val Gly Ser Met 370 375
380Ile Ser Asn Met Asn Ala Ser Arg Ala Glu Phe Gln Ala Lys Ile
Asp385 390 395 400Ser Ile
Lys Gln Tyr Met Gln Phe Arg Lys Val Thr Lys Asp Leu Glu
405 410 415Thr Arg Val Ile Arg Trp Phe
Asp Tyr Leu Trp Ala Asn Lys Lys Thr 420 425
430Val Asp Glu Lys Glu Val Leu Lys Ser Leu Pro Asp Lys Leu
Lys Ala 435 440 445Glu Ile Ala Ile
Asn Val His Leu Asp Thr Leu Lys Lys Val Arg Ile 450
455 460Phe Gln Asp Cys Glu Ala Gly Leu Leu Val Glu Leu
Val Leu Lys Leu465 470 475
480Arg Pro Thr Val Phe Ser Pro Gly Asp Tyr Ile Cys Lys Lys Gly Asp
485 490 495Ile Gly Lys Glu Met
Tyr Ile Ile Asn Glu Gly Lys Leu Ala Val Val 500
505 510Ala Asp Asp Gly Val Thr Gln Phe Val Val Leu Ser
Asp Gly Ser Tyr 515 520 525Phe Gly
Glu Ile Ser Ile Leu Asn Ile Lys Gly Ser Lys Ser Gly Asn 530
535 540Arg Arg Thr Ala Asn Ile Arg Ser Ile Gly Tyr
Ser Asp Leu Phe Cys545 550 555
560Leu Ser Lys Asp Asp Leu Met Glu Ala Leu Thr Glu Tyr Pro Glu Ala
565 570 575Lys Lys Ala Leu
Glu Glu Lys Gly Arg Gln Ile Leu Met Lys Asp Asn 580
585 590Leu Ile Asp Glu Glu Leu Ala Arg Ala Gly Ala
Asp Pro Lys Asp Leu 595 600 605Glu
Glu Lys Val Glu Gln Leu Gly Ser Ser Leu Asp Thr Leu Gln Thr 610
615 620Arg Phe Ala Arg Leu Leu Ala Glu Tyr Asn
Ala Thr Gln Met Lys Met625 630 635
640Lys Gln Arg Leu Ser Gln Leu Glu Ser Gln Val Lys Gly Gly Gly
Asp 645 650 655Lys Pro Leu
Ala Asp Gly Glu Val Pro Gly Asp Ala Thr Lys Thr Glu 660
665 670Asp Lys Gln Gln 67527694PRTHomo
sapiens 27Met Ala Lys Ile Asn Thr Gln Tyr Ser His Pro Ser Arg Thr His
Leu1 5 10 15Lys Val Lys
Thr Ser Asp Arg Asp Leu Asn Arg Ala Glu Asn Gly Leu 20
25 30Ser Arg Ala His Ser Ser Ser Glu Glu Thr
Ser Ser Val Leu Gln Pro 35 40
45Gly Ile Ala Met Glu Thr Arg Gly Leu Ala Asp Ser Gly Gln Gly Ser 50
55 60Phe Thr Gly Gln Gly Ile Ala Arg Leu
Ser Arg Leu Ile Phe Leu Leu65 70 75
80Arg Arg Trp Ala Ala Arg His Val His His Gln Asp Gln Gly
Pro Asp 85 90 95Ser Phe
Pro Asp Arg Phe Arg Gly Ala Glu Leu Lys Glu Val Ser Ser 100
105 110Gln Glu Ser Asn Ala Gln Ala Asn Val
Gly Ser Gln Glu Pro Ala Asp 115 120
125Arg Gly Arg Ser Ala Trp Pro Leu Ala Lys Cys Asn Thr Asn Thr Ser
130 135 140Asn Asn Thr Glu Glu Glu Lys
Lys Thr Lys Lys Lys Asp Ala Ile Val145 150
155 160Val Asp Pro Ser Ser Asn Leu Tyr Tyr Arg Trp Leu
Thr Ala Ile Ala 165 170
175Leu Pro Val Phe Tyr Asn Trp Tyr Leu Leu Ile Cys Arg Ala Cys Phe
180 185 190Asp Glu Leu Gln Ser Glu
Tyr Leu Met Leu Trp Leu Val Leu Asp Tyr 195 200
205Ser Ala Asp Val Leu Tyr Val Leu Asp Val Leu Val Arg Ala
Arg Thr 210 215 220Gly Phe Leu Glu Gln
Gly Leu Met Val Ser Asp Thr Asn Arg Leu Trp225 230
235 240Gln His Tyr Lys Thr Thr Thr Gln Phe Lys
Leu Asp Val Leu Ser Leu 245 250
255Val Pro Thr Asp Leu Ala Tyr Leu Lys Val Gly Thr Asn Tyr Pro Glu
260 265 270Val Arg Phe Asn Arg
Leu Leu Lys Phe Ser Arg Leu Phe Glu Phe Phe 275
280 285Asp Arg Thr Glu Thr Arg Thr Asn Tyr Pro Asn Met
Phe Arg Ile Gly 290 295 300Asn Leu Val
Leu Tyr Ile Leu Ile Ile Ile His Trp Asn Ala Cys Ile305
310 315 320Tyr Phe Ala Ile Ser Lys Phe
Ile Gly Phe Gly Thr Asp Ser Trp Val 325
330 335Tyr Pro Asn Ile Ser Ile Pro Glu His Gly Arg Leu
Ser Arg Lys Tyr 340 345 350Ile
Tyr Ser Leu Tyr Trp Ser Thr Leu Thr Leu Thr Thr Ile Gly Glu 355
360 365Thr Pro Pro Pro Val Lys Asp Glu Glu
Tyr Leu Phe Val Val Val Asp 370 375
380Phe Leu Val Gly Val Leu Ile Phe Ala Thr Ile Val Gly Asn Val Gly385
390 395 400Ser Met Ile Ser
Asn Met Asn Ala Ser Arg Ala Glu Phe Gln Ala Lys 405
410 415Ile Asp Ser Ile Lys Gln Tyr Met Gln Phe
Arg Lys Val Thr Lys Asp 420 425
430Leu Glu Thr Arg Val Ile Arg Trp Phe Asp Tyr Leu Trp Ala Asn Lys
435 440 445Lys Thr Val Asp Glu Lys Glu
Val Leu Lys Ser Leu Pro Asp Lys Leu 450 455
460Lys Ala Glu Ile Ala Ile Asn Val His Leu Asp Thr Leu Lys Lys
Val465 470 475 480Arg Ile
Phe Gln Asp Cys Glu Ala Gly Leu Leu Val Glu Leu Val Leu
485 490 495Lys Leu Arg Pro Thr Val Phe
Ser Pro Gly Asp Tyr Ile Cys Lys Lys 500 505
510Gly Asp Ile Gly Lys Glu Met Tyr Ile Ile Asn Glu Gly Lys
Leu Ala 515 520 525Val Val Ala Asp
Asp Gly Val Thr Gln Phe Val Val Leu Ser Asp Gly 530
535 540Ser Tyr Phe Gly Glu Ile Ser Ile Leu Asn Ile Lys
Gly Ser Lys Ser545 550 555
560Gly Asn Arg Arg Thr Ala Asn Ile Arg Ser Ile Gly Tyr Ser Asp Leu
565 570 575Phe Cys Leu Ser Lys
Asp Asp Leu Met Glu Ala Leu Thr Glu Tyr Pro 580
585 590Glu Ala Lys Lys Ala Leu Glu Glu Lys Gly Arg Gln
Ile Leu Met Lys 595 600 605Asp Asn
Leu Ile Asp Glu Glu Leu Ala Arg Ala Gly Ala Asp Pro Lys 610
615 620Asp Leu Glu Glu Lys Val Glu Gln Leu Gly Ser
Ser Leu Asp Thr Leu625 630 635
640Gln Thr Arg Phe Ala Arg Leu Leu Ala Glu Tyr Asn Ala Thr Gln Met
645 650 655Lys Met Lys Gln
Arg Leu Ser Gln Leu Glu Ser Gln Val Lys Gly Gly 660
665 670Gly Asp Lys Pro Leu Ala Asp Gly Glu Val Pro
Gly Asp Ala Thr Lys 675 680 685Thr
Glu Asp Lys Gln Gln 69028354PRTHomo sapiens 28Met Gly Ser Gly Ala Ser
Ala Glu Asp Lys Glu Leu Ala Lys Arg Ser1 5
10 15Lys Glu Leu Glu Lys Lys Leu Gln Glu Asp Ala Asp
Lys Glu Ala Lys 20 25 30Thr
Val Lys Leu Leu Leu Leu Gly Ala Gly Glu Ser Gly Lys Ser Thr 35
40 45Ile Val Lys Gln Met Lys Ile Ile His
Gln Asp Gly Tyr Ser Pro Glu 50 55
60Glu Cys Leu Glu Phe Lys Ala Ile Ile Tyr Gly Asn Val Leu Gln Ser65
70 75 80Ile Leu Ala Ile Ile
Arg Ala Met Thr Thr Leu Gly Ile Asp Tyr Ala 85
90 95Glu Pro Ser Cys Ala Asp Asp Gly Arg Gln Leu
Asn Asn Leu Ala Asp 100 105
110Ser Ile Glu Glu Gly Thr Met Pro Pro Glu Leu Val Glu Val Ile Arg
115 120 125Arg Leu Trp Lys Asp Gly Gly
Val Gln Ala Cys Phe Glu Arg Ala Ala 130 135
140Glu Tyr Gln Leu Asn Asp Ser Ala Ser Tyr Tyr Leu Asn Gln Leu
Glu145 150 155 160Arg Ile
Thr Asp Pro Glu Tyr Leu Pro Ser Glu Gln Asp Val Leu Arg
165 170 175Ser Arg Val Lys Thr Thr Gly
Ile Ile Glu Thr Lys Phe Ser Val Lys 180 185
190Asp Leu Asn Phe Arg Met Phe Asp Val Gly Gly Gln Arg Ser
Glu Arg 195 200 205Lys Lys Trp Ile
His Cys Phe Glu Gly Val Thr Cys Ile Ile Phe Cys 210
215 220Ala Ala Leu Ser Ala Tyr Asp Met Val Leu Val Glu
Asp Asp Glu Val225 230 235
240Asn Arg Met His Glu Ser Leu His Leu Phe Asn Ser Ile Cys Asn His
245 250 255Lys Phe Phe Ala Ala
Thr Ser Ile Val Leu Phe Leu Asn Lys Lys Asp 260
265 270Leu Phe Glu Glu Lys Ile Lys Lys Val His Leu Ser
Ile Cys Phe Pro 275 280 285Glu Tyr
Asp Gly Asn Asn Ser Tyr Asp Asp Ala Gly Asn Tyr Ile Lys 290
295 300Ser Gln Phe Leu Asp Leu Asn Met Arg Lys Asp
Val Lys Glu Ile Tyr305 310 315
320Ser His Met Thr Cys Ala Thr Asp Thr Gln Asn Val Lys Phe Val Phe
325 330 335Asp Ala Val Thr
Asp Ile Ile Ile Lys Glu Asn Leu Lys Asp Cys Gly 340
345 350Leu Phe 29858PRTHomo sapiens 29Met Gly Glu
Ile Asn Gln Val Ala Val Glu Lys Tyr Leu Glu Glu Asn1 5
10 15Pro Gln Phe Ala Lys Glu Tyr Phe Asp
Arg Lys Leu Arg Val Glu Val 20 25
30Leu Gly Glu Ile Phe Lys Asn Ser Gln Val Pro Val Gln Ser Ser Met
35 40 45Ser Phe Ser Glu Leu Thr Gln
Val Glu Glu Ser Ala Leu Cys Leu Glu 50 55
60Leu Leu Trp Thr Val Gln Glu Glu Gly Gly Thr Pro Glu Gln Gly Val65
70 75 80His Arg Ala Leu
Gln Arg Leu Ala His Leu Leu Gln Ala Asp Arg Cys 85
90 95Ser Met Phe Leu Cys Arg Ser Arg Asn Gly
Ile Pro Glu Val Ala Ser 100 105
110Arg Leu Leu Asp Val Thr Pro Thr Ser Lys Phe Glu Asp Asn Leu Val
115 120 125Gly Pro Asp Lys Glu Val Val
Phe Pro Leu Asp Ile Gly Ile Val Gly 130 135
140Trp Ala Ala His Thr Lys Lys Thr His Asn Val Pro Asp Val Lys
Lys145 150 155 160Asn Ser
His Phe Ser Asp Phe Met Asp Lys Gln Thr Gly Tyr Val Thr
165 170 175Lys Asn Leu Leu Ala Thr Pro
Ile Val Val Gly Lys Glu Val Leu Ala 180 185
190Val Ile Met Ala Val Asn Lys Val Asn Ala Ser Glu Phe Ser
Lys Gln 195 200 205Asp Glu Glu Val
Phe Ser Lys Tyr Leu Asn Phe Val Ser Ile Ile Leu 210
215 220Arg Leu His His Thr Ser Tyr Met Tyr Asn Ile Glu
Ser Arg Arg Ser225 230 235
240Gln Ile Leu Met Trp Ser Ala Asn Lys Val Phe Glu Glu Leu Thr Asp
245 250 255Val Glu Arg Gln Phe
His Lys Ala Leu Tyr Thr Val Arg Ser Tyr Leu 260
265 270Asn Cys Glu Arg Tyr Ser Ile Gly Leu Leu Asp Met
Thr Lys Glu Lys 275 280 285Glu Phe
Tyr Asp Glu Trp Pro Ile Lys Leu Gly Glu Val Glu Pro Tyr 290
295 300Lys Gly Pro Lys Thr Pro Asp Gly Arg Glu Val
Asn Phe Tyr Lys Ile305 310 315
320Ile Asp Tyr Ile Leu His Gly Lys Glu Glu Ile Lys Val Ile Pro Thr
325 330 335Pro Pro Ala Asp
His Trp Thr Leu Ile Ser Gly Leu Pro Thr Tyr Val 340
345 350Ala Glu Asn Gly Phe Ile Cys Asn Met Met Asn
Ala Pro Ala Asp Glu 355 360 365Tyr
Phe Thr Phe Gln Lys Gly Pro Val Asp Glu Thr Gly Trp Val Ile 370
375 380Lys Asn Val Leu Ser Leu Pro Ile Val Asn
Lys Lys Glu Asp Ile Val385 390 395
400Gly Val Ala Thr Phe Tyr Asn Arg Lys Asp Gly Lys Pro Phe Asp
Glu 405 410 415His Asp Glu
Tyr Ile Thr Glu Thr Leu Thr Gln Phe Leu Gly Trp Ser 420
425 430Leu Leu Asn Thr Asp Thr Tyr Asp Lys Met
Asn Lys Leu Glu Asn Arg 435 440
445Lys Asp Ile Ala Gln Glu Met Leu Met Asn Gln Thr Lys Ala Thr Pro 450
455 460Glu Glu Ile Lys Ser Ile Leu Lys
Phe Gln Glu Lys Leu Asn Val Asp465 470
475 480Val Ile Asp Asp Cys Glu Glu Lys Gln Leu Val Ala
Ile Leu Lys Glu 485 490
495Asp Leu Pro Asp Pro Arg Ser Ala Glu Leu Tyr Glu Phe Arg Phe Ser
500 505 510Asp Phe Pro Leu Thr Glu
His Gly Leu Ile Lys Cys Gly Ile Arg Leu 515 520
525Phe Phe Glu Ile Asn Val Val Glu Lys Phe Lys Val Pro Val
Glu Val 530 535 540Leu Thr Arg Trp Met
Tyr Thr Val Arg Lys Gly Tyr Arg Ala Val Thr545 550
555 560Tyr His Asn Trp Arg His Gly Phe Asn Val
Gly Gln Thr Met Phe Thr 565 570
575Leu Leu Met Thr Gly Arg Leu Lys Lys Tyr Tyr Thr Asp Leu Glu Ala
580 585 590Phe Ala Met Leu Ala
Ala Ala Phe Cys His Asp Ile Asp His Arg Gly 595
600 605Thr Asn Asn Leu Tyr Gln Met Lys Ser Thr Ser Pro
Leu Ala Arg Leu 610 615 620His Gly Ser
Ser Ile Leu Glu Arg His His Leu Glu Tyr Ser Lys Thr625
630 635 640Leu Leu Gln Asp Glu Ser Leu
Asn Ile Phe Gln Asn Leu Asn Lys Arg 645
650 655Gln Phe Glu Thr Val Ile His Leu Phe Glu Val Ala
Ile Ile Ala Thr 660 665 670Asp
Leu Ala Leu Tyr Phe Lys Lys Arg Thr Met Phe Gln Lys Ile Val 675
680 685Asp Ala Cys Glu Gln Met Gln Thr Glu
Glu Glu Ala Ile Lys Tyr Val 690 695
700Thr Val Asp Pro Thr Lys Lys Glu Ile Ile Met Ala Met Met Met Thr705
710 715 720Ala Cys Asp Leu
Ser Ala Ile Thr Lys Pro Trp Glu Val Gln Ser Gln 725
730 735Val Ala Leu Met Val Ala Asn Glu Phe Trp
Glu Gln Gly Asp Leu Glu 740 745
750Arg Thr Val Leu Gln Gln Gln Pro Ile Pro Met Met Asp Arg Asn Lys
755 760 765Arg Asp Glu Leu Pro Lys Leu
Gln Val Gly Phe Ile Asp Phe Val Cys 770 775
780Thr Phe Val Tyr Lys Glu Phe Ser Arg Phe His Lys Glu Ile Thr
Pro785 790 795 800Met Leu
Ser Gly Leu Gln Asn Asn Arg Val Glu Trp Lys Ser Leu Ala
805 810 815Asp Glu Tyr Asp Ala Lys Met
Lys Val Ile Glu Glu Glu Ala Lys Lys 820 825
830Gln Glu Gly Gly Ala Glu Lys Ala Ala Glu Asp Ser Gly Gly
Gly Asp 835 840 845Asp Lys Lys Ser
Lys Thr Cys Leu Met Leu 850 8553083PRTHomo sapiens
30Met Ser Asp Asn Thr Thr Leu Pro Ala Pro Ala Ser Asn Gln Gly Pro1
5 10 15Thr Thr Pro Arg Lys Gly
Pro Pro Lys Phe Lys Gln Arg Gln Thr Arg 20 25
30Gln Phe Lys Ser Lys Pro Pro Lys Lys Gly Val Lys Gly
Phe Gly Asp 35 40 45Asp Ile Pro
Gly Met Glu Gly Leu Gly Thr Asp Ile Thr Val Ile Cys 50
55 60Pro Trp Glu Ala Phe Ser His Leu Glu Leu His Glu
Leu Ala Gln Phe65 70 75
80Gly Ile Ile31299PRTHomo sapiens 31Met Met Ala Tyr Met Asn Pro Gly Pro
His Tyr Ser Val Asn Ala Leu1 5 10
15Ala Leu Ser Gly Pro Ser Val Asp Leu Met His Gln Ala Val Pro
Tyr 20 25 30Pro Ser Ala Pro
Arg Lys Gln Arg Arg Glu Arg Thr Thr Phe Thr Arg 35
40 45Ser Gln Leu Glu Glu Leu Glu Ala Leu Phe Ala Lys
Thr Gln Tyr Pro 50 55 60Asp Val Tyr
Ala Arg Glu Glu Val Ala Leu Lys Ile Asn Leu Pro Glu65 70
75 80Ser Arg Val Gln Val Trp Phe Lys
Asn Arg Arg Ala Lys Cys Arg Gln 85 90
95Gln Arg Gln Gln Gln Lys Gln Gln Gln Gln Pro Pro Gly Gly
Gln Ala 100 105 110Lys Ala Arg
Pro Ala Lys Arg Lys Ala Gly Thr Ser Pro Arg Pro Ser 115
120 125Thr Asp Val Cys Pro Asp Pro Leu Gly Ile Ser
Asp Ser Tyr Ser Pro 130 135 140Pro Leu
Pro Gly Pro Ser Gly Ser Pro Thr Thr Ala Val Ala Thr Val145
150 155 160Ser Ile Trp Ser Pro Ala Ser
Glu Ser Pro Leu Pro Glu Ala Gln Arg 165
170 175Ala Gly Leu Val Ala Ser Gly Pro Ser Leu Thr Ser
Ala Pro Tyr Ala 180 185 190Met
Thr Tyr Ala Pro Ala Ser Ala Phe Cys Ser Ser Pro Ser Ala Tyr 195
200 205Gly Ser Pro Ser Ser Tyr Phe Ser Gly
Leu Asp Pro Tyr Leu Ser Pro 210 215
220Met Val Pro Gln Leu Gly Gly Pro Ala Leu Ser Pro Leu Ser Gly Pro225
230 235 240Ser Val Gly Pro
Ser Leu Ala Gln Ser Pro Thr Ser Leu Ser Gly Gln 245
250 255Ser Tyr Gly Ala Tyr Ser Pro Val Asp Ser
Leu Glu Phe Lys Asp Pro 260 265
270Thr Gly Thr Trp Lys Phe Thr Tyr Asn Pro Met Asp Pro Leu Asp Tyr
275 280 285Lys Asp Gln Ser Ala Trp Lys
Phe Gln Ile Leu 290 29532809PRTHomo sapiens 32Met Phe
Lys Ser Leu Thr Lys Val Asn Lys Val Lys Pro Ile Gly Glu1 5
10 15Asn Asn Glu Asn Glu Gln Ser Ser
Arg Arg Asn Glu Glu Gly Ser His 20 25
30Pro Ser Asn Gln Ser Gln Gln Thr Thr Ala Gln Glu Glu Asn Lys
Gly 35 40 45Glu Glu Lys Ser Leu
Lys Thr Lys Ser Thr Pro Val Thr Ser Glu Glu 50 55
60Pro His Thr Asn Ile Gln Asp Lys Leu Ser Lys Lys Asn Ser
Ser Gly65 70 75 80Asp
Leu Thr Thr Asn Pro Asp Pro Gln Asn Ala Ala Glu Pro Thr Gly
85 90 95Thr Val Pro Glu Gln Lys Glu
Met Asp Pro Gly Lys Glu Gly Pro Asn 100 105
110Ser Pro Gln Asn Lys Pro Pro Ala Ala Pro Val Ile Asn Glu
Tyr Ala 115 120 125Asp Ala Gln Leu
His Asn Leu Val Lys Arg Met Arg Gln Arg Thr Ala 130
135 140Leu Tyr Lys Lys Lys Leu Val Glu Gly Asp Leu Ser
Ser Pro Glu Ala145 150 155
160Ser Pro Gln Thr Ala Lys Pro Thr Ala Val Pro Pro Val Lys Glu Ser
165 170 175Asp Asp Lys Pro Thr
Glu His Tyr Tyr Arg Leu Leu Trp Phe Lys Val 180
185 190Lys Lys Met Pro Leu Thr Glu Tyr Leu Lys Arg Ile
Lys Leu Pro Asn 195 200 205Ser Ile
Asp Ser Tyr Thr Asp Arg Leu Tyr Leu Leu Trp Leu Leu Leu 210
215 220Val Thr Leu Ala Tyr Asn Trp Asn Cys Trp Phe
Ile Pro Leu Arg Leu225 230 235
240Val Phe Pro Tyr Gln Thr Ala Asp Asn Ile His Tyr Trp Leu Ile Ala
245 250 255Asp Ile Ile Cys
Asp Ile Ile Tyr Leu Tyr Asp Met Leu Phe Ile Gln 260
265 270Pro Arg Leu Gln Phe Val Arg Gly Gly Asp Ile
Ile Val Asp Ser Asn 275 280 285Glu
Leu Arg Lys His Tyr Arg Thr Ser Thr Lys Phe Gln Leu Asp Val 290
295 300Ala Ser Ile Ile Pro Phe Asp Ile Cys Tyr
Leu Phe Phe Gly Phe Asn305 310 315
320Pro Met Phe Arg Ala Asn Arg Met Leu Lys Tyr Thr Ser Phe Phe
Glu 325 330 335Phe Asn His
His Leu Glu Ser Ile Met Asp Lys Ala Tyr Ile Tyr Arg 340
345 350Val Ile Arg Thr Thr Gly Tyr Leu Leu Phe
Ile Leu His Ile Asn Ala 355 360
365Cys Val Tyr Tyr Trp Ala Ser Asn Tyr Glu Gly Ile Gly Thr Thr Arg 370
375 380Trp Val Tyr Asp Gly Glu Gly Asn
Glu Tyr Leu Arg Cys Tyr Tyr Trp385 390
395 400Ala Val Arg Thr Leu Ile Thr Ile Gly Gly Leu Pro
Glu Pro Gln Thr 405 410
415Leu Phe Glu Ile Val Phe Gln Leu Leu Asn Phe Phe Ser Gly Val Phe
420 425 430Val Phe Ser Ser Leu Ile
Gly Gln Met Arg Asp Val Ile Gly Ala Ala 435 440
445Thr Ala Asn Gln Asn Tyr Phe Arg Ala Cys Met Asp Asp Thr
Ile Ala 450 455 460Tyr Met Asn Asn Tyr
Ser Ile Pro Lys Leu Val Gln Lys Arg Val Arg465 470
475 480Thr Trp Tyr Glu Tyr Thr Trp Asp Ser Gln
Arg Met Leu Asp Glu Ser 485 490
495Asp Leu Leu Lys Thr Leu Pro Thr Thr Val Gln Leu Ala Leu Ala Ile
500 505 510Asp Val Asn Phe Ser
Ile Ile Ser Lys Val Asp Leu Phe Lys Gly Cys 515
520 525Asp Thr Gln Met Ile Tyr Asp Met Leu Leu Arg Leu
Lys Ser Val Leu 530 535 540Tyr Leu Pro
Gly Asp Phe Val Cys Lys Lys Gly Glu Ile Gly Lys Glu545
550 555 560Met Tyr Ile Ile Lys His Gly
Glu Val Gln Val Leu Gly Gly Pro Asp 565
570 575Gly Thr Lys Val Leu Val Thr Leu Lys Ala Gly Ser
Val Phe Gly Glu 580 585 590Ile
Ser Leu Leu Ala Ala Gly Gly Gly Asn Arg Arg Thr Ala Asn Val 595
600 605Val Ala His Gly Phe Ala Asn Leu Leu
Thr Leu Asp Lys Lys Thr Leu 610 615
620Gln Glu Ile Leu Val His Tyr Pro Asp Ser Glu Arg Ile Leu Met Lys625
630 635 640Lys Ala Arg Val
Leu Leu Lys Gln Lys Ala Lys Thr Ala Glu Ala Thr 645
650 655Pro Pro Arg Lys Asp Leu Ala Leu Leu Phe
Pro Pro Lys Glu Glu Thr 660 665
670Pro Lys Leu Phe Lys Thr Leu Leu Gly Gly Thr Gly Lys Ala Ser Leu
675 680 685Ala Arg Leu Leu Lys Leu Lys
Arg Glu Gln Ala Ala Gln Lys Lys Glu 690 695
700Asn Ser Glu Gly Gly Glu Glu Glu Gly Lys Glu Asn Glu Asp Lys
Gln705 710 715 720Lys Glu
Asn Glu Asp Lys Gln Lys Glu Asn Glu Asp Lys Gly Lys Glu
725 730 735Asn Glu Asp Lys Asp Lys Gly
Arg Glu Pro Glu Glu Lys Pro Leu Asp 740 745
750Arg Pro Glu Cys Thr Ala Ser Pro Ile Ala Val Glu Glu Glu
Pro His 755 760 765Ser Val Arg Arg
Thr Val Leu Pro Arg Gly Thr Ser Arg Gln Ser Leu 770
775 780Ile Ile Ser Met Ala Pro Ser Ala Glu Gly Gly Glu
Glu Val Leu Thr785 790 795
800Ile Glu Val Lys Glu Lys Ala Lys Gln 80533610PRTHomo
sapiens 33Met Pro Leu Thr Glu Tyr Leu Lys Arg Ile Lys Leu Pro Asn Ser
Ile1 5 10 15Asp Ser Tyr
Thr Asp Arg Leu Tyr Leu Leu Trp Leu Leu Leu Val Thr 20
25 30Leu Ala Tyr Asn Trp Asn Cys Cys Phe Ile
Pro Leu Arg Leu Val Phe 35 40
45Pro Tyr Gln Thr Ala Asp Asn Ile His Tyr Trp Leu Ile Ala Asp Ile 50
55 60Ile Cys Asp Ile Ile Tyr Leu Tyr Asp
Met Leu Phe Ile Gln Pro Arg65 70 75
80Leu Gln Phe Val Arg Gly Gly Asp Ile Ile Val Asp Ser Asn
Glu Leu 85 90 95Arg Lys
His Tyr Arg Thr Ser Thr Lys Phe Gln Leu Asp Val Ala Ser 100
105 110Ile Ile Pro Phe Asp Ile Cys Tyr Leu
Phe Phe Gly Phe Asn Pro Met 115 120
125Phe Arg Ala Asn Arg Met Leu Lys Tyr Thr Ser Phe Phe Glu Phe Asn
130 135 140His His Leu Glu Ser Ile Met
Asp Lys Ala Tyr Ile Tyr Arg Val Ile145 150
155 160Arg Thr Thr Gly Tyr Leu Leu Phe Ile Leu His Ile
Asn Ala Cys Val 165 170
175Tyr Tyr Trp Ala Ser Asn Tyr Glu Gly Ile Gly Thr Thr Arg Trp Val
180 185 190Tyr Asp Gly Glu Gly Asn
Glu Tyr Leu Arg Cys Tyr Tyr Trp Ala Val 195 200
205Arg Thr Leu Ile Thr Ile Gly Gly Leu Pro Glu Pro Gln Thr
Leu Phe 210 215 220Glu Ile Val Phe Gln
Leu Leu Asn Phe Phe Ser Gly Val Phe Val Phe225 230
235 240Ser Ser Leu Ile Gly Gln Met Arg Asp Val
Ile Gly Ala Ala Thr Ala 245 250
255Asn Gln Asn Tyr Phe Arg Ala Cys Met Asp Asp Thr Ile Ala Tyr Met
260 265 270Asn Asn Tyr Ser Ile
Pro Lys Leu Val Gln Lys Arg Val Arg Thr Trp 275
280 285Tyr Glu Tyr Thr Trp Asp Ser Gln Arg Met Leu Asp
Glu Ser Asp Leu 290 295 300Leu Lys Thr
Leu Pro Thr Thr Val Gln Leu Ala Leu Ala Ile Asp Val305
310 315 320Asn Phe Ser Ile Ile Ser Lys
Val Asp Leu Phe Lys Gly Cys Asp Thr 325
330 335Gln Met Ile Tyr Asp Met Leu Leu Arg Leu Lys Ser
Val Leu Tyr Leu 340 345 350Pro
Gly Asp Phe Val Cys Lys Lys Gly Glu Ile Gly Lys Glu Met Tyr 355
360 365Ile Ile Lys His Gly Glu Val Gln Val
Leu Gly Gly Pro Asp Gly Thr 370 375
380Lys Val Leu Val Thr Leu Lys Ala Gly Ser Val Leu Leu Ala Ala Gly385
390 395 400Gly Gly Asn Arg
Arg Thr Ala Asn Val Val Ala His Gly Phe Ala Asn 405
410 415Leu Leu Thr Leu Asp Lys Lys Thr Leu Gln
Glu Ile Leu Val His Tyr 420 425
430Pro Asp Ser Glu Arg Ile Leu Met Lys Lys Ala Arg Val Leu Leu Lys
435 440 445Gln Lys Ala Lys Thr Ala Glu
Ala Thr Pro Pro Arg Lys Asp Leu Ala 450 455
460Leu Leu Phe Pro Pro Lys Glu Glu Thr Pro Lys Leu Phe Lys Thr
Leu465 470 475 480Leu Gly
Gly Thr Gly Lys Ala Ser Leu Ala Arg Leu Leu Lys Leu Lys
485 490 495Arg Glu Gln Ala Ala Gln Lys
Lys Glu Asn Ser Glu Gly Gly Glu Glu 500 505
510Glu Gly Lys Glu Asn Glu Asp Lys Gln Lys Glu Asn Glu Asp
Lys Gln 515 520 525Lys Glu Asn Glu
Asp Lys Gly Lys Glu Asn Glu Asp Lys Asp Lys Gly 530
535 540Arg Glu Pro Glu Glu Lys Pro Leu Asp Arg Pro Glu
Cys Thr Ala Ser545 550 555
560Pro Ile Ala Val Glu Glu Glu Pro His Ser Val Arg Arg Thr Val Leu
565 570 575Pro Arg Gly Thr Ser
Arg Gln Ser Leu Ile Ile Ser Met Ala Pro Ser 580
585 590Ala Glu Gly Gly Glu Glu Val Leu Thr Ile Glu Val
Lys Glu Lys Ala 595 600 605Lys Gln
610347100DNAHomo sapiens 34gacatactga gaataaatcc aaagacatta gtttctttgc
acgaaatgag gttacatatc 60cagtgacatt tatttgagct atttaaacaa cttaaacatc
tttttctttt cttaataagg 120gacgtttcaa gttgtggtct cagccaaaat gagtgatacc
ccttctactg gtttttccat 180cattcatcct acgtcttctg aaggtcaagt tccaccccct
cgccatttga gcctcactca 240tcctgttgtg gccaagcgaa tcagtttcta caagagcgga
gacccccaat tcggcggggt 300cagggtggtg gtcaaccctc gctcctttaa gtcctttgat
gctctgctgg ataacttgtc 360caggaaggtg cccctccctt ttggagtgag gaacatcagc
acccctcggg gcaggcacag 420catcacgcgc ctggaggagc tggaggacgg cgagtcctac
ctatgttccc acggcaggaa 480ggtgcagcct gtagacctgg acaaagcccg tcggcgcccg
cggccctggc tcagcagccg 540ggccattagc gcgcactcac cgccccaccc cgtagccgtc
gctgctcccg gcatgccccg 600ccccccacgg agcctagtgg tcttcaggaa tggcgacccg
aagacgaggc gtgcggttct 660tctgagcagg agggtcaccc agagcttcga ggcatttcta
cagcacctga cagaggtcat 720gcagcgccct gtggtcaagc tgtacgctac ggacggaagg
agggttccca gcctccaggc 780agtgatcctg agctctggag ctgtggtggc ggcaggaagg
gagccattta aaccaggaaa 840ttatgacatc caaaaatact tgcttcctgc tagattacca
gggatctctc agcgtgtgta 900ccccaaggga aatgcaaagt cagaaagcag aaagataagc
acacatatgt cttcaagctc 960aaggtcccag atttattctg tttcttctga gaaaacacat
aataatgatt gctacttaga 1020ctattctttt gttcctgaaa agtacttggc cttagaaaag
aatgattctc agaatttacc 1080aatatatcct tctgaagatg atattgagaa atcaattatt
tttaatcaag acggcactat 1140gacagttgag atgaaagttc gattcagaat aaaagaggaa
gaaaccataa aatggacaac 1200tactgtcagt aaaactggtc cttctaataa tgatgaaaag
agtgagatga gttttccagg 1260aagaacagaa agtcgatcat ctggtttaaa gcttgcagca
tgttcattct ctgcagatgt 1320gtcacctatg gagcgaagca gtaatcaaga gggcagtttg
gcagaggaga taaacattca 1380aatgacagat caagtggctg aaacttgcag ttctgctagt
tgggagaatg ctactgtgga 1440cacagatatc atccagggaa ctcaagacca agcaaagcat
cgtttttata ggccccctac 1500acctggacta agaagagtga gacaaaagaa atctgtgatt
ggcagtgtga ccttagtatc 1560tgaaactgag gttcaagaga aaatgattgg acagttttca
tatagtgaag aaagggaaag 1620tggggaaaac aagtctgagt atcacatgtt tacacattct
tgcagtaaaa tgtcatcagt 1680atctaacaaa ccagtacttg ttcagatcaa taacaatgat
caaatggagg agtcatcatt 1740agaaagaaaa aaggaaaaca gtctgcttaa gtcaagtgca
ataagtgctg gtgttataga 1800aattacaagt cagaagatgt tagagatgtc acataataat
ggtttgccat caactatatc 1860aaataactca attgtggagg aagatgtagt tgattgtgtg
gtattggaca acaaaactgg 1920tatcaagaac ttcaaaactt atggtaacac caatgatagg
ttcagtccta tttcagcaga 1980tgcaacccat ttttcaagta ataactctgg aactgacaaa
aatatttctg aggctccagc 2040ttcagaagca tcctctactg tcactgcaag aattgacaga
ctaattaatg aatttgctca 2100gtgtggttta acaaaacttc caaaaaatga aaagaagatt
ttgtcatctg ttgccagcaa 2160aaagaagaaa aaatctcgac agcaagcaat aaattccagg
tatcaagatg gacagcttgc 2220aaccaaagga attcttaata agaatgagag aataaacaca
aaaggtagaa ttacaaagga 2280aatgatagtg caagattcag atagtcccct taaaggaggg
atactttgtg aggaagacct 2340ccagaaaagt gatactgtaa ttgaatcaaa tactttttgt
tccaaaagta atctcaattc 2400cacgatttcc aagaatttcc atagaaataa attaaatact
actcaaaatt ccaaggttca 2460aggactttta accaaaagaa aatctagatc actaaataaa
ataagcttag gagcacctaa 2520aaaaagagaa atcggtcaaa gagataaagt gtttcctcac
aatgaatcta aatattgcaa 2580aagtactttt gaaaacaaaa gtttatttca tgtatttaac
atccttgagc aaaaacccaa 2640agatttttat gcaccgcaat ctcaagcaga agtggcatct
gggtatttga gaggaatggc 2700aaagaagagt ttagtttcaa aagttactga ttcacacata
actttaaaaa gccagaaaaa 2760acgtaaaggg gataaagtga aagcaagtgc tattttaagt
aaacaacatg ctacaaccag 2820ggcaaattct ttagcttctt tgaaaaaacc tgattttcct
gaggctattg ctcatcattc 2880aattcaaaat tatatacaga gttggttgca gaacataaat
ccatatccaa ctttaaagcc 2940tataaaatca gctccagtat gtagaaatga aacgagtgtg
gtaaattgta gcaataatag 3000tttttcaggg aatgatcccc atacaaattc tggaaaaata
agtaattttg ttatggaaag 3060taataagcac ataactaaaa ttgccggttt gacaggagat
aatctatgta aagagggaga 3120taagtctttt attgccaatg acactggtga agaagatctc
catgagacac aggttggatc 3180tctgaatgat gcttatttgg ttcccctgca tgaacactgt
actttgtcac agtcagctat 3240taatgatcat aatactaaaa gtcatatagc tgctgaaaaa
tcaggaccag agaaaaaact 3300tgtttaccag gaaataaacc tagctagaaa aaggcaaagt
gtagaggctg ccattcaagt 3360agatcctata gaagaggaaa ctccaaaaga cctcttacca
gtcctgatgc ttcaccaatt 3420gcaagcttca gttcctggta ttcacaagac tcagaatgga
gttgttcaaa tgccaggttc 3480acttgcaggt gttccctttc attctgcaat atgtaattca
tccactaatc tccttctagc 3540ttggctcttg gtgctaaacc taaagggaag tatgaatagc
ttctgtcaag ttgatgctca 3600caaggctacc aacaaatctt cagaaacact tgcattgttg
gagattctaa agcacatagc 3660tatcacagag gaagctgatg acttgaaagc tgctgttgcc
aatttagtgg agtcaactac 3720aagccacttt ggactcagtg agaaagaaca agacatggtt
ccaatagatc tttctgcaaa 3780ttgttccacg gtcaacattc agagtgttcc taagtgcagt
gaaaatgaaa gaacacaagg 3840aatctcctct ttggatggag gttgctctgc cagtgaggca
tgtgcccctg aagtctgtgt 3900tttggaagtg acttgctctc catgtgagat gtgcactgta
aataaggctt attctccaaa 3960agagacatgt aaccccagtg acactttttt tcctagtgat
ggttatggtg tggatcagac 4020ttctatgaat aaggcttgtt tcctaggaga ggtctgttca
cttactgata ctgtgttttc 4080tgataaggct tgtgctcaaa aggagaacca tacctatgag
ggagcttgcc caattgatga 4140gacctacgtt cctgtcaatg tctgcaatac cattgacttt
ttaaactcca aagaaaacac 4200atatactgat aacttggatt caactgaaga gttagaaaga
ggtgatgaca ttcagaaaga 4260tctaaatatt ttgacagacc ctgaatataa aaatggattt
aatacattgg tgtcacatca 4320aaatgtcagt aatttaagct cctgtggcct ttgcctaagt
gaaaaagaag cagaacttga 4380taagaaacat agttctctag atgattttga aaattgttca
ctaaggaagt ttcaggatga 4440aaatgcatat acttcctttg atatggaaga accacggact
tctgaagaac caggctcaat 4500aaccaacagc atgacatcaa gtgaaagaaa catttcagaa
ttggaatctt ttgaagaatt 4560agaaaaccat gacactgata tctttaatac agtggtaaat
ggaggagagc aagccactga 4620agaattaatc caagaagagg tagaggctag taaaacttta
gaattgatag acatctctag 4680taagaatatt atggaagaaa aaagaatgaa cggtataatt
tatgaaataa tcagtaagag 4740gctggcaaca ccaccatctt tagatttttg ctatgattct
aagcaaaata gtgaaaagga 4800gaccaatgaa ggagaaacta agatggtaaa aatgatggtg
aaaactatgg aaactggaag 4860ttattcagag tcctctcctg atttaaaaaa atgcatcaaa
agtccagtga cttctgattg 4920gtcagactat cggcctgaca gtgacagtga gcagccatat
aaaacatcca gtgatgatcc 4980caatgacagt ggcgaactta cccaagagaa agaatataac
ataggatttg ttaaaagggc 5040aatagaaaaa ctgtacggta aagcagatat tatcaaacca
tctttttttc ctgggtctac 5100ccgcaaatct caggtttgtc cttataattc tgtggaattt
cagtgttcca ggaaagcaag 5160tctttatgat tctgaagggc agtcatttgg ctcttctgaa
caggtatcta gtagttcatc 5220tatgttgcag gaattccagg aggaaagaca agataagtgt
gatgttagtg ctgtgaggga 5280caattattgt aggggtgaca ttgtagaacc tggtacaaaa
caaaatgatg atagcagaat 5340cctcacagac atagaggaag gagtactgat tgacaaaggc
aaatggcttc tgaaagaaaa 5400tcatttgcta aggatgtcat ctgaaaatcc tggcatgtgt
ggcaatgcag acaccacatc 5460agtggacacc ctacttgata ataacagcag tgaggtacca
tattcacatt ttggtaattt 5520ggccccaggc ccaacgatgg atgaactctc ctcttcagaa
ctcgaggaac tgactcaacc 5580ccttgaacta aaatgcaatt actttaacat gcctcatggt
agtgactcag aaccttttca 5640tgaggacttg ctggatgttc gcaatgaaac ctgtgccaag
gaaagaatag caaatcatca 5700tacagaggag aagggtagtc atcagtcaga aagagtatgc
acatctgtca ctcattcctt 5760tatttctgct ggtaacaaag tctaccctgt ctctgatgat
gctattaaaa accaaccatt 5820gcctggcagt aatatgattc atggtacact tcaggaagct
gactctttgg ataaactgta 5880tgctctttgt ggtcaacatt gcccaatact aactgttatt
atccaaccca tgaatgagga 5940agaccgagga tttgcatatc gcaaagaatc tgatattgaa
aatttcttgg gtttttattt 6000atggatgaaa atacacccat atttacttca gacagacaaa
aatgtgttca gggaagagaa 6060caataaagca agtatgagac aaaatcttat tgataatgcc
attggtgata tatttgatca 6120gttttatttc agtaacacat ttgacttgat gggtaaaaga
agaaaacaaa aaagaattaa 6180cttcttgggg ttagaggaag aaggtaattt aaagaaattt
caaccagatt tgaaggaaag 6240gttttgtatg aatttcttgc acacatcatt gttagttgtg
ggtaatgtgg attcaaatac 6300acaagacctc agcggtcaga caaatgaaat ctttaaagca
gtcgatgaga ataacaactt 6360attaaataac agattccagg gctcaagaac aaatctcaac
caagtagtaa gagaaaatat 6420caactgtcat tacttctttg aaatgcttgg tcaagcttgc
ctcttagata tttgccaagt 6480tgagacctcc ttaaatatta gcaacagaaa tattttagaa
ctttgtatgt ttgagggtga 6540aaatcttttc atttgggaag aggaagacat attaaattta
actgatcttg aaagcagtag 6600agaacaagaa gatttataat ttcaatatca gcacactcat
tctttgtcaa ttcatttttt 6660cccatgagat gaagcacatg tgacgaatac ggactagata
acctctaaga attttccact 6720tcttcaaaat gaacttactc tagaaagctt acccttggat
aaccagtttg actttcataa 6780tgtctctgtt ttttgttttt ccaacaatta cagactcagg
ttctcttatt ttggaagttt 6840ctatctggtt ttgttctgaa cttacatttt tttttttttt
ggtatctatg attttttttg 6900ctcagggcat caaaatgtgc taaggacaag aattatatcc
tttttaaaaa atgttgttag 6960cttggtgtaa aatgtatatt gactgtattg gtgaataaat
tgaatagaca taacctcaaa 7020gtacttcact tattcttttt aactactgat ttgataaaaa
gtatgattat aagatatcca 7080cgacaatctc atagtttctt
7100352156PRTHomo sapiens 35Met Ser Asp Thr Pro Ser
Thr Gly Phe Ser Ile Ile His Pro Thr Ser1 5
10 15Ser Glu Gly Gln Val Pro Pro Pro Arg His Leu Ser
Leu Thr His Pro 20 25 30Val
Val Ala Lys Arg Ile Ser Phe Tyr Lys Ser Gly Asp Pro Gln Phe 35
40 45Gly Gly Val Arg Val Val Val Asn Pro
Arg Ser Phe Lys Ser Phe Asp 50 55
60Ala Leu Leu Asp Asn Leu Ser Arg Lys Val Pro Leu Pro Phe Gly Val65
70 75 80Arg Asn Ile Ser Thr
Pro Arg Gly Arg His Ser Ile Thr Arg Leu Glu 85
90 95Glu Leu Glu Asp Gly Glu Ser Tyr Leu Cys Ser
His Gly Arg Lys Val 100 105
110Gln Pro Val Asp Leu Asp Lys Ala Arg Arg Arg Pro Arg Pro Trp Leu
115 120 125Ser Ser Arg Ala Ile Ser Ala
His Ser Pro Pro His Pro Val Ala Val 130 135
140Ala Ala Pro Gly Met Pro Arg Pro Pro Arg Ser Leu Val Val Phe
Arg145 150 155 160Asn Gly
Asp Pro Lys Thr Arg Arg Ala Val Leu Leu Ser Arg Arg Val
165 170 175Thr Gln Ser Phe Glu Ala Phe
Leu Gln His Leu Thr Glu Val Met Gln 180 185
190Arg Pro Val Val Lys Leu Tyr Ala Thr Asp Gly Arg Arg Val
Pro Ser 195 200 205Leu Gln Ala Val
Ile Leu Ser Ser Gly Ala Val Val Ala Ala Gly Arg 210
215 220Glu Pro Phe Lys Pro Gly Asn Tyr Asp Ile Gln Lys
Tyr Leu Leu Pro225 230 235
240Ala Arg Leu Pro Gly Ile Ser Gln Arg Val Tyr Pro Lys Gly Asn Ala
245 250 255Lys Ser Glu Ser Arg
Lys Ile Ser Thr His Met Ser Ser Ser Ser Arg 260
265 270Ser Gln Ile Tyr Ser Val Ser Ser Glu Lys Thr His
Asn Asn Asp Cys 275 280 285Tyr Leu
Asp Tyr Ser Phe Val Pro Glu Lys Tyr Leu Ala Leu Glu Lys 290
295 300Asn Asp Ser Gln Asn Leu Pro Ile Tyr Pro Ser
Glu Asp Asp Ile Glu305 310 315
320Lys Ser Ile Ile Phe Asn Gln Asp Gly Thr Met Thr Val Glu Met Lys
325 330 335Val Arg Phe Arg
Ile Lys Glu Glu Glu Thr Ile Lys Trp Thr Thr Thr 340
345 350Val Ser Lys Thr Gly Pro Ser Asn Asn Asp Glu
Lys Ser Glu Met Ser 355 360 365Phe
Pro Gly Arg Thr Glu Ser Arg Ser Ser Gly Leu Lys Leu Ala Ala 370
375 380Cys Ser Phe Ser Ala Asp Val Ser Pro Met
Glu Arg Ser Ser Asn Gln385 390 395
400Glu Gly Ser Leu Ala Glu Glu Ile Asn Ile Gln Met Thr Asp Gln
Val 405 410 415Ala Glu Thr
Cys Ser Ser Ala Ser Trp Glu Asn Ala Thr Val Asp Thr 420
425 430Asp Ile Ile Gln Gly Thr Gln Asp Gln Ala
Lys His Arg Phe Tyr Arg 435 440
445Pro Pro Thr Pro Gly Leu Arg Arg Val Arg Gln Lys Lys Ser Val Ile 450
455 460Gly Ser Val Thr Leu Val Ser Glu
Thr Glu Val Gln Glu Lys Met Ile465 470
475 480Gly Gln Phe Ser Tyr Ser Glu Glu Arg Glu Ser Gly
Glu Asn Lys Ser 485 490
495Glu Tyr His Met Phe Thr His Ser Cys Ser Lys Met Ser Ser Val Ser
500 505 510Asn Lys Pro Val Leu Val
Gln Ile Asn Asn Asn Asp Gln Met Glu Glu 515 520
525Ser Ser Leu Glu Arg Lys Lys Glu Asn Ser Leu Leu Lys Ser
Ser Ala 530 535 540Ile Ser Ala Gly Val
Ile Glu Ile Thr Ser Gln Lys Met Leu Glu Met545 550
555 560Ser His Asn Asn Gly Leu Pro Ser Thr Ile
Ser Asn Asn Ser Ile Val 565 570
575Glu Glu Asp Val Val Asp Cys Val Val Leu Asp Asn Lys Thr Gly Ile
580 585 590Lys Asn Phe Lys Thr
Tyr Gly Asn Thr Asn Asp Arg Phe Ser Pro Ile 595
600 605Ser Ala Asp Ala Thr His Phe Ser Ser Asn Asn Ser
Gly Thr Asp Lys 610 615 620Asn Ile Ser
Glu Ala Pro Ala Ser Glu Ala Ser Ser Thr Val Thr Ala625
630 635 640Arg Ile Asp Arg Leu Ile Asn
Glu Phe Ala Gln Cys Gly Leu Thr Lys 645
650 655Leu Pro Lys Asn Glu Lys Lys Ile Leu Ser Ser Val
Ala Ser Lys Lys 660 665 670Lys
Lys Lys Ser Arg Gln Gln Ala Ile Asn Ser Arg Tyr Gln Asp Gly 675
680 685Gln Leu Ala Thr Lys Gly Ile Leu Asn
Lys Asn Glu Arg Ile Asn Thr 690 695
700Lys Gly Arg Ile Thr Lys Glu Met Ile Val Gln Asp Ser Asp Ser Pro705
710 715 720Leu Lys Gly Gly
Ile Leu Cys Glu Glu Asp Leu Gln Lys Ser Asp Thr 725
730 735Val Ile Glu Ser Asn Thr Phe Cys Ser Lys
Ser Asn Leu Asn Ser Thr 740 745
750Ile Ser Lys Asn Phe His Arg Asn Lys Leu Asn Thr Thr Gln Asn Ser
755 760 765Lys Val Gln Gly Leu Leu Thr
Lys Arg Lys Ser Arg Ser Leu Asn Lys 770 775
780Ile Ser Leu Gly Ala Pro Lys Lys Arg Glu Ile Gly Gln Arg Asp
Lys785 790 795 800Val Phe
Pro His Asn Glu Ser Lys Tyr Cys Lys Ser Thr Phe Glu Asn
805 810 815Lys Ser Leu Phe His Val Phe
Asn Ile Leu Glu Gln Lys Pro Lys Asp 820 825
830Phe Tyr Ala Pro Gln Ser Gln Ala Glu Val Ala Ser Gly Tyr
Leu Arg 835 840 845Gly Met Ala Lys
Lys Ser Leu Val Ser Lys Val Thr Asp Ser His Ile 850
855 860Thr Leu Lys Ser Gln Lys Lys Arg Lys Gly Asp Lys
Val Lys Ala Ser865 870 875
880Ala Ile Leu Ser Lys Gln His Ala Thr Thr Arg Ala Asn Ser Leu Ala
885 890 895Ser Leu Lys Lys Pro
Asp Phe Pro Glu Ala Ile Ala His His Ser Ile 900
905 910Gln Asn Tyr Ile Gln Ser Trp Leu Gln Asn Ile Asn
Pro Tyr Pro Thr 915 920 925Leu Lys
Pro Ile Lys Ser Ala Pro Val Cys Arg Asn Glu Thr Ser Val 930
935 940Val Asn Cys Ser Asn Asn Ser Phe Ser Gly Asn
Asp Pro His Thr Asn945 950 955
960Ser Gly Lys Ile Ser Asn Phe Val Met Glu Ser Asn Lys His Ile Thr
965 970 975Lys Ile Ala Gly
Leu Thr Gly Asp Asn Leu Cys Lys Glu Gly Asp Lys 980
985 990Ser Phe Ile Ala Asn Asp Thr Gly Glu Glu Asp
Leu His Glu Thr Gln 995 1000
1005Val Gly Ser Leu Asn Asp Ala Tyr Leu Val Pro Leu His Glu His
1010 1015 1020Cys Thr Leu Ser Gln Ser
Ala Ile Asn Asp His Asn Thr Lys Ser 1025 1030
1035His Ile Ala Ala Glu Lys Ser Gly Pro Glu Lys Lys Leu Val
Tyr 1040 1045 1050Gln Glu Ile Asn Leu
Ala Arg Lys Arg Gln Ser Val Glu Ala Ala 1055 1060
1065Ile Gln Val Asp Pro Ile Glu Glu Glu Thr Pro Lys Asp
Leu Leu 1070 1075 1080Pro Val Leu Met
Leu His Gln Leu Gln Ala Ser Val Pro Gly Ile 1085
1090 1095His Lys Thr Gln Asn Gly Val Val Gln Met Pro
Gly Ser Leu Ala 1100 1105 1110Gly Val
Pro Phe His Ser Ala Ile Cys Asn Ser Ser Thr Asn Leu 1115
1120 1125Leu Leu Ala Trp Leu Leu Val Leu Asn Leu
Lys Gly Ser Met Asn 1130 1135 1140Ser
Phe Cys Gln Val Asp Ala His Lys Ala Thr Asn Lys Ser Ser 1145
1150 1155Glu Thr Leu Ala Leu Leu Glu Ile Leu
Lys His Ile Ala Ile Thr 1160 1165
1170Glu Glu Ala Asp Asp Leu Lys Ala Ala Val Ala Asn Leu Val Glu
1175 1180 1185Ser Thr Thr Ser His Phe
Gly Leu Ser Glu Lys Glu Gln Asp Met 1190 1195
1200Val Pro Ile Asp Leu Ser Ala Asn Cys Ser Thr Val Asn Ile
Gln 1205 1210 1215Ser Val Pro Lys Cys
Ser Glu Asn Glu Arg Thr Gln Gly Ile Ser 1220 1225
1230Ser Leu Asp Gly Gly Cys Ser Ala Ser Glu Ala Cys Ala
Pro Glu 1235 1240 1245Val Cys Val Leu
Glu Val Thr Cys Ser Pro Cys Glu Met Cys Thr 1250
1255 1260Val Asn Lys Ala Tyr Ser Pro Lys Glu Thr Cys
Asn Pro Ser Asp 1265 1270 1275Thr Phe
Phe Pro Ser Asp Gly Tyr Gly Val Asp Gln Thr Ser Met 1280
1285 1290Asn Lys Ala Cys Phe Leu Gly Glu Val Cys
Ser Leu Thr Asp Thr 1295 1300 1305Val
Phe Ser Asp Lys Ala Cys Ala Gln Lys Glu Asn His Thr Tyr 1310
1315 1320Glu Gly Ala Cys Pro Ile Asp Glu Thr
Tyr Val Pro Val Asn Val 1325 1330
1335Cys Asn Thr Ile Asp Phe Leu Asn Ser Lys Glu Asn Thr Tyr Thr
1340 1345 1350Asp Asn Leu Asp Ser Thr
Glu Glu Leu Glu Arg Gly Asp Asp Ile 1355 1360
1365Gln Lys Asp Leu Asn Ile Leu Thr Asp Pro Glu Tyr Lys Asn
Gly 1370 1375 1380Phe Asn Thr Leu Val
Ser His Gln Asn Val Ser Asn Leu Ser Ser 1385 1390
1395Cys Gly Leu Cys Leu Ser Glu Lys Glu Ala Glu Leu Asp
Lys Lys 1400 1405 1410His Ser Ser Leu
Asp Asp Phe Glu Asn Cys Ser Leu Arg Lys Phe 1415
1420 1425Gln Asp Glu Asn Ala Tyr Thr Ser Phe Asp Met
Glu Glu Pro Arg 1430 1435 1440Thr Ser
Glu Glu Pro Gly Ser Ile Thr Asn Ser Met Thr Ser Ser 1445
1450 1455Glu Arg Asn Ile Ser Glu Leu Glu Ser Phe
Glu Glu Leu Glu Asn 1460 1465 1470His
Asp Thr Asp Ile Phe Asn Thr Val Val Asn Gly Gly Glu Gln 1475
1480 1485Ala Thr Glu Glu Leu Ile Gln Glu Glu
Val Glu Ala Ser Lys Thr 1490 1495
1500Leu Glu Leu Ile Asp Ile Ser Ser Lys Asn Ile Met Glu Glu Lys
1505 1510 1515Arg Met Asn Gly Ile Ile
Tyr Glu Ile Ile Ser Lys Arg Leu Ala 1520 1525
1530Thr Pro Pro Ser Leu Asp Phe Cys Tyr Asp Ser Lys Gln Asn
Ser 1535 1540 1545Glu Lys Glu Thr Asn
Glu Gly Glu Thr Lys Met Val Lys Met Met 1550 1555
1560Val Lys Thr Met Glu Thr Gly Ser Tyr Ser Glu Ser Ser
Pro Asp 1565 1570 1575Leu Lys Lys Cys
Ile Lys Ser Pro Val Thr Ser Asp Trp Ser Asp 1580
1585 1590Tyr Arg Pro Asp Ser Asp Ser Glu Gln Pro Tyr
Lys Thr Ser Ser 1595 1600 1605Asp Asp
Pro Asn Asp Ser Gly Glu Leu Thr Gln Glu Lys Glu Tyr 1610
1615 1620Asn Ile Gly Phe Val Lys Arg Ala Ile Glu
Lys Leu Tyr Gly Lys 1625 1630 1635Ala
Asp Ile Ile Lys Pro Ser Phe Phe Pro Gly Ser Thr Arg Lys 1640
1645 1650Ser Gln Val Cys Pro Tyr Asn Ser Val
Glu Phe Gln Cys Ser Arg 1655 1660
1665Lys Ala Ser Leu Tyr Asp Ser Glu Gly Gln Ser Phe Gly Ser Ser
1670 1675 1680Glu Gln Val Ser Ser Ser
Ser Ser Met Leu Gln Glu Phe Gln Glu 1685 1690
1695Glu Arg Gln Asp Lys Cys Asp Val Ser Ala Val Arg Asp Asn
Tyr 1700 1705 1710Cys Arg Gly Asp Ile
Val Glu Pro Gly Thr Lys Gln Asn Asp Asp 1715 1720
1725Ser Arg Ile Leu Thr Asp Ile Glu Glu Gly Val Leu Ile
Asp Lys 1730 1735 1740Gly Lys Trp Leu
Leu Lys Glu Asn His Leu Leu Arg Met Ser Ser 1745
1750 1755Glu Asn Pro Gly Met Cys Gly Asn Ala Asp Thr
Thr Ser Val Asp 1760 1765 1770Thr Leu
Leu Asp Asn Asn Ser Ser Glu Val Pro Tyr Ser His Phe 1775
1780 1785Gly Asn Leu Ala Pro Gly Pro Thr Met Asp
Glu Leu Ser Ser Ser 1790 1795 1800Glu
Leu Glu Glu Leu Thr Gln Pro Leu Glu Leu Lys Cys Asn Tyr 1805
1810 1815Phe Asn Met Pro His Gly Ser Asp Ser
Glu Pro Phe His Glu Asp 1820 1825
1830Leu Leu Asp Val Arg Asn Glu Thr Cys Ala Lys Glu Arg Ile Ala
1835 1840 1845Asn His His Thr Glu Glu
Lys Gly Ser His Gln Ser Glu Arg Val 1850 1855
1860Cys Thr Ser Val Thr His Ser Phe Ile Ser Ala Gly Asn Lys
Val 1865 1870 1875Tyr Pro Val Ser Asp
Asp Ala Ile Lys Asn Gln Pro Leu Pro Gly 1880 1885
1890Ser Asn Met Ile His Gly Thr Leu Gln Glu Ala Asp Ser
Leu Asp 1895 1900 1905Lys Leu Tyr Ala
Leu Cys Gly Gln His Cys Pro Ile Leu Thr Val 1910
1915 1920Ile Ile Gln Pro Met Asn Glu Glu Asp Arg Gly
Phe Ala Tyr Arg 1925 1930 1935Lys Glu
Ser Asp Ile Glu Asn Phe Leu Gly Phe Tyr Leu Trp Met 1940
1945 1950Lys Ile His Pro Tyr Leu Leu Gln Thr Asp
Lys Asn Val Phe Arg 1955 1960 1965Glu
Glu Asn Asn Lys Ala Ser Met Arg Gln Asn Leu Ile Asp Asn 1970
1975 1980Ala Ile Gly Asp Ile Phe Asp Gln Phe
Tyr Phe Ser Asn Thr Phe 1985 1990
1995Asp Leu Met Gly Lys Arg Arg Lys Gln Lys Arg Ile Asn Phe Leu
2000 2005 2010Gly Leu Glu Glu Glu Gly
Asn Leu Lys Lys Phe Gln Pro Asp Leu 2015 2020
2025Lys Glu Arg Phe Cys Met Asn Phe Leu His Thr Ser Leu Leu
Val 2030 2035 2040Val Gly Asn Val Asp
Ser Asn Thr Gln Asp Leu Ser Gly Gln Thr 2045 2050
2055Asn Glu Ile Phe Lys Ala Val Asp Glu Asn Asn Asn Leu
Leu Asn 2060 2065 2070Asn Arg Phe Gln
Gly Ser Arg Thr Asn Leu Asn Gln Val Val Arg 2075
2080 2085Glu Asn Ile Asn Cys His Tyr Phe Phe Glu Met
Leu Gly Gln Ala 2090 2095 2100Cys Leu
Leu Asp Ile Cys Gln Val Glu Thr Ser Leu Asn Ile Ser 2105
2110 2115Asn Arg Asn Ile Leu Glu Leu Cys Met Phe
Glu Gly Glu Asn Leu 2120 2125 2130Phe
Ile Trp Glu Glu Glu Asp Ile Leu Asn Leu Thr Asp Leu Glu 2135
2140 2145Ser Ser Arg Glu Gln Glu Asp Leu
2150 2155363950DNAHomo sapiens 36atgtcacatc tggtggaccc
tacatcagga gacttgccag ttagagacat agatgctata 60cctctggtgc taccagcctc
aaaaggtaag aatatgaaaa ctcaaccacc cttgagcagg 120atgaaccggg aggaattgga
ggacagtttc tttcgacttc gcgaagatca catgttggtg 180aaggagcttt cttggaagca
acaggatgag atcaaaaggc tgaggaccac cttgctgcgg 240ttgaccgctg ctggccggga
cctgcgggtc gcggaggagg cggcgccgct ctcggagacc 300gcaaggcgcg ggcagaaggc
gggatggcgg cagcgcctct ccatgcacca gcgcccccag 360atgcaccgac tgcaagggca
tttccactgc gtcggccctg ccagcccccg ccgcgcccag 420cctcgcgtcc aagtgggaca
cagacagctc cacacagccg gtgcaccggt gccggagaaa 480cccaagaggg ggccaaggga
caggctgagc tacacagccc ctccatcgtt taaggagcat 540gcgacaaatg aaaacagagg
tgaagtagcc agtaaaccca gtgaacttgt ttctggttct 600aacagcataa tttctttcag
cagtgtcata agtatggcta aacccattgg tctatgcatg 660cctaacagtg cccacatcat
ggccagcaat accatgcaag tggaagagcc acccaagtct 720cctgagaaaa tgtggcctaa
agatgaaaat tttgaacaga gaagctcatt ggagtgtgct 780cagaaggctg cagagcttcg
agcttccatt aaagagaagg tagagctgat tcgacttaag 840aagctcttac atgaaagaaa
tgcttcattg gttatgacaa aagcacaatt aacagaagtt 900caagaggcat acgaaacctt
gctccagaag aatcagggaa tcctgagtgc agcccatgag 960gccctcctca agcaagtgaa
tgagctcagg gcagagctga aggaagaaag caagaaggct 1020gtgagcttga agagccaact
ggaagatgtg tctatcttgc agatgactct gaaggagttt 1080caggagagag ttgaagattt
ggaaaaagaa cgaaaattgc tgaatgacaa ttatgacaaa 1140ctcttagaaa gcatgctgga
cagcagtgac agctccagtc agccccactg gagcaacgag 1200ctcatagcgg aacagctaca
gcagcaagtc tctcagctgc aggatcagct ggatgctgag 1260ctggaggaca agagaaaagt
tttacttgag ctgtccaggg agaaagccca aaatgaggat 1320ctgaagcttg aagtcaccaa
catacttcag aagcataaac aggaagtaga gctcctccaa 1380aatgcagcca caatttccca
acctcctgac aggcaatctg aaccagccac tcacccagct 1440gtattgcaag agaacactca
gatcgagcca agtgaaccca aaaaccaaga agaaaagaaa 1500ctgtcccagg tgctaaatga
gttgcaagta tcacacgcag agaccacatt ggaactagaa 1560aagaccaggg acatgcttat
tctgcagcgc aaaatcaacg tgtgttatca ggaggaactg 1620gaggcaatga tgacaaaagc
tgacaatgat aatagagatc acaaagaaaa gctggagagg 1680ttgactcgac tactagacct
caagaataac cgtatcaagc agctggaagg tattttaaga 1740agccatgacc ttccaacatc
tgaacagctc aaagatgttg cttatggcac ccgaccgttg 1800tcgttatgtt tggaaacact
gccagcccat ggagatgagg ataaagtgga tatttctctg 1860ctgcatcagg gtgagaatct
ttttgaactg cacatccacc aggccttcct gacatctgcc 1920gccctagctc aggctggaga
tacccaacct accactttct gcacctattc cttctatgac 1980tttgaaaccc actgtacccc
attatctgtg gggccacagc ccctctatga cttcacctcc 2040cagtatgtga tggagacaga
ttcgcttttc ttacactacc ttcaagaggc ttcagcccgg 2100cttgacatac accaggccat
ggccagtgaa cacagcactc ttgctgcagg atggatttgc 2160tttgacaggg tgctagagac
tgtggagaaa gtccatggct tggccacact gattggagct 2220ggtggagaag agttcggggt
tctagagtac tggatgaggc tgcgtttccc cataaaaccc 2280agcctacagg cgtgcaataa
acgaaagaaa gcccaggtct acctgtcaac cgatgtgctt 2340ggaggccgga aggcccagga
agaggagttc agatcggagt cttgggaacc tcagaacgag 2400ctgtggattg aaatcaccaa
gtgctgtggc ctccggagtc gatggctggg aactcaaccc 2460agtccatatg ctgtgtaccg
cttcttcacc ttttctgacc atgacactgc catcattcca 2520gccagtaaca acccctactt
tagagaccag gctcgattcc cagtgcttgt gacctctgac 2580ctggaccatt atctgagacg
ggaggccttg tctatacatg tttttgatga tgaagactta 2640gagcctggct cgtatcttgg
ccgagcccga gtgcctttac tgcctcttgc aaaaaatgaa 2700tctatcaaag gtgattttaa
cctcactgac cctgcagaga aacccaacgg atctattcaa 2760gtgcaactgg attggaagtt
tccctacata ccccctgaga gcttcctgaa accagaagct 2820cagactaagg ggaaggatac
caaggacagt tcaaagatct catctgaaga ggaaaaggct 2880tcatttcctt cccaggatca
gatggcatct cctgaggttc ccattgaagc tggccagtat 2940cgatctaaga gaaaacctcc
tcatggggga gaaagaaagg agaaggagca ccaggttgtg 3000agctactcaa gaagaaaaca
tggcaaaaga ataggtgttc aaggaaagaa tagaatggag 3060tatcttagcc ttaacatctt
aaatggaaat acaccagagc aggtgaatta cactgagtgg 3120aagttctcag agactaacag
cttcataggt gatggcttta aaaatcagca cgaggaagag 3180gaaatgacat tatcccattc
agcactgaaa cagaaggaac ctctacatcc tgtaaatgac 3240aaagaatcct ctgaacaagg
ttctgaagtc agtgaagcac aaactaccga cagtgatgat 3300gtcatagtgc cacccatgtc
tcagaaatat cctaaggcag attcagagaa gatgtgcatt 3360gaaattgtct ccctggcctt
ctacccagag gcagaagtga tgtctgatga gaacataaaa 3420caggtgtatg tggagtacaa
attctacgac ctacccttgt cggagacaga gactccagtg 3480tccctaagga agcctagggc
aggagaagaa atccactttc actttagcaa ggtaatagac 3540ctggacccac aggagcagca
aggccgaagg cggtttctgt tcgacatgct gaatggacaa 3600gatcctgatc aaggacattt
aaagtttaca gtggtaagtg atcctctgga tgaagaaaag 3660aaagaatgtg aagaagtggg
atatgcatat cttcaactgt ggcagatcct ggagtcagga 3720agagatattc tagagcaaga
gctagacatt gttagccctg aagatctggc taccccaata 3780ggaaggctga aggtttccct
tcaagcagct gctgtcctcc atgctattta caaggagatg 3840actgaagatt tgttttcatg
aaggaacaag tgctattcca atctaaaagt ctctgaggga 3900accatagtaa aaagtctctt
ataaagttag cttgctataa catgaaaaaa 3950371286PRTHomo sapiens
37Met Ser His Leu Val Asp Pro Thr Ser Gly Asp Leu Pro Val Arg Asp1
5 10 15Ile Asp Ala Ile Pro Leu
Val Leu Pro Ala Ser Lys Gly Lys Asn Met 20 25
30Lys Thr Gln Pro Pro Leu Ser Arg Met Asn Arg Glu Glu
Leu Glu Asp 35 40 45Ser Phe Phe
Arg Leu Arg Glu Asp His Met Leu Val Lys Glu Leu Ser 50
55 60Trp Lys Gln Gln Asp Glu Ile Lys Arg Leu Arg Thr
Thr Leu Leu Arg65 70 75
80Leu Thr Ala Ala Gly Arg Asp Leu Arg Val Ala Glu Glu Ala Ala Pro
85 90 95Leu Ser Glu Thr Ala Arg
Arg Gly Gln Lys Ala Gly Trp Arg Gln Arg 100
105 110Leu Ser Met His Gln Arg Pro Gln Met His Arg Leu
Gln Gly His Phe 115 120 125His Cys
Val Gly Pro Ala Ser Pro Arg Arg Ala Gln Pro Arg Val Gln 130
135 140Val Gly His Arg Gln Leu His Thr Ala Gly Ala
Pro Val Pro Glu Lys145 150 155
160Pro Lys Arg Gly Pro Arg Asp Arg Leu Ser Tyr Thr Ala Pro Pro Ser
165 170 175Phe Lys Glu His
Ala Thr Asn Glu Asn Arg Gly Glu Val Ala Ser Lys 180
185 190Pro Ser Glu Leu Val Ser Gly Ser Asn Ser Ile
Ile Ser Phe Ser Ser 195 200 205Val
Ile Ser Met Ala Lys Pro Ile Gly Leu Cys Met Pro Asn Ser Ala 210
215 220His Ile Met Ala Ser Asn Thr Met Gln Val
Glu Glu Pro Pro Lys Ser225 230 235
240Pro Glu Lys Met Trp Pro Lys Asp Glu Asn Phe Glu Gln Arg Ser
Ser 245 250 255Leu Glu Cys
Ala Gln Lys Ala Ala Glu Leu Arg Ala Ser Ile Lys Glu 260
265 270Lys Val Glu Leu Ile Arg Leu Lys Lys Leu
Leu His Glu Arg Asn Ala 275 280
285Ser Leu Val Met Thr Lys Ala Gln Leu Thr Glu Val Gln Glu Ala Tyr 290
295 300Glu Thr Leu Leu Gln Lys Asn Gln
Gly Ile Leu Ser Ala Ala His Glu305 310
315 320Ala Leu Leu Lys Gln Val Asn Glu Leu Arg Ala Glu
Leu Lys Glu Glu 325 330
335Ser Lys Lys Ala Val Ser Leu Lys Ser Gln Leu Glu Asp Val Ser Ile
340 345 350Leu Gln Met Thr Leu Lys
Glu Phe Gln Glu Arg Val Glu Asp Leu Glu 355 360
365Lys Glu Arg Lys Leu Leu Asn Asp Asn Tyr Asp Lys Leu Leu
Glu Ser 370 375 380Met Leu Asp Ser Ser
Asp Ser Ser Ser Gln Pro His Trp Ser Asn Glu385 390
395 400Leu Ile Ala Glu Gln Leu Gln Gln Gln Val
Ser Gln Leu Gln Asp Gln 405 410
415Leu Asp Ala Glu Leu Glu Asp Lys Arg Lys Val Leu Leu Glu Leu Ser
420 425 430Arg Glu Lys Ala Gln
Asn Glu Asp Leu Lys Leu Glu Val Thr Asn Ile 435
440 445Leu Gln Lys His Lys Gln Glu Val Glu Leu Leu Gln
Asn Ala Ala Thr 450 455 460Ile Ser Gln
Pro Pro Asp Arg Gln Ser Glu Pro Ala Thr His Pro Ala465
470 475 480Val Leu Gln Glu Asn Thr Gln
Ile Glu Pro Ser Glu Pro Lys Asn Gln 485
490 495Glu Glu Lys Lys Leu Ser Gln Val Leu Asn Glu Leu
Gln Val Ser His 500 505 510Ala
Glu Thr Thr Leu Glu Leu Glu Lys Thr Arg Asp Met Leu Ile Leu 515
520 525Gln Arg Lys Ile Asn Val Cys Tyr Gln
Glu Glu Leu Glu Ala Met Met 530 535
540Thr Lys Ala Asp Asn Asp Asn Arg Asp His Lys Glu Lys Leu Glu Arg545
550 555 560Leu Thr Arg Leu
Leu Asp Leu Lys Asn Asn Arg Ile Lys Gln Leu Glu 565
570 575Gly Ile Leu Arg Ser His Asp Leu Pro Thr
Ser Glu Gln Leu Lys Asp 580 585
590Val Ala Tyr Gly Thr Arg Pro Leu Ser Leu Cys Leu Glu Thr Leu Pro
595 600 605Ala His Gly Asp Glu Asp Lys
Val Asp Ile Ser Leu Leu His Gln Gly 610 615
620Glu Asn Leu Phe Glu Leu His Ile His Gln Ala Phe Leu Thr Ser
Ala625 630 635 640Ala Leu
Ala Gln Ala Gly Asp Thr Gln Pro Thr Thr Phe Cys Thr Tyr
645 650 655Ser Phe Tyr Asp Phe Glu Thr
His Cys Thr Pro Leu Ser Val Gly Pro 660 665
670Gln Pro Leu Tyr Asp Phe Thr Ser Gln Tyr Val Met Glu Thr
Asp Ser 675 680 685Leu Phe Leu His
Tyr Leu Gln Glu Ala Ser Ala Arg Leu Asp Ile His 690
695 700Gln Ala Met Ala Ser Glu His Ser Thr Leu Ala Ala
Gly Trp Ile Cys705 710 715
720Phe Asp Arg Val Leu Glu Thr Val Glu Lys Val His Gly Leu Ala Thr
725 730 735Leu Ile Gly Ala Gly
Gly Glu Glu Phe Gly Val Leu Glu Tyr Trp Met 740
745 750Arg Leu Arg Phe Pro Ile Lys Pro Ser Leu Gln Ala
Cys Asn Lys Arg 755 760 765Lys Lys
Ala Gln Val Tyr Leu Ser Thr Asp Val Leu Gly Gly Arg Lys 770
775 780Ala Gln Glu Glu Glu Phe Arg Ser Glu Ser Trp
Glu Pro Gln Asn Glu785 790 795
800Leu Trp Ile Glu Ile Thr Lys Cys Cys Gly Leu Arg Ser Arg Trp Leu
805 810 815Gly Thr Gln Pro
Ser Pro Tyr Ala Val Tyr Arg Phe Phe Thr Phe Ser 820
825 830Asp His Asp Thr Ala Ile Ile Pro Ala Ser Asn
Asn Pro Tyr Phe Arg 835 840 845Asp
Gln Ala Arg Phe Pro Val Leu Val Thr Ser Asp Leu Asp His Tyr 850
855 860Leu Arg Arg Glu Ala Leu Ser Ile His Val
Phe Asp Asp Glu Asp Leu865 870 875
880Glu Pro Gly Ser Tyr Leu Gly Arg Ala Arg Val Pro Leu Leu Pro
Leu 885 890 895Ala Lys Asn
Glu Ser Ile Lys Gly Asp Phe Asn Leu Thr Asp Pro Ala 900
905 910Glu Lys Pro Asn Gly Ser Ile Gln Val Gln
Leu Asp Trp Lys Phe Pro 915 920
925Tyr Ile Pro Pro Glu Ser Phe Leu Lys Pro Glu Ala Gln Thr Lys Gly 930
935 940Lys Asp Thr Lys Asp Ser Ser Lys
Ile Ser Ser Glu Glu Glu Lys Ala945 950
955 960Ser Phe Pro Ser Gln Asp Gln Met Ala Ser Pro Glu
Val Pro Ile Glu 965 970
975Ala Gly Gln Tyr Arg Ser Lys Arg Lys Pro Pro His Gly Gly Glu Arg
980 985 990Lys Glu Lys Glu His Gln
Val Val Ser Tyr Ser Arg Arg Lys His Gly 995 1000
1005Lys Arg Ile Gly Val Gln Gly Lys Asn Arg Met Glu
Tyr Leu Ser 1010 1015 1020Leu Asn Ile
Leu Asn Gly Asn Thr Pro Glu Gln Val Asn Tyr Thr 1025
1030 1035Glu Trp Lys Phe Ser Glu Thr Asn Ser Phe Ile
Gly Asp Gly Phe 1040 1045 1050Lys Asn
Gln His Glu Glu Glu Glu Met Thr Leu Ser His Ser Ala 1055
1060 1065Leu Lys Gln Lys Glu Pro Leu His Pro Val
Asn Asp Lys Glu Ser 1070 1075 1080Ser
Glu Gln Gly Ser Glu Val Ser Glu Ala Gln Thr Thr Asp Ser 1085
1090 1095Asp Asp Val Ile Val Pro Pro Met Ser
Gln Lys Tyr Pro Lys Ala 1100 1105
1110Asp Ser Glu Lys Met Cys Ile Glu Ile Val Ser Leu Ala Phe Tyr
1115 1120 1125Pro Glu Ala Glu Val Met
Ser Asp Glu Asn Ile Lys Gln Val Tyr 1130 1135
1140Val Glu Tyr Lys Phe Tyr Asp Leu Pro Leu Ser Glu Thr Glu
Thr 1145 1150 1155Pro Val Ser Leu Arg
Lys Pro Arg Ala Gly Glu Glu Ile His Phe 1160 1165
1170His Phe Ser Lys Val Ile Asp Leu Asp Pro Gln Glu Gln
Gln Gly 1175 1180 1185Arg Arg Arg Phe
Leu Phe Asp Met Leu Asn Gly Gln Asp Pro Asp 1190
1195 1200Gln Gly His Leu Lys Phe Thr Val Val Ser Asp
Pro Leu Asp Glu 1205 1210 1215Glu Lys
Lys Glu Cys Glu Glu Val Gly Tyr Ala Tyr Leu Gln Leu 1220
1225 1230Trp Gln Ile Leu Glu Ser Gly Arg Asp Ile
Leu Glu Gln Glu Leu 1235 1240 1245Asp
Ile Val Ser Pro Glu Asp Leu Ala Thr Pro Ile Gly Arg Leu 1250
1255 1260Lys Val Ser Leu Gln Ala Ala Ala Val
Leu His Ala Ile Tyr Lys 1265 1270
1275Glu Met Thr Glu Asp Leu Phe Ser 1280
1285387221DNAHomo sapiens 38cgggcggcct cttgtgtgag ggcctgtggg attctccgga
tatggccgga gtgtttcctt 60atcgagggcc gggtaacccg gtgcctggcc ctctagcccc
gctaccggac tacatgtcgg 120aggagaagct gcaggagaaa gctcgaaaat ggcagcaatt
gcaggccaag cgctatgcag 180aaaagcggaa gtttgggttt gtggatgccc agaaggaaga
catgccccca gaacatgtca 240gggagatcat tcgagaccat ggagacatga ccaacaggaa
gttccgccat gacaaaaggg 300tttacttggg tgccctaaag tacatgcccc acgcagtcct
caaactcctg gagaacatgc 360ctatgccttg ggagcagatt cgggatgtgc ccgtgctgta
ccacatcact ggagccattt 420ccttcgtcaa tgagattccc tgggtcattg aacctgtcta
catctcccag tgggggtcaa 480tgtggattat gatgcgccga gaaaaaagag ataggaggca
tttcaagaga atgcgttttc 540ccccttttga tgatgaggag ccgcccttgg actatgctga
caacatccta aatgttgagc 600cactggaggc cattcagcta gagctggacc ctgaggagga
cgcccctgtg ttggactggt 660tctatgacca ccagccgttg agggacagca ggaagtatgt
aaatggctcc acttaccagc 720gctggcagtt cacactacct atgatgtcaa ctctctaccg
cctggctaat cagctcctga 780cagacttggt ggatgacaac tacttctacc tgtttgattt
gaaggccttc tttacgtcca 840aggcactcaa tatggccatt cctggaggcc ccaaatttga
acctcttgtt cgagacatca 900acctacagga tgaagactgg aatgaattca atgatattaa
caagattatc atccggcagc 960ctatccggac tgagtacaag attgcttttc cttacttgta
caacaatctt ccacaccatg 1020tccacctcac ctggtaccat actcccaatg ttgtattcat
caaaactgaa gatcctgact 1080tgccagcttt ctactttgac cctttgatca acccaatctc
ccataggcac tcagtcaaga 1140gccaggaacc attgccggat gatgatgagg aatttgagct
cccggagttt gtggagccct 1200tcctgaagga cacacccctc tatacagaca atacagccaa
tggcattgcc ctgctctggg 1260ccccgcggcc cttcaaccta cgctctggtc gcacccgtcg
ggccctggac ataccccttg 1320tcaagaactg gtatcgggag cattgtcctg ccgggcagcc
tgtgaaagtg agggtctcct 1380accagaagct gcttaagtac tatgtgctga atgccctgaa
gcatcggccc cctaaggctc 1440aaaagaagag gtatttgttc cgctccttca aagccaccaa
attctttcag tccacaaagc 1500tggactgggt ggagggttgg ctccaggttt gccgccaggg
ctacaacatg ctcaaccttc 1560tcattcaccg caaaaacctc aactacctgc acctggacta
caacttcaac ctcaagcctg 1620tgaaaacgct caccaccaag gaaagaaaga aatctcgttt
tgggaatgct ttccacctgt 1680gtcgggaagt tctgcgtttg actaagctgg tggtggatag
tcacgtgcag tatcggctgg 1740gcaatgtgga tgccttccag ctggcagatg gattgcagta
tatatttgcc catgttgggc 1800agttgacggg catgtatcga tacaaataca agctgatgcg
acagattcgc gtgtgcaagg 1860acctgaagca tctcatctat tatcgtttca acacaggccc
tgtagggaag ggtcctggct 1920gtggcttctg ggctgccggt tggcgagtct ggctcttttt
catgcgtggc attacccctt 1980tattagagcg atggcttggc aacctcctgg cccggcagtt
tgaaggtcga cactcaaagg 2040gggtggcaaa gacagtaaca aagcagcgag tggagtcaca
ttttgacctt gagctgcggg 2100cagctgtgat gcatgatatt ctggacatga tgcctgaggg
gatcaagcag aacaaggccc 2160ggacaatcct gcagcacctc agtgaagcct ggcgctgctg
gaaagccaac attccctgga 2220aggtccctgg gctgccgacg cccatagaga atatgatcct
tcgatacgtg aaggccaagg 2280ctgactggtg gaccaacact gcccactaca accgagaacg
gatccgccga ggggccactg 2340tggacaagac tgtttgtaaa aagaatctgg gccgcctcac
ccggctctat ctgaaggcag 2400aacaggagcg gcagcacaac tacctgaagg acgggcctta
catcacagcg gaggaaacag 2460tggcagtata taccaccaca gtgcattggt tggaaagccg
caggttttca cccatcccat 2520tccccccact ctcctataag catgacacca agttgctcat
cttggcattg gagcggctca 2580aggaagctta tagtgtgaag tctcggttga accagtctca
gagggaggag ctaggtctga 2640tcgagcaggc ctacgataac ctccacgagg cgctgtcccg
cataaagcgt cacctcctca 2700cacagagagc cttcaaagag gtgggcattg agttcatgga
tctgtatagc cacctcgttc 2760cagtatatga tgttgagccc ctggagaaga taactgatgc
ttacctggac cagtacctgt 2820ggtatgaagc cgacaagcgc cgcctgttcc caccctggat
taagcctgca gacacagaac 2880cacctccact gcttgtttac aagtggtgtc aaggcatcaa
taacctgcag gacgtgtggg 2940agacgagtga aggcgagtgc aatgtcatgc tggaatcccg
ctttgagaag atgtatgaga 3000agatcgactt gactctgctc aacaggctcg tgcgcctcat
cgtggaccac aacatagccg 3060actacatgac agccaagaac aacgtcgtca tcaactataa
ggacatgaac catacgaatt 3120catatgggat catcagaggc ctgcagtttg cctcattcat
agtgcagtat tatggcctgg 3180tgatggattt gcttgtattg ggattgcacc gggccagtga
gatggctggg ccccctcaga 3240tgccaaatga ctttctcagt ttccaggaca tagccactga
ggctgcccac cccatccgtc 3300tcttctgcag atacattgat cgcatccata tttttttcag
gttcacagca gatgaggctc 3360gggacctgat tcaacgttac ctgacagagc accctgaccc
caataatgaa aacatcgttg 3420gctataataa caagaagtgc tggccccgag atgcccgcat
gcgcctcatg aaacatgatg 3480ttaacttagg ccgggcggta ttctgggaca tcaagaaccg
cttgccacgg tcagtgacta 3540cagttcagtg ggagaacagc ttcgtgtctg tgtacagtaa
ggacaacccc aacctgctgt 3600tcaacatgtg tggcttcgag tgccgcatcc tgcctaagtg
ccgcaccagc tatgaggagt 3660tcacccacaa ggacggggtc tggaacctgc agaatgaggt
tactaaggag cgcacagctc 3720agtgtttcct gcgtgtggac gatgagtcaa tgcagcgctt
ccacaaccgc gtgcgtcaga 3780ttctcatggc ctctgggtcc accaccttca ccaagattgt
gaataagtgg aatacagctc 3840tcattggcct tatgacatac tttcgggagg ctgtggtgaa
cacccaagag ctcttggact 3900tactggtgaa gtgtgagcac aaaatccaga cacgtatcaa
gattggactc aactccaaga 3960tgccaagtcg gttccccccg gttgtgttct acacccctaa
ggagttgggt ggactcggca 4020tgctctcaat gggccatgtg ctcatccccc aatccgacct
caggtggtcc aaacagacag 4080atgtaggtat cacacacttt cgttcaggaa tgagccatga
agaagaccag ctcattccca 4140acttgtaccg ctacatacag ccatgggaga gcgagttcat
tgattctcag cgggtctggg 4200ctgagtactc actcaagaga caagaggcca ttgctcagaa
cagacgcctg actttagaag 4260acctagaaga ttcatgggat cgtggcattc ctcgaatcaa
taccctcttc cagaaggacc 4320ggcacacact ggcttatgat aagggctggc gtgtcagaac
tgactttaag cagtatcagg 4380ttttgaagca gaatccgttc tggtggacac accagcggca
tgatgggaag ctctggaacc 4440tgaacaacta ccgtacagac atgatccagg ccctgggcgg
tgtggaaggc attctggaac 4500acacactctt taagggcact tacttcccta cctgggaggg
gcttttctgg gagaaggcca 4560gtggctttga ggaatctatg aagtggaaga agctaactaa
tgctcagcga tcaggactga 4620accagattcc caatcgtaga ttcaccctct ggtggtcccc
gaccattaat cgagccaatg 4680tatatgtagg ctttcaggtg cagctagacc tgacgggtat
cttcatgcac ggcaagatcc 4740ccacgctgaa gatctctctc atccagatct tccgagctca
cttgtggcag aagatccatg 4800agagcattgt tatggactta tgtcaggtgt ttgaccagga
acttgatgca ctggaaattg 4860agacagtaca aaaggagaca atccatcccc gaaagtcata
taagatgaac tcttcctgtg 4920cagatatcct gctctttgcc tcctataagt ggaatgtctc
ccggccctca ttgctggctg 4980actccaagga tgtgatggac agcaccacca cccagaaata
ctggattgac atccagttgc 5040gctgggggga ctatgattcc cacgacattg agcgctacgc
ccgggccaag ttcctggact 5100acaccaccga caacatgagt atctaccctt cgcccacagg
tgtactcatc gccattgacc 5160tggcctataa cttgcacagt gcctatggaa actggttccc
aggcagcaag cctctcatac 5220aacaggccat ggccaagatc atgaaggcaa accctgccct
gtatgtgtta cgtgaacgga 5280tccgcaaggg gctacagctc tattcatctg aacccactga
gccttatttg tcttctcaga 5340actatggtga gctcttctcc aaccagatta tctggtttgt
ggatgacacc aacgtctaca 5400gagtgactat tcacaagacc tttgaaggga acttgacaac
caagcccatc aacggagcca 5460tcttcatctt caacccacgc acagggcagc tgttcctcaa
gataatccac acgtccgtgt 5520gggcgggaca gaagcgtttg gggcagttgg ctaagtggaa
gacagctgag gaggtggccg 5580ccctgatccg atctctgcct gtggaggagc agcccaagca
gatcattgtc accaggaagg 5640acatgctgga cccactggag gtgcacttac tggacttccc
caatattgtc atcaaaggat 5700cggagctcca actccctttc caggcgtgtc tcaaggtgga
aaaattcggg gatctcatcc 5760ttaaagccac tgagccccag atggttctct tcaacctcta
tgacgactgg ctcaagacta 5820tttcatctta cacggccttc tcccgtctca tcctgattct
gcgtgcccta catgtgaaca 5880acgatcgggc aaaagtgatc ctgaagccag acaagactac
tattacagaa ccacaccaca 5940tctggcccac tctgactgac gaagaatgga tcaaggtcga
ggtgcagctc aaggatctga 6000tcttggctga ctacggcaag aaaaacaatg tgaacgtggc
atcactgaca caatcagaaa 6060ttcgagacat catcctgggt atggagatct cggcaccgtc
acagcagcgg cagcagatcg 6120ctgagatcga gaagcagacc aaggaacaat cgcagctgac
ggcaacacag actcgcactg 6180tcaacaagca tggcgatgag atcatcacct ccaccaccag
caactatgag acccagactt 6240tctcatccaa gactgagtgg agggtcaggg ccatctctgc
tgccaacctg cacctaagga 6300ccaatcacat ctatgtttca tctgacgaca tcaaggagac
tggctacacc tacatccttc 6360ccaagaatgt gcttaagaag ttcatctgca tatctgacct
tcgggcccaa attgcaggat 6420acctatatgg ggtgagccca ccagataacc cccaggtgaa
ggagatccgc tgcattgtga 6480tggtgccgca gtggggcact caccagaccg tgcacctgcc
tggccagctg ccccagcatg 6540agtacctcaa ggagatggaa cccttaggtt ggatccacac
tcagcccaat gagtccccgc 6600agttatcacc ccaggatgtc accacccatg ccaagatcat
ggctgacaac ccatcttggg 6660atggcgagaa gaccattatc atcacatgca gcttcacgcc
aggctcctgt acactgacgg 6720cctacaagct gacccctagt ggctacgaat ggggccgcca
gaacacagac aagggcaaca 6780accccaaggg ctacctgcct tcacactatg agagggtgca
gatgctgctg tcggaccgtt 6840tccttggctt cttcatggtc cctgcccagt cctcgtggaa
ctacaacttc atgggtgttc 6900ggcatgaccc caacatgaaa tatgagctac agctggcgaa
ccccaaagag ttctaccacg 6960aggtgcacag gccctctcac ttcctcaact ttgctctcct
gcaggagggg gaggtttact 7020ctgcggatcg ggaggacctg tatgcctgac cgtttccctg
cctcctgctt cagcctcccg 7080aggccgaagc ctcagcccct ccagacaggc cgctgacatt
cagcagtttg gcctctttcc 7140ctctgtctgt gcttgtgttg ttgacctcct gatggcttgt
catcctgaat aaaatataat 7200aataaatttt gtataaatag g
7221392335PRTHomo sapiens 39Met Ala Gly Val Phe Pro
Tyr Arg Gly Pro Gly Asn Pro Val Pro Gly1 5
10 15Pro Leu Ala Pro Leu Pro Asp Tyr Met Ser Glu Glu
Lys Leu Gln Glu 20 25 30Lys
Ala Arg Lys Trp Gln Gln Leu Gln Ala Lys Arg Tyr Ala Glu Lys 35
40 45Arg Lys Phe Gly Phe Val Asp Ala Gln
Lys Glu Asp Met Pro Pro Glu 50 55
60His Val Arg Glu Ile Ile Arg Asp His Gly Asp Met Thr Asn Arg Lys65
70 75 80Phe Arg His Asp Lys
Arg Val Tyr Leu Gly Ala Leu Lys Tyr Met Pro 85
90 95His Ala Val Leu Lys Leu Leu Glu Asn Met Pro
Met Pro Trp Glu Gln 100 105
110Ile Arg Asp Val Pro Val Leu Tyr His Ile Thr Gly Ala Ile Ser Phe
115 120 125Val Asn Glu Ile Pro Trp Val
Ile Glu Pro Val Tyr Ile Ser Gln Trp 130 135
140Gly Ser Met Trp Ile Met Met Arg Arg Glu Lys Arg Asp Arg Arg
His145 150 155 160Phe Lys
Arg Met Arg Phe Pro Pro Phe Asp Asp Glu Glu Pro Pro Leu
165 170 175Asp Tyr Ala Asp Asn Ile Leu
Asn Val Glu Pro Leu Glu Ala Ile Gln 180 185
190Leu Glu Leu Asp Pro Glu Glu Asp Ala Pro Val Leu Asp Trp
Phe Tyr 195 200 205Asp His Gln Pro
Leu Arg Asp Ser Arg Lys Tyr Val Asn Gly Ser Thr 210
215 220Tyr Gln Arg Trp Gln Phe Thr Leu Pro Met Met Ser
Thr Leu Tyr Arg225 230 235
240Leu Ala Asn Gln Leu Leu Thr Asp Leu Val Asp Asp Asn Tyr Phe Tyr
245 250 255Leu Phe Asp Leu Lys
Ala Phe Phe Thr Ser Lys Ala Leu Asn Met Ala 260
265 270Ile Pro Gly Gly Pro Lys Phe Glu Pro Leu Val Arg
Asp Ile Asn Leu 275 280 285Gln Asp
Glu Asp Trp Asn Glu Phe Asn Asp Ile Asn Lys Ile Ile Ile 290
295 300Arg Gln Pro Ile Arg Thr Glu Tyr Lys Ile Ala
Phe Pro Tyr Leu Tyr305 310 315
320Asn Asn Leu Pro His His Val His Leu Thr Trp Tyr His Thr Pro Asn
325 330 335Val Val Phe Ile
Lys Thr Glu Asp Pro Asp Leu Pro Ala Phe Tyr Phe 340
345 350Asp Pro Leu Ile Asn Pro Ile Ser His Arg His
Ser Val Lys Ser Gln 355 360 365Glu
Pro Leu Pro Asp Asp Asp Glu Glu Phe Glu Leu Pro Glu Phe Val 370
375 380Glu Pro Phe Leu Lys Asp Thr Pro Leu Tyr
Thr Asp Asn Thr Ala Asn385 390 395
400Gly Ile Ala Leu Leu Trp Ala Pro Arg Pro Phe Asn Leu Arg Ser
Gly 405 410 415Arg Thr Arg
Arg Ala Leu Asp Ile Pro Leu Val Lys Asn Trp Tyr Arg 420
425 430Glu His Cys Pro Ala Gly Gln Pro Val Lys
Val Arg Val Ser Tyr Gln 435 440
445Lys Leu Leu Lys Tyr Tyr Val Leu Asn Ala Leu Lys His Arg Pro Pro 450
455 460Lys Ala Gln Lys Lys Arg Tyr Leu
Phe Arg Ser Phe Lys Ala Thr Lys465 470
475 480Phe Phe Gln Ser Thr Lys Leu Asp Trp Val Glu Gly
Trp Leu Gln Val 485 490
495Cys Arg Gln Gly Tyr Asn Met Leu Asn Leu Leu Ile His Arg Lys Asn
500 505 510Leu Asn Tyr Leu His Leu
Asp Tyr Asn Phe Asn Leu Lys Pro Val Lys 515 520
525Thr Leu Thr Thr Lys Glu Arg Lys Lys Ser Arg Phe Gly Asn
Ala Phe 530 535 540His Leu Cys Arg Glu
Val Leu Arg Leu Thr Lys Leu Val Val Asp Ser545 550
555 560His Val Gln Tyr Arg Leu Gly Asn Val Asp
Ala Phe Gln Leu Ala Asp 565 570
575Gly Leu Gln Tyr Ile Phe Ala His Val Gly Gln Leu Thr Gly Met Tyr
580 585 590Arg Tyr Lys Tyr Lys
Leu Met Arg Gln Ile Arg Val Cys Lys Asp Leu 595
600 605Lys His Leu Ile Tyr Tyr Arg Phe Asn Thr Gly Pro
Val Gly Lys Gly 610 615 620Pro Gly Cys
Gly Phe Trp Ala Ala Gly Trp Arg Val Trp Leu Phe Phe625
630 635 640Met Arg Gly Ile Thr Pro Leu
Leu Glu Arg Trp Leu Gly Asn Leu Leu 645
650 655Ala Arg Gln Phe Glu Gly Arg His Ser Lys Gly Val
Ala Lys Thr Val 660 665 670Thr
Lys Gln Arg Val Glu Ser His Phe Asp Leu Glu Leu Arg Ala Ala 675
680 685Val Met His Asp Ile Leu Asp Met Met
Pro Glu Gly Ile Lys Gln Asn 690 695
700Lys Ala Arg Thr Ile Leu Gln His Leu Ser Glu Ala Trp Arg Cys Trp705
710 715 720Lys Ala Asn Ile
Pro Trp Lys Val Pro Gly Leu Pro Thr Pro Ile Glu 725
730 735Asn Met Ile Leu Arg Tyr Val Lys Ala Lys
Ala Asp Trp Trp Thr Asn 740 745
750Thr Ala His Tyr Asn Arg Glu Arg Ile Arg Arg Gly Ala Thr Val Asp
755 760 765Lys Thr Val Cys Lys Lys Asn
Leu Gly Arg Leu Thr Arg Leu Tyr Leu 770 775
780Lys Ala Glu Gln Glu Arg Gln His Asn Tyr Leu Lys Asp Gly Pro
Tyr785 790 795 800Ile Thr
Ala Glu Glu Thr Val Ala Val Tyr Thr Thr Thr Val His Trp
805 810 815Leu Glu Ser Arg Arg Phe Ser
Pro Ile Pro Phe Pro Pro Leu Ser Tyr 820 825
830Lys His Asp Thr Lys Leu Leu Ile Leu Ala Leu Glu Arg Leu
Lys Glu 835 840 845Ala Tyr Ser Val
Lys Ser Arg Leu Asn Gln Ser Gln Arg Glu Glu Leu 850
855 860Gly Leu Ile Glu Gln Ala Tyr Asp Asn Leu His Glu
Ala Leu Ser Arg865 870 875
880Ile Lys Arg His Leu Leu Thr Gln Arg Ala Phe Lys Glu Val Gly Ile
885 890 895Glu Phe Met Asp Leu
Tyr Ser His Leu Val Pro Val Tyr Asp Val Glu 900
905 910Pro Leu Glu Lys Ile Thr Asp Ala Tyr Leu Asp Gln
Tyr Leu Trp Tyr 915 920 925Glu Ala
Asp Lys Arg Arg Leu Phe Pro Pro Trp Ile Lys Pro Ala Asp 930
935 940Thr Glu Pro Pro Pro Leu Leu Val Tyr Lys Trp
Cys Gln Gly Ile Asn945 950 955
960Asn Leu Gln Asp Val Trp Glu Thr Ser Glu Gly Glu Cys Asn Val Met
965 970 975Leu Glu Ser Arg
Phe Glu Lys Met Tyr Glu Lys Ile Asp Leu Thr Leu 980
985 990Leu Asn Arg Leu Val Arg Leu Ile Val Asp His
Asn Ile Ala Asp Tyr 995 1000
1005Met Thr Ala Lys Asn Asn Val Val Ile Asn Tyr Lys Asp Met Asn
1010 1015 1020His Thr Asn Ser Tyr Gly
Ile Ile Arg Gly Leu Gln Phe Ala Ser 1025 1030
1035Phe Ile Val Gln Tyr Tyr Gly Leu Val Met Asp Leu Leu Val
Leu 1040 1045 1050Gly Leu His Arg Ala
Ser Glu Met Ala Gly Pro Pro Gln Met Pro 1055 1060
1065Asn Asp Phe Leu Ser Phe Gln Asp Ile Ala Thr Glu Ala
Ala His 1070 1075 1080Pro Ile Arg Leu
Phe Cys Arg Tyr Ile Asp Arg Ile His Ile Phe 1085
1090 1095Phe Arg Phe Thr Ala Asp Glu Ala Arg Asp Leu
Ile Gln Arg Tyr 1100 1105 1110Leu Thr
Glu His Pro Asp Pro Asn Asn Glu Asn Ile Val Gly Tyr 1115
1120 1125Asn Asn Lys Lys Cys Trp Pro Arg Asp Ala
Arg Met Arg Leu Met 1130 1135 1140Lys
His Asp Val Asn Leu Gly Arg Ala Val Phe Trp Asp Ile Lys 1145
1150 1155Asn Arg Leu Pro Arg Ser Val Thr Thr
Val Gln Trp Glu Asn Ser 1160 1165
1170Phe Val Ser Val Tyr Ser Lys Asp Asn Pro Asn Leu Leu Phe Asn
1175 1180 1185Met Cys Gly Phe Glu Cys
Arg Ile Leu Pro Lys Cys Arg Thr Ser 1190 1195
1200Tyr Glu Glu Phe Thr His Lys Asp Gly Val Trp Asn Leu Gln
Asn 1205 1210 1215Glu Val Thr Lys Glu
Arg Thr Ala Gln Cys Phe Leu Arg Val Asp 1220 1225
1230Asp Glu Ser Met Gln Arg Phe His Asn Arg Val Arg Gln
Ile Leu 1235 1240 1245Met Ala Ser Gly
Ser Thr Thr Phe Thr Lys Ile Val Asn Lys Trp 1250
1255 1260Asn Thr Ala Leu Ile Gly Leu Met Thr Tyr Phe
Arg Glu Ala Val 1265 1270 1275Val Asn
Thr Gln Glu Leu Leu Asp Leu Leu Val Lys Cys Glu His 1280
1285 1290Lys Ile Gln Thr Arg Ile Lys Ile Gly Leu
Asn Ser Lys Met Pro 1295 1300 1305Ser
Arg Phe Pro Pro Val Val Phe Tyr Thr Pro Lys Glu Leu Gly 1310
1315 1320Gly Leu Gly Met Leu Ser Met Gly His
Val Leu Ile Pro Gln Ser 1325 1330
1335Asp Leu Arg Trp Ser Lys Gln Thr Asp Val Gly Ile Thr His Phe
1340 1345 1350Arg Ser Gly Met Ser His
Glu Glu Asp Gln Leu Ile Pro Asn Leu 1355 1360
1365Tyr Arg Tyr Ile Gln Pro Trp Glu Ser Glu Phe Ile Asp Ser
Gln 1370 1375 1380Arg Val Trp Ala Glu
Tyr Ser Leu Lys Arg Gln Glu Ala Ile Ala 1385 1390
1395Gln Asn Arg Arg Leu Thr Leu Glu Asp Leu Glu Asp Ser
Trp Asp 1400 1405 1410Arg Gly Ile Pro
Arg Ile Asn Thr Leu Phe Gln Lys Asp Arg His 1415
1420 1425Thr Leu Ala Tyr Asp Lys Gly Trp Arg Val Arg
Thr Asp Phe Lys 1430 1435 1440Gln Tyr
Gln Val Leu Lys Gln Asn Pro Phe Trp Trp Thr His Gln 1445
1450 1455Arg His Asp Gly Lys Leu Trp Asn Leu Asn
Asn Tyr Arg Thr Asp 1460 1465 1470Met
Ile Gln Ala Leu Gly Gly Val Glu Gly Ile Leu Glu His Thr 1475
1480 1485Leu Phe Lys Gly Thr Tyr Phe Pro Thr
Trp Glu Gly Leu Phe Trp 1490 1495
1500Glu Lys Ala Ser Gly Phe Glu Glu Ser Met Lys Trp Lys Lys Leu
1505 1510 1515Thr Asn Ala Gln Arg Ser
Gly Leu Asn Gln Ile Pro Asn Arg Arg 1520 1525
1530Phe Thr Leu Trp Trp Ser Pro Thr Ile Asn Arg Ala Asn Val
Tyr 1535 1540 1545Val Gly Phe Gln Val
Gln Leu Asp Leu Thr Gly Ile Phe Met His 1550 1555
1560Gly Lys Ile Pro Thr Leu Lys Ile Ser Leu Ile Gln Ile
Phe Arg 1565 1570 1575Ala His Leu Trp
Gln Lys Ile His Glu Ser Ile Val Met Asp Leu 1580
1585 1590Cys Gln Val Phe Asp Gln Glu Leu Asp Ala Leu
Glu Ile Glu Thr 1595 1600 1605Val Gln
Lys Glu Thr Ile His Pro Arg Lys Ser Tyr Lys Met Asn 1610
1615 1620Ser Ser Cys Ala Asp Ile Leu Leu Phe Ala
Ser Tyr Lys Trp Asn 1625 1630 1635Val
Ser Arg Pro Ser Leu Leu Ala Asp Ser Lys Asp Val Met Asp 1640
1645 1650Ser Thr Thr Thr Gln Lys Tyr Trp Ile
Asp Ile Gln Leu Arg Trp 1655 1660
1665Gly Asp Tyr Asp Ser His Asp Ile Glu Arg Tyr Ala Arg Ala Lys
1670 1675 1680Phe Leu Asp Tyr Thr Thr
Asp Asn Met Ser Ile Tyr Pro Ser Pro 1685 1690
1695Thr Gly Val Leu Ile Ala Ile Asp Leu Ala Tyr Asn Leu His
Ser 1700 1705 1710Ala Tyr Gly Asn Trp
Phe Pro Gly Ser Lys Pro Leu Ile Gln Gln 1715 1720
1725Ala Met Ala Lys Ile Met Lys Ala Asn Pro Ala Leu Tyr
Val Leu 1730 1735 1740Arg Glu Arg Ile
Arg Lys Gly Leu Gln Leu Tyr Ser Ser Glu Pro 1745
1750 1755Thr Glu Pro Tyr Leu Ser Ser Gln Asn Tyr Gly
Glu Leu Phe Ser 1760 1765 1770Asn Gln
Ile Ile Trp Phe Val Asp Asp Thr Asn Val Tyr Arg Val 1775
1780 1785Thr Ile His Lys Thr Phe Glu Gly Asn Leu
Thr Thr Lys Pro Ile 1790 1795 1800Asn
Gly Ala Ile Phe Ile Phe Asn Pro Arg Thr Gly Gln Leu Phe 1805
1810 1815Leu Lys Ile Ile His Thr Ser Val Trp
Ala Gly Gln Lys Arg Leu 1820 1825
1830Gly Gln Leu Ala Lys Trp Lys Thr Ala Glu Glu Val Ala Ala Leu
1835 1840 1845Ile Arg Ser Leu Pro Val
Glu Glu Gln Pro Lys Gln Ile Ile Val 1850 1855
1860Thr Arg Lys Asp Met Leu Asp Pro Leu Glu Val His Leu Leu
Asp 1865 1870 1875Phe Pro Asn Ile Val
Ile Lys Gly Ser Glu Leu Gln Leu Pro Phe 1880 1885
1890Gln Ala Cys Leu Lys Val Glu Lys Phe Gly Asp Leu Ile
Leu Lys 1895 1900 1905Ala Thr Glu Pro
Gln Met Val Leu Phe Asn Leu Tyr Asp Asp Trp 1910
1915 1920Leu Lys Thr Ile Ser Ser Tyr Thr Ala Phe Ser
Arg Leu Ile Leu 1925 1930 1935Ile Leu
Arg Ala Leu His Val Asn Asn Asp Arg Ala Lys Val Ile 1940
1945 1950Leu Lys Pro Asp Lys Thr Thr Ile Thr Glu
Pro His His Ile Trp 1955 1960 1965Pro
Thr Leu Thr Asp Glu Glu Trp Ile Lys Val Glu Val Gln Leu 1970
1975 1980Lys Asp Leu Ile Leu Ala Asp Tyr Gly
Lys Lys Asn Asn Val Asn 1985 1990
1995Val Ala Ser Leu Thr Gln Ser Glu Ile Arg Asp Ile Ile Leu Gly
2000 2005 2010Met Glu Ile Ser Ala Pro
Ser Gln Gln Arg Gln Gln Ile Ala Glu 2015 2020
2025Ile Glu Lys Gln Thr Lys Glu Gln Ser Gln Leu Thr Ala Thr
Gln 2030 2035 2040Thr Arg Thr Val Asn
Lys His Gly Asp Glu Ile Ile Thr Ser Thr 2045 2050
2055Thr Ser Asn Tyr Glu Thr Gln Thr Phe Ser Ser Lys Thr
Glu Trp 2060 2065 2070Arg Val Arg Ala
Ile Ser Ala Ala Asn Leu His Leu Arg Thr Asn 2075
2080 2085His Ile Tyr Val Ser Ser Asp Asp Ile Lys Glu
Thr Gly Tyr Thr 2090 2095 2100Tyr Ile
Leu Pro Lys Asn Val Leu Lys Lys Phe Ile Cys Ile Ser 2105
2110 2115Asp Leu Arg Ala Gln Ile Ala Gly Tyr Leu
Tyr Gly Val Ser Pro 2120 2125 2130Pro
Asp Asn Pro Gln Val Lys Glu Ile Arg Cys Ile Val Met Val 2135
2140 2145Pro Gln Trp Gly Thr His Gln Thr Val
His Leu Pro Gly Gln Leu 2150 2155
2160Pro Gln His Glu Tyr Leu Lys Glu Met Glu Pro Leu Gly Trp Ile
2165 2170 2175His Thr Gln Pro Asn Glu
Ser Pro Gln Leu Ser Pro Gln Asp Val 2180 2185
2190Thr Thr His Ala Lys Ile Met Ala Asp Asn Pro Ser Trp Asp
Gly 2195 2200 2205Glu Lys Thr Ile Ile
Ile Thr Cys Ser Phe Thr Pro Gly Ser Cys 2210 2215
2220Thr Leu Thr Ala Tyr Lys Leu Thr Pro Ser Gly Tyr Glu
Trp Gly 2225 2230 2235Arg Gln Asn Thr
Asp Lys Gly Asn Asn Pro Lys Gly Tyr Leu Pro 2240
2245 2250Ser His Tyr Glu Arg Val Gln Met Leu Leu Ser
Asp Arg Phe Leu 2255 2260 2265Gly Phe
Phe Met Val Pro Ala Gln Ser Ser Trp Asn Tyr Asn Phe 2270
2275 2280Met Gly Val Arg His Asp Pro Asn Met Lys
Tyr Glu Leu Gln Leu 2285 2290 2295Ala
Asn Pro Lys Glu Phe Tyr His Glu Val His Arg Pro Ser His 2300
2305 2310Phe Leu Asn Phe Ala Leu Leu Gln Glu
Gly Glu Val Tyr Ser Ala 2315 2320
2325Asp Arg Glu Asp Leu Tyr Ala 2330
2335407972DNAHomo sapiens 40atttgaagtc ctcgttccac gccttctcat catcctgaac
accgagctct gggactccgg 60cggagaatct aaacgtaaag catcacccac ggtcgtgaac
tgtaggctct cctggcatcc 120gggatcttat tctggccttg gcggagttgg ggatggtgtc
gcctagcagc cgctgccgct 180ttggcttgct cgggaccatt tggctggacc cagagtccgc
gtggaaccgc gatagggatc 240tgtcagggcc cgcggccggg tccagcttgg tggttgcggt
agtgagaggc ctccgctggt 300tgccaggctt ggtctagagg tggagcacag tgaaagaatt
caagatgcca cctaatataa 360actggaaaga aataatgaaa gttgacccag atgacctgcc
ccgtcaagaa gaactggcag 420ataatttatt gatttcctta tccaaggtgg aagtaaatga
gctaaaaagt gaaaagcaag 480aaaatgtgat acaccttttc agaattactc agtcactaat
gaagatgaaa gctcaagaag 540tggagctggc tttggaagaa gtagaaaaag ctggagaaga
acaagcaaaa tttgaaaatc 600aattaaaaac taaagtaatg aaactggaaa atgaactgga
gatggctcag cagtctgcag 660gtggacgaga tactcggttt ttacgtaatg aaatttgcca
acttgaaaaa caattagaac 720aaaaagatag agaattggag gacatggaaa aggagttgga
gaaagagaag aaagttaatg 780agcaattggc tcttcgaaat gaggaggcag aaaatgaaaa
cagcaaatta agaagagaga 840acaaacgtct aaagaaaaag aatgaacaac tttgtcagga
tattattgac taccagaaac 900aaatagattc acagaaagaa acacttttat caagaagagg
ggaagacagt gactaccgat 960cacagttgtc taaaaaaaac tatgagctta tccaatatct
tgatgaaatt cagactttaa 1020cagaagctaa tgagaaaatt gaagttcaga atcaagaaat
gagaaaaaat ttagaagagt 1080ctgtacagga aatggagaag atgactgatg aatataatag
aatgaaagct attgtgcatc 1140agacagataa tgtaatagat cagttaaaaa aagaaaacga
tcattatcaa cttcaagtgc 1200aggagcttac agatcttctg aaatcaaaaa atgaagaaga
tgatccaatt atggtagctg 1260tcaatgcaaa agtagaagaa tggaagctaa ttttgtcttc
taaagatgat gaaattattg 1320agtatcagca aatgttacat aacctaaggg agaaacttaa
gaatgctcag cttgatgctg 1380ataaaagtaa tgttatggct ctacagcagg gtatacagga
acgagacagt caaattaaga 1440tgctcaccga acaagtagaa caatatacaa aagaaatgga
aaagaatact tgtattattg 1500aagatttgaa aaatgagctc caaagaaaca aaggtgcttc
aaccctttct caacagactc 1560atatgaaaat tcagtcaacg ttagacattt taaaagagaa
aactaaagag gctgagagaa 1620cagctgaact ggctgaggct gatgctaggg aaaaggataa
agaattagtt gaggctctga 1680agaggttaaa agattatgaa tcgggagtat atggtttaga
agatgctgtc gttgaaataa 1740agaattgtaa aaaccaaatt aaaataagag atcgagagat
tgaaatatta acaaaggaaa 1800tcaataaact tgaattgaag atcagtgatt tccttgatga
aaatgaggca cttagagagc 1860gtgtgggcct tgaaccaaag acaatgattg atttaactga
atttagaaat agcaaacact 1920taaaacagca gcagtacaga gctgaaaacc agattctttt
gaaagagatt gaaagtctag 1980aggaagaacg acttgatctg aaaaaaaaaa ttcgtcaaat
ggctcaagaa agaggaaaaa 2040gaagtgcaac ttcaggatta accactgagg acctgaacct
aactgaaaac atttctcaag 2100gagatagaat aagtgaaaga aaattggatt tattgagcct
caaaaatatg agtgaagcac 2160aatcaaagaa tgaatttctt tcaagagaac taattgaaaa
agaaagagat ttagaaagga 2220gtaggacagt gatagccaaa tttcagaata aattaaaaga
attagttgaa gaaaataagc 2280aacttgaaga aggtatgaaa gaaatattgc aagcaattaa
ggaaatgcag aaagatcctg 2340atgttaaagg aggagaaaca tctctaatta tccctagcct
tgaaagacta gttaatgcta 2400tagaatcaaa gaatgcagaa ggaatctttg atgcgagtct
gcatttgaaa gcccaagttg 2460atcagcttac cggaagaaat gaagaattaa gacaggagct
cagggaatct cggaaagagg 2520ctataaatta ttcacagcag ttggcaaaag ctaatttaaa
gatagaccat cttgaaaaag 2580aaactagtct tttacgacaa tcagaaggat cgaatgttgt
ttttaaagga attgacttac 2640ctgatgggat agcaccatct agtgccagta tcattaattc
tcagaatgaa tatttaatac 2700atttgttaca ggaactagaa aataaagaaa aaaagttaaa
gaatttagaa gattctcttg 2760aagattacaa cagaaaattt gctgtaattc gtcatcaaca
aagtttgttg tataaagaat 2820acctaagtga aaaggagacc tggaaaacag aatctaaaac
aataaaagag gaaaagagaa 2880aacttgagga tcaagtccaa caagatgcta taaaagtaaa
agaatataat aatttgctca 2940atgctcttca gatggattcg gatgaaatga aaaaaatact
tgcagaaaat agtaggaaaa 3000ttactgtttt gcaagtgaat gaaaaatcac ttataaggca
atatacaacc ttagtagaat 3060tggagcgaca acttagaaaa gaaaatgaga agcaaaagaa
tgaattgttg tcaatggagg 3120ctgaagtttg tgaaaaaatt gggtgtttgc aaagatttaa
ggaaatggcc attttcaaga 3180ttgcagctct ccaaaaagtt gtagataata gtgtttcttt
gtctgaacta gaactggcta 3240ataaacagta caatgaactg actgctaagt acagggacat
cttgcaaaaa gataatatgc 3300ttgttcaaag aacaagtaac ttggaacacc tggagtgtga
aaacatctcc ttaaaagaac 3360aagtggagtc tataaataaa gaactggaga ttaccaagga
aaaacttcac actattgaac 3420aagcctggga acaggaaact aaattaggta atgaatctag
catggataag gcaaagaaat 3480caataaccaa cagtgacatt gtttccattt caaaaaaaat
aactatgctg gaaatgaagg 3540aattaaatga aaggcagcgg gctgaacatt gtcaaaaaat
gtatgaacac ttacggactt 3600cgttaaagca aatggaggaa cgtaattttg aattggaaac
caaatttgct gagcttacca 3660aaatcaattt ggatgcacag aaggtggaac agatgttaag
agatgaatta gctgatagtg 3720tgagcaaggc agtaagtgat gctgataggc aacggattct
agaattagag aagaatgaaa 3780tggaactaaa agttgaagtg tcaaaactga gagagatttc
tgatattgcc agaagacaag 3840ttgaaatttt gaatgcacaa caacaatcta gggacaagga
agtagagtcc ctcagaatgc 3900aactgctaga ctatcaggca cagtctgatg aaaagtcgct
cattgccaag ttgcaccaac 3960ataatgtctc tcttcaactg agtgaggcta ctgctcttgg
taagttggag tcaattacat 4020ctaaactgca gaagatggag gcctacaact tgcgcttaga
gcagaaactt gatgaaaaag 4080aacaggctct ctattatgct cgtttggagg gaagaaacag
agcaaaacat ctgcgccaaa 4140caattcagtc tctacgacga cagtttagtg gagctttacc
cttggcacaa caggaaaagt 4200tctccaaaac aatgattcaa ctacaaaatg acaaacttaa
gataatgcaa gaaatgaaaa 4260attctcaaca agaacataga aatatggaga acaaaacatt
ggagatggaa ttaaaattaa 4320agggcctgga agagttaata agcactttaa aggataccaa
aggagcccaa aaggtaatca 4380actggcatat gaaaatagaa gaacttcgtc ttcaagaact
taaactaaat cgggaattag 4440tcaaggataa agaagaaata aaatatttga ataacataat
ttctgaatat gaacgtacaa 4500tcagcagtct tgaagaagaa attgtgcaac agaacaagtt
tcatgaagaa agacaaatgg 4560cctgggatca aagagaagtt gacctggaac gccaactaga
catttttgac cgtcagcaaa 4620atgaaatact aaatgcggca caaaagtttg aagaagctac
aggatcaatc cctgacccta 4680gtttgcccct tccaaatcaa cttgagatcg ctctaaggaa
aattaaggag aacattcgaa 4740taattctaga aacacgggca acttgcaaat cactagaaga
gaaactaaaa gagaaagaat 4800ctgctttaag gttagcagaa caaaatatac tgtcaagaga
caaagtaatc aatgaactga 4860ggcttcgatt gcctgccact gcagaaagag aaaagctcat
agctgagcta ggcagaaaag 4920agatggaacc aaaatctcac cacacattga aaattgctca
tcaaaccatt gcaaacatgc 4980aagcaaggtt aaatcaaaaa gaagaagtat taaagaagta
tcaacgtctt ctagaaaaag 5040ccagagagga gcaaagagaa attgtgaaga aacatgagga
agaccttcat attcttcatc 5100acagattaga actacaggct gatagttcac taaataaatt
caaacaaacg gcttgggatt 5160taatgaaaca gtctcccact ccagttccta ccaacaagca
ttttattcgt ctggctgaga 5220tggaacagac agtagcagaa caagatgact ctctttcctc
actcttggtc aaactaaaga 5280aagtatcaca agatttggag agacaaagag aaatcactga
attaaaagta aaagaatttg 5340aaaatatcaa attacagctt caagaaaacc atgaagatga
agtgaaaaaa gtaaaagcgg 5400aagtagagga tttaaagtat cttctggacc agtcacaaaa
ggagtcacag tgtttaaaat 5460ctgaacttca ggctcaaaaa gaagcaaatt caagagctcc
aacaactaca atgagaaatc 5520tagtagaacg gctaaagagc caattagcct tgaaggagaa
acaacagaaa gcacttagtc 5580gggcactttt agaactccgg gcagaaatga cagcagctgc
tgaagaacgt attatttctg 5640caacttctca aaaagaggcc catctcaatg ttcaacaaat
cgttgatcga catactagag 5700agctaaagac acaagttgaa gatttaaatg aaaatctttt
aaaattgaaa gaagcactta 5760aaacaagtaa aaacagagaa aactcactaa ctgataattt
gaatgactta aataatgaac 5820tgcaaaagaa acaaaaagcc tataataaaa tacttagaga
gaaagaggaa attgatcaag 5880agaatgatga actgaaaagg caaattaaaa gactaaccag
tggattacag ggcaaacccc 5940tgacagataa taaacaaagt ctaattgaag aactccaaag
gaaagttaaa aaactagaga 6000accaattaga gggaaaggtg gaggaagtag acctaaaacc
tatgaaagaa aagaatgcta 6060aagaagaatt aattaggtgg gaagaaggta aaaagtggca
agccaaaata gaaggaattc 6120gaaacaagtt aaaagagaaa gagggggaag tctttacttt
aacaaagcag ttgaatactt 6180tgaaggatct ttttgccaaa gccgataaag agaaacttac
tttgcagagg aaactaaaaa 6240caactggcat gactgttgat caggttttgg gaatacgagc
tttggagtca gaaaaagaat 6300tggaagaatt aaaaaagaga aatcttgact tagaaaatga
tatattgtat atgagggccc 6360accaagctct tcctcgagat tctgttgtag aagatttaca
tttacaaaat agatacctcc 6420aagaaaaact tcatgcttta gaaaaacagt tttcaaagga
tacatattct aagccttcaa 6480tttcaggaat agagtcagat gatcattgtc agagagaaca
ggagcttcag aaggaaaact 6540tgaagttgtc atctgaaaat attgaactga aatttcagct
tgaacaagca aataaagatt 6600tgccaagatt aaagaatcaa gtcagagatt tgaaggaaat
gtgtgaattt cttaagaaag 6660aaaaagcaga agttcagcgg aaacttggcc atgttagagg
gtctggtaga agtggaaaga 6720caatcccaga actggaaaaa accattggtt taatgaaaaa
agtagttgaa aaagtccaga 6780gagaaaatga acagttgaaa aaagcatcag gaatattgac
tagtgaaaaa atggctaata 6840ttgagcagga aaatgaaaaa ttgaaggctg aattagaaaa
acttaaagct catcttgggc 6900atcagttgag catgcactat gaatccaaga ccaaaggcac
agaaaaaatt attgctgaaa 6960atgaaaggct tcgtaaagaa cttaaaaaag aaactgatgc
tgcagagaaa ttacggatag 7020caaagaataa tttagagata ttaaatgaga agatgacagt
tcaactagaa gagactggta 7080agagattgca gtttgcagaa agcagaggtc cacagcttga
aggtgctgac agtaagagct 7140ggaaatccat tgtggttaca agaatgtatg aaaccaagtt
aaaagaattg gaaactgata 7200ttgccaaaaa aaatcaaagc attactgacc ttaaacagct
tgtaaaagaa gcaacagaga 7260gagaacaaaa agttaacaaa tacaatgaag accttgaaca
acagattaag attcttaaac 7320atgttcctga aggtgctgag acagagcaag gccttaaacg
ggagcttcaa gttcttagat 7380tagctaatca tcagctggat aaagagaaag cagaattaat
ccatcagata gaagctaaca 7440aggaccaaag tggagctgaa agcaccatac ctgatgctga
tcaactaaag gaaaaaataa 7500aagatctaga gacacagctc aaaatgtcag atctagaaaa
gcagcatttg aaggaggaaa 7560taaagaagct gaaaaaagaa ctggaaaatt ttgatccttc
attttttgaa gaaattgaag 7620atcttaagta taattacaag gaagaagtga agaagaatat
tctcttagaa gagaaggtaa 7680aaaaactttc agaacaattg ggagttgaat taactagccc
tgttgctgct tctgaagagt 7740ttgaagatga agaagaaagt cctgttaatt tccccattta
ctaaaggtca cctataaact 7800ttgtttcatt taactattta ttaactttat aagttaaata
tacttggaaa taagcagttc 7860tccgaactgt agtatttcct tctcactacc ttgtaccttt
atacttagat tggaattctt 7920aataaataaa attatatgaa attttcaact tattaaaaaa
aaaaaaaaaa aa 7972412479PRTHomo sapiens 41Met Pro Pro Asn Ile
Asn Trp Lys Glu Ile Met Lys Val Asp Pro Asp1 5
10 15Asp Leu Pro Arg Gln Glu Glu Leu Ala Asp Asn
Leu Leu Ile Ser Leu 20 25
30Ser Lys Val Glu Val Asn Glu Leu Lys Ser Glu Lys Gln Glu Asn Val
35 40 45Ile His Leu Phe Arg Ile Thr Gln
Ser Leu Met Lys Met Lys Ala Gln 50 55
60Glu Val Glu Leu Ala Leu Glu Glu Val Glu Lys Ala Gly Glu Glu Gln65
70 75 80Ala Lys Phe Glu Asn
Gln Leu Lys Thr Lys Val Met Lys Leu Glu Asn 85
90 95Glu Leu Glu Met Ala Gln Gln Ser Ala Gly Gly
Arg Asp Thr Arg Phe 100 105
110Leu Arg Asn Glu Ile Cys Gln Leu Glu Lys Gln Leu Glu Gln Lys Asp
115 120 125Arg Glu Leu Glu Asp Met Glu
Lys Glu Leu Glu Lys Glu Lys Lys Val 130 135
140Asn Glu Gln Leu Ala Leu Arg Asn Glu Glu Ala Glu Asn Glu Asn
Ser145 150 155 160Lys Leu
Arg Arg Glu Asn Lys Arg Leu Lys Lys Lys Asn Glu Gln Leu
165 170 175Cys Gln Asp Ile Ile Asp Tyr
Gln Lys Gln Ile Asp Ser Gln Lys Glu 180 185
190Thr Leu Leu Ser Arg Arg Gly Glu Asp Ser Asp Tyr Arg Ser
Gln Leu 195 200 205Ser Lys Lys Asn
Tyr Glu Leu Ile Gln Tyr Leu Asp Glu Ile Gln Thr 210
215 220Leu Thr Glu Ala Asn Glu Lys Ile Glu Val Gln Asn
Gln Glu Met Arg225 230 235
240Lys Asn Leu Glu Glu Ser Val Gln Glu Met Glu Lys Met Thr Asp Glu
245 250 255Tyr Asn Arg Met Lys
Ala Ile Val His Gln Thr Asp Asn Val Ile Asp 260
265 270Gln Leu Lys Lys Glu Asn Asp His Tyr Gln Leu Gln
Val Gln Glu Leu 275 280 285Thr Asp
Leu Leu Lys Ser Lys Asn Glu Glu Asp Asp Pro Ile Met Val 290
295 300Ala Val Asn Ala Lys Val Glu Glu Trp Lys Leu
Ile Leu Ser Ser Lys305 310 315
320Asp Asp Glu Ile Ile Glu Tyr Gln Gln Met Leu His Asn Leu Arg Glu
325 330 335Lys Leu Lys Asn
Ala Gln Leu Asp Ala Asp Lys Ser Asn Val Met Ala 340
345 350Leu Gln Gln Gly Ile Gln Glu Arg Asp Ser Gln
Ile Lys Met Leu Thr 355 360 365Glu
Gln Val Glu Gln Tyr Thr Lys Glu Met Glu Lys Asn Thr Cys Ile 370
375 380Ile Glu Asp Leu Lys Asn Glu Leu Gln Arg
Asn Lys Gly Ala Ser Thr385 390 395
400Leu Ser Gln Gln Thr His Met Lys Ile Gln Ser Thr Leu Asp Ile
Leu 405 410 415Lys Glu Lys
Thr Lys Glu Ala Glu Arg Thr Ala Glu Leu Ala Glu Ala 420
425 430Asp Ala Arg Glu Lys Asp Lys Glu Leu Val
Glu Ala Leu Lys Arg Leu 435 440
445Lys Asp Tyr Glu Ser Gly Val Tyr Gly Leu Glu Asp Ala Val Val Glu 450
455 460Ile Lys Asn Cys Lys Asn Gln Ile
Lys Ile Arg Asp Arg Glu Ile Glu465 470
475 480Ile Leu Thr Lys Glu Ile Asn Lys Leu Glu Leu Lys
Ile Ser Asp Phe 485 490
495Leu Asp Glu Asn Glu Ala Leu Arg Glu Arg Val Gly Leu Glu Pro Lys
500 505 510Thr Met Ile Asp Leu Thr
Glu Phe Arg Asn Ser Lys His Leu Lys Gln 515 520
525Gln Gln Tyr Arg Ala Glu Asn Gln Ile Leu Leu Lys Glu Ile
Glu Ser 530 535 540Leu Glu Glu Glu Arg
Leu Asp Leu Lys Lys Lys Ile Arg Gln Met Ala545 550
555 560Gln Glu Arg Gly Lys Arg Ser Ala Thr Ser
Gly Leu Thr Thr Glu Asp 565 570
575Leu Asn Leu Thr Glu Asn Ile Ser Gln Gly Asp Arg Ile Ser Glu Arg
580 585 590Lys Leu Asp Leu Leu
Ser Leu Lys Asn Met Ser Glu Ala Gln Ser Lys 595
600 605Asn Glu Phe Leu Ser Arg Glu Leu Ile Glu Lys Glu
Arg Asp Leu Glu 610 615 620Arg Ser Arg
Thr Val Ile Ala Lys Phe Gln Asn Lys Leu Lys Glu Leu625
630 635 640Val Glu Glu Asn Lys Gln Leu
Glu Glu Gly Met Lys Glu Ile Leu Gln 645
650 655Ala Ile Lys Glu Met Gln Lys Asp Pro Asp Val Lys
Gly Gly Glu Thr 660 665 670Ser
Leu Ile Ile Pro Ser Leu Glu Arg Leu Val Asn Ala Ile Glu Ser 675
680 685Lys Asn Ala Glu Gly Ile Phe Asp Ala
Ser Leu His Leu Lys Ala Gln 690 695
700Val Asp Gln Leu Thr Gly Arg Asn Glu Glu Leu Arg Gln Glu Leu Arg705
710 715 720Glu Ser Arg Lys
Glu Ala Ile Asn Tyr Ser Gln Gln Leu Ala Lys Ala 725
730 735Asn Leu Lys Ile Asp His Leu Glu Lys Glu
Thr Ser Leu Leu Arg Gln 740 745
750Ser Glu Gly Ser Asn Val Val Phe Lys Gly Ile Asp Leu Pro Asp Gly
755 760 765Ile Ala Pro Ser Ser Ala Ser
Ile Ile Asn Ser Gln Asn Glu Tyr Leu 770 775
780Ile His Leu Leu Gln Glu Leu Glu Asn Lys Glu Lys Lys Leu Lys
Asn785 790 795 800Leu Glu
Asp Ser Leu Glu Asp Tyr Asn Arg Lys Phe Ala Val Ile Arg
805 810 815His Gln Gln Ser Leu Leu Tyr
Lys Glu Tyr Leu Ser Glu Lys Glu Thr 820 825
830Trp Lys Thr Glu Ser Lys Thr Ile Lys Glu Glu Lys Arg Lys
Leu Glu 835 840 845Asp Gln Val Gln
Gln Asp Ala Ile Lys Val Lys Glu Tyr Asn Asn Leu 850
855 860Leu Asn Ala Leu Gln Met Asp Ser Asp Glu Met Lys
Lys Ile Leu Ala865 870 875
880Glu Asn Ser Arg Lys Ile Thr Val Leu Gln Val Asn Glu Lys Ser Leu
885 890 895Ile Arg Gln Tyr Thr
Thr Leu Val Glu Leu Glu Arg Gln Leu Arg Lys 900
905 910Glu Asn Glu Lys Gln Lys Asn Glu Leu Leu Ser Met
Glu Ala Glu Val 915 920 925Cys Glu
Lys Ile Gly Cys Leu Gln Arg Phe Lys Glu Met Ala Ile Phe 930
935 940Lys Ile Ala Ala Leu Gln Lys Val Val Asp Asn
Ser Val Ser Leu Ser945 950 955
960Glu Leu Glu Leu Ala Asn Lys Gln Tyr Asn Glu Leu Thr Ala Lys Tyr
965 970 975Arg Asp Ile Leu
Gln Lys Asp Asn Met Leu Val Gln Arg Thr Ser Asn 980
985 990Leu Glu His Leu Glu Cys Glu Asn Ile Ser Leu
Lys Glu Gln Val Glu 995 1000
1005Ser Ile Asn Lys Glu Leu Glu Ile Thr Lys Glu Lys Leu His Thr
1010 1015 1020Ile Glu Gln Ala Trp Glu
Gln Glu Thr Lys Leu Gly Asn Glu Ser 1025 1030
1035Ser Met Asp Lys Ala Lys Lys Ser Ile Thr Asn Ser Asp Ile
Val 1040 1045 1050Ser Ile Ser Lys Lys
Ile Thr Met Leu Glu Met Lys Glu Leu Asn 1055 1060
1065Glu Arg Gln Arg Ala Glu His Cys Gln Lys Met Tyr Glu
His Leu 1070 1075 1080Arg Thr Ser Leu
Lys Gln Met Glu Glu Arg Asn Phe Glu Leu Glu 1085
1090 1095Thr Lys Phe Ala Glu Leu Thr Lys Ile Asn Leu
Asp Ala Gln Lys 1100 1105 1110Val Glu
Gln Met Leu Arg Asp Glu Leu Ala Asp Ser Val Ser Lys 1115
1120 1125Ala Val Ser Asp Ala Asp Arg Gln Arg Ile
Leu Glu Leu Glu Lys 1130 1135 1140Asn
Glu Met Glu Leu Lys Val Glu Val Ser Lys Leu Arg Glu Ile 1145
1150 1155Ser Asp Ile Ala Arg Arg Gln Val Glu
Ile Leu Asn Ala Gln Gln 1160 1165
1170Gln Ser Arg Asp Lys Glu Val Glu Ser Leu Arg Met Gln Leu Leu
1175 1180 1185Asp Tyr Gln Ala Gln Ser
Asp Glu Lys Ser Leu Ile Ala Lys Leu 1190 1195
1200His Gln His Asn Val Ser Leu Gln Leu Ser Glu Ala Thr Ala
Leu 1205 1210 1215Gly Lys Leu Glu Ser
Ile Thr Ser Lys Leu Gln Lys Met Glu Ala 1220 1225
1230Tyr Asn Leu Arg Leu Glu Gln Lys Leu Asp Glu Lys Glu
Gln Ala 1235 1240 1245Leu Tyr Tyr Ala
Arg Leu Glu Gly Arg Asn Arg Ala Lys His Leu 1250
1255 1260Arg Gln Thr Ile Gln Ser Leu Arg Arg Gln Phe
Ser Gly Ala Leu 1265 1270 1275Pro Leu
Ala Gln Gln Glu Lys Phe Ser Lys Thr Met Ile Gln Leu 1280
1285 1290Gln Asn Asp Lys Leu Lys Ile Met Gln Glu
Met Lys Asn Ser Gln 1295 1300 1305Gln
Glu His Arg Asn Met Glu Asn Lys Thr Leu Glu Met Glu Leu 1310
1315 1320Lys Leu Lys Gly Leu Glu Glu Leu Ile
Ser Thr Leu Lys Asp Thr 1325 1330
1335Lys Gly Ala Gln Lys Val Ile Asn Trp His Met Lys Ile Glu Glu
1340 1345 1350Leu Arg Leu Gln Glu Leu
Lys Leu Asn Arg Glu Leu Val Lys Asp 1355 1360
1365Lys Glu Glu Ile Lys Tyr Leu Asn Asn Ile Ile Ser Glu Tyr
Glu 1370 1375 1380Arg Thr Ile Ser Ser
Leu Glu Glu Glu Ile Val Gln Gln Asn Lys 1385 1390
1395Phe His Glu Glu Arg Gln Met Ala Trp Asp Gln Arg Glu
Val Asp 1400 1405 1410Leu Glu Arg Gln
Leu Asp Ile Phe Asp Arg Gln Gln Asn Glu Ile 1415
1420 1425Leu Asn Ala Ala Gln Lys Phe Glu Glu Ala Thr
Gly Ser Ile Pro 1430 1435 1440Asp Pro
Ser Leu Pro Leu Pro Asn Gln Leu Glu Ile Ala Leu Arg 1445
1450 1455Lys Ile Lys Glu Asn Ile Arg Ile Ile Leu
Glu Thr Arg Ala Thr 1460 1465 1470Cys
Lys Ser Leu Glu Glu Lys Leu Lys Glu Lys Glu Ser Ala Leu 1475
1480 1485Arg Leu Ala Glu Gln Asn Ile Leu Ser
Arg Asp Lys Val Ile Asn 1490 1495
1500Glu Leu Arg Leu Arg Leu Pro Ala Thr Ala Glu Arg Glu Lys Leu
1505 1510 1515Ile Ala Glu Leu Gly Arg
Lys Glu Met Glu Pro Lys Ser His His 1520 1525
1530Thr Leu Lys Ile Ala His Gln Thr Ile Ala Asn Met Gln Ala
Arg 1535 1540 1545Leu Asn Gln Lys Glu
Glu Val Leu Lys Lys Tyr Gln Arg Leu Leu 1550 1555
1560Glu Lys Ala Arg Glu Glu Gln Arg Glu Ile Val Lys Lys
His Glu 1565 1570 1575Glu Asp Leu His
Ile Leu His His Arg Leu Glu Leu Gln Ala Asp 1580
1585 1590Ser Ser Leu Asn Lys Phe Lys Gln Thr Ala Trp
Asp Leu Met Lys 1595 1600 1605Gln Ser
Pro Thr Pro Val Pro Thr Asn Lys His Phe Ile Arg Leu 1610
1615 1620Ala Glu Met Glu Gln Thr Val Ala Glu Gln
Asp Asp Ser Leu Ser 1625 1630 1635Ser
Leu Leu Val Lys Leu Lys Lys Val Ser Gln Asp Leu Glu Arg 1640
1645 1650Gln Arg Glu Ile Thr Glu Leu Lys Val
Lys Glu Phe Glu Asn Ile 1655 1660
1665Lys Leu Gln Leu Gln Glu Asn His Glu Asp Glu Val Lys Lys Val
1670 1675 1680Lys Ala Glu Val Glu Asp
Leu Lys Tyr Leu Leu Asp Gln Ser Gln 1685 1690
1695Lys Glu Ser Gln Cys Leu Lys Ser Glu Leu Gln Ala Gln Lys
Glu 1700 1705 1710Ala Asn Ser Arg Ala
Pro Thr Thr Thr Met Arg Asn Leu Val Glu 1715 1720
1725Arg Leu Lys Ser Gln Leu Ala Leu Lys Glu Lys Gln Gln
Lys Ala 1730 1735 1740Leu Ser Arg Ala
Leu Leu Glu Leu Arg Ala Glu Met Thr Ala Ala 1745
1750 1755Ala Glu Glu Arg Ile Ile Ser Ala Thr Ser Gln
Lys Glu Ala His 1760 1765 1770Leu Asn
Val Gln Gln Ile Val Asp Arg His Thr Arg Glu Leu Lys 1775
1780 1785Thr Gln Val Glu Asp Leu Asn Glu Asn Leu
Leu Lys Leu Lys Glu 1790 1795 1800Ala
Leu Lys Thr Ser Lys Asn Arg Glu Asn Ser Leu Thr Asp Asn 1805
1810 1815Leu Asn Asp Leu Asn Asn Glu Leu Gln
Lys Lys Gln Lys Ala Tyr 1820 1825
1830Asn Lys Ile Leu Arg Glu Lys Glu Glu Ile Asp Gln Glu Asn Asp
1835 1840 1845Glu Leu Lys Arg Gln Ile
Lys Arg Leu Thr Ser Gly Leu Gln Gly 1850 1855
1860Lys Pro Leu Thr Asp Asn Lys Gln Ser Leu Ile Glu Glu Leu
Gln 1865 1870 1875Arg Lys Val Lys Lys
Leu Glu Asn Gln Leu Glu Gly Lys Val Glu 1880 1885
1890Glu Val Asp Leu Lys Pro Met Lys Glu Lys Asn Ala Lys
Glu Glu 1895 1900 1905Leu Ile Arg Trp
Glu Glu Gly Lys Lys Trp Gln Ala Lys Ile Glu 1910
1915 1920Gly Ile Arg Asn Lys Leu Lys Glu Lys Glu Gly
Glu Val Phe Thr 1925 1930 1935Leu Thr
Lys Gln Leu Asn Thr Leu Lys Asp Leu Phe Ala Lys Ala 1940
1945 1950Asp Lys Glu Lys Leu Thr Leu Gln Arg Lys
Leu Lys Thr Thr Gly 1955 1960 1965Met
Thr Val Asp Gln Val Leu Gly Ile Arg Ala Leu Glu Ser Glu 1970
1975 1980Lys Glu Leu Glu Glu Leu Lys Lys Arg
Asn Leu Asp Leu Glu Asn 1985 1990
1995Asp Ile Leu Tyr Met Arg Ala His Gln Ala Leu Pro Arg Asp Ser
2000 2005 2010Val Val Glu Asp Leu His
Leu Gln Asn Arg Tyr Leu Gln Glu Lys 2015 2020
2025Leu His Ala Leu Glu Lys Gln Phe Ser Lys Asp Thr Tyr Ser
Lys 2030 2035 2040Pro Ser Ile Ser Gly
Ile Glu Ser Asp Asp His Cys Gln Arg Glu 2045 2050
2055Gln Glu Leu Gln Lys Glu Asn Leu Lys Leu Ser Ser Glu
Asn Ile 2060 2065 2070Glu Leu Lys Phe
Gln Leu Glu Gln Ala Asn Lys Asp Leu Pro Arg 2075
2080 2085Leu Lys Asn Gln Val Arg Asp Leu Lys Glu Met
Cys Glu Phe Leu 2090 2095 2100Lys Lys
Glu Lys Ala Glu Val Gln Arg Lys Leu Gly His Val Arg 2105
2110 2115Gly Ser Gly Arg Ser Gly Lys Thr Ile Pro
Glu Leu Glu Lys Thr 2120 2125 2130Ile
Gly Leu Met Lys Lys Val Val Glu Lys Val Gln Arg Glu Asn 2135
2140 2145Glu Gln Leu Lys Lys Ala Ser Gly Ile
Leu Thr Ser Glu Lys Met 2150 2155
2160Ala Asn Ile Glu Gln Glu Asn Glu Lys Leu Lys Ala Glu Leu Glu
2165 2170 2175Lys Leu Lys Ala His Leu
Gly His Gln Leu Ser Met His Tyr Glu 2180 2185
2190Ser Lys Thr Lys Gly Thr Glu Lys Ile Ile Ala Glu Asn Glu
Arg 2195 2200 2205Leu Arg Lys Glu Leu
Lys Lys Glu Thr Asp Ala Ala Glu Lys Leu 2210 2215
2220Arg Ile Ala Lys Asn Asn Leu Glu Ile Leu Asn Glu Lys
Met Thr 2225 2230 2235Val Gln Leu Glu
Glu Thr Gly Lys Arg Leu Gln Phe Ala Glu Ser 2240
2245 2250Arg Gly Pro Gln Leu Glu Gly Ala Asp Ser Lys
Ser Trp Lys Ser 2255 2260 2265Ile Val
Val Thr Arg Met Tyr Glu Thr Lys Leu Lys Glu Leu Glu 2270
2275 2280Thr Asp Ile Ala Lys Lys Asn Gln Ser Ile
Thr Asp Leu Lys Gln 2285 2290 2295Leu
Val Lys Glu Ala Thr Glu Arg Glu Gln Lys Val Asn Lys Tyr 2300
2305 2310Asn Glu Asp Leu Glu Gln Gln Ile Lys
Ile Leu Lys His Val Pro 2315 2320
2325Glu Gly Ala Glu Thr Glu Gln Gly Leu Lys Arg Glu Leu Gln Val
2330 2335 2340Leu Arg Leu Ala Asn His
Gln Leu Asp Lys Glu Lys Ala Glu Leu 2345 2350
2355Ile His Gln Ile Glu Ala Asn Lys Asp Gln Ser Gly Ala Glu
Ser 2360 2365 2370Thr Ile Pro Asp Ala
Asp Gln Leu Lys Glu Lys Ile Lys Asp Leu 2375 2380
2385Glu Thr Gln Leu Lys Met Ser Asp Leu Glu Lys Gln His
Leu Lys 2390 2395 2400Glu Glu Ile Lys
Lys Leu Lys Lys Glu Leu Glu Asn Phe Asp Pro 2405
2410 2415Ser Phe Phe Glu Glu Ile Glu Asp Leu Lys Tyr
Asn Tyr Lys Glu 2420 2425 2430Glu Val
Lys Lys Asn Ile Leu Leu Glu Glu Lys Val Lys Lys Leu 2435
2440 2445Ser Glu Gln Leu Gly Val Glu Leu Thr Ser
Pro Val Ala Ala Ser 2450 2455 2460Glu
Glu Phe Glu Asp Glu Glu Glu Ser Pro Val Asn Phe Pro Ile 2465
2470 2475Tyr422625DNAHomo sapiens 42actcgaccgg
gctgcgctca ctgcccagcc ggggccccgg gagcctccag gctcccgccc 60gccctgagct
gcggcctccg catggagggg ccactcactc caccaccgct gcagggaggc 120ggagccgccg
ctgttccgga gcccggagcc cggcaacacc cgggacacga gacggcggcg 180cagcggtaca
gcgcccgact gctgcaggcc ggctacgagc ccgagagccc tagattggac 240ctcgctacac
acccgacgac accccgttca gaactatctt cagtggtctt actggcaggt 300gttggtgtcc
agatggatcg ccttcgcagg gctagcatgg cggactacct gatcagcggc 360ggcaccggct
acgtgcccga ggatgggctc accgcgcagc agctcttcgc cagcgccgac 420ggcctcacct
acaacgactt cctgattctc ccaggattca tagacttcat agctgatgag 480gtggacctga
cctcagccct gacccggaag atcacgctga agacgccact gatctcctcc 540cccatggaca
ctgtgacaga ggctgacatg gccattgcca tggctctgat gggaggtatt 600ggtttcattc
accacaactg caccccagag ttccaggcca acgaggtgcg gaaggtcaag 660aagtttgaac
agggcttcat cacggaccct gtggtgctga gcccctcgca cactgtgggc 720gatgtgctgg
aggccaagat gcggcatggc ttctctggca tccccatcac tgagacgggc 780accatgggca
gcaagctggt gggcatcgtc acctcccgag acatcgactt tcttgctgag 840aaggaccaca
ccaccctcct cagtgaggtg atgacgccaa ggattgaact ggtggtggct 900ccagcaggtg
tgacgttgaa agaggcaaat gagatcctgc agcgtagcaa gaaagggaag 960ctgcctatcg
tcaatgattg cgatgagctg gtggccatca tcgcccgcac cgacctgaag 1020aagaaccgag
actaccctct ggcctccaag gattcccaga agcagctgct ctgtggggca 1080gctgtgggca
cccgtgagga tgacaaatac cgtctggacc tgctcaccca ggcgggcgtc 1140gacgtcatag
tcttggactc gtcccaaggg aattcggtgt atcagatcgc catggtgcat 1200tacatcaaac
agaagtaccc ccacctccag gtgattgggg ggaacgtggt gacagcagcc 1260caggccaaga
acctgattga tgctggtgtg gacgggctgc gcgtgggcat gggctgcggc 1320tccatctgca
tcacccagga agtgatggcc tgtggtcggc cccagggcac tgctgtgtac 1380aaggtggctg
agtatgcccg gcgctttggt gtgcccatca tagccgatgg cggcatccag 1440accgtgggac
acgtggtcaa ggccctggcc cttggagcct ccacagtgat gatgggctcc 1500ctgctggccg
ccactacgga ggcccctggc gagtacttct tctcagacgg ggtgcggctc 1560aagaagtacc
ggggcatggg ctcactggat gccatggaga agagcagcag cagccagaaa 1620cgatacttca
gcgaggggga taaagtgaag atcgcgcagg gtgtctcggg ctccatccag 1680gacaaaggat
ccattcagaa gttcgtgccc tacctcatag caggcatcca acacggctgc 1740caggatatcg
gggcccgcag cctgtctgtc cttcggtcca tgatgtactc aggagagctc 1800aagtttgaga
agcggaccat gtcggcccag attgagggtg gtgtccatgg cctgcactct 1860tacgaaaagc
ggctgtactg aggacagcgg tggaggccga ggtggtggag gggatgcacc 1920ccagtgtcca
cttttgggca cagcctccct ccataactga gtggtccaca gatttgcact 1980acgggttctc
cagctccttt ccaggcagag aggaggggag gtcctgaggg gactgctgcc 2040cctcactcgg
catcccctgc agagtcagga ctgctcccgg ggccaggctg ccctgggagc 2100ccccctccga
gcccagccag ccaggctctc aggccctgcg cctgcctcag gtctttcttg 2160ctgcagcctg
ctccagcctg gcccccaccc caggggcagg cggcccctcc tggcttctcc 2220tgtagggcac
ctccctgccc ctagcctccc aggaaatggt gctctcctgg ccctgcctct 2280ggcccttccc
gggccgctgc ccctcagcca tgtggcactt ctgagctcct gacctaggcc 2340aaggggaggt
ctctgccccc ttccccggcc ctgggctacc cttgggtcct gctcctcagg 2400ccgctcccct
gtccctggcc atgggtagga gactgccctg gtcatggccg cctgcctgtc 2460attcctgact
caccaccgtc cccaggtgaa ccattcctcc cttctcctca gctgcagtcg 2520aaggctttaa
ctttgcacac ttgggatcac agttgcgtca ttgtgtatta aatacttgga 2580ataaatcaag
caggtctcaa cgcctccact aaaaaaaaaa aaaaa 262543599PRTHomo
sapiens 43Met Glu Gly Pro Leu Thr Pro Pro Pro Leu Gln Gly Gly Gly Ala
Ala1 5 10 15Ala Val Pro
Glu Pro Gly Ala Arg Gln His Pro Gly His Glu Thr Ala 20
25 30Ala Gln Arg Tyr Ser Ala Arg Leu Leu Gln
Ala Gly Tyr Glu Pro Glu 35 40
45Ser Pro Arg Leu Asp Leu Ala Thr His Pro Thr Thr Pro Arg Ser Glu 50
55 60Leu Ser Ser Val Val Leu Leu Ala Gly
Val Gly Val Gln Met Asp Arg65 70 75
80Leu Arg Arg Ala Ser Met Ala Asp Tyr Leu Ile Ser Gly Gly
Thr Gly 85 90 95Tyr Val
Pro Glu Asp Gly Leu Thr Ala Gln Gln Leu Phe Ala Ser Ala 100
105 110Asp Gly Leu Thr Tyr Asn Asp Phe Leu
Ile Leu Pro Gly Phe Ile Asp 115 120
125Phe Ile Ala Asp Glu Val Asp Leu Thr Ser Ala Leu Thr Arg Lys Ile
130 135 140Thr Leu Lys Thr Pro Leu Ile
Ser Ser Pro Met Asp Thr Val Thr Glu145 150
155 160Ala Asp Met Ala Ile Ala Met Ala Leu Met Gly Gly
Ile Gly Phe Ile 165 170
175His His Asn Cys Thr Pro Glu Phe Gln Ala Asn Glu Val Arg Lys Val
180 185 190Lys Lys Phe Glu Gln Gly
Phe Ile Thr Asp Pro Val Val Leu Ser Pro 195 200
205Ser His Thr Val Gly Asp Val Leu Glu Ala Lys Met Arg His
Gly Phe 210 215 220Ser Gly Ile Pro Ile
Thr Glu Thr Gly Thr Met Gly Ser Lys Leu Val225 230
235 240Gly Ile Val Thr Ser Arg Asp Ile Asp Phe
Leu Ala Glu Lys Asp His 245 250
255Thr Thr Leu Leu Ser Glu Val Met Thr Pro Arg Ile Glu Leu Val Val
260 265 270Ala Pro Ala Gly Val
Thr Leu Lys Glu Ala Asn Glu Ile Leu Gln Arg 275
280 285Ser Lys Lys Gly Lys Leu Pro Ile Val Asn Asp Cys
Asp Glu Leu Val 290 295 300Ala Ile Ile
Ala Arg Thr Asp Leu Lys Lys Asn Arg Asp Tyr Pro Leu305
310 315 320Ala Ser Lys Asp Ser Gln Lys
Gln Leu Leu Cys Gly Ala Ala Val Gly 325
330 335Thr Arg Glu Asp Asp Lys Tyr Arg Leu Asp Leu Leu
Thr Gln Ala Gly 340 345 350Val
Asp Val Ile Val Leu Asp Ser Ser Gln Gly Asn Ser Val Tyr Gln 355
360 365Ile Ala Met Val His Tyr Ile Lys Gln
Lys Tyr Pro His Leu Gln Val 370 375
380Ile Gly Gly Asn Val Val Thr Ala Ala Gln Ala Lys Asn Leu Ile Asp385
390 395 400Ala Gly Val Asp
Gly Leu Arg Val Gly Met Gly Cys Gly Ser Ile Cys 405
410 415Ile Thr Gln Glu Val Met Ala Cys Gly Arg
Pro Gln Gly Thr Ala Val 420 425
430Tyr Lys Val Ala Glu Tyr Ala Arg Arg Phe Gly Val Pro Ile Ile Ala
435 440 445Asp Gly Gly Ile Gln Thr Val
Gly His Val Val Lys Ala Leu Ala Leu 450 455
460Gly Ala Ser Thr Val Met Met Gly Ser Leu Leu Ala Ala Thr Thr
Glu465 470 475 480Ala Pro
Gly Glu Tyr Phe Phe Ser Asp Gly Val Arg Leu Lys Lys Tyr
485 490 495Arg Gly Met Gly Ser Leu Asp
Ala Met Glu Lys Ser Ser Ser Ser Gln 500 505
510Lys Arg Tyr Phe Ser Glu Gly Asp Lys Val Lys Ile Ala Gln
Gly Val 515 520 525Ser Gly Ser Ile
Gln Asp Lys Gly Ser Ile Gln Lys Phe Val Pro Tyr 530
535 540Leu Ile Ala Gly Ile Gln His Gly Cys Gln Asp Ile
Gly Ala Arg Ser545 550 555
560Leu Ser Val Leu Arg Ser Met Met Tyr Ser Gly Glu Leu Lys Phe Glu
565 570 575Lys Arg Thr Met Ser
Ala Gln Ile Glu Gly Gly Val His Gly Leu His 580
585 590Ser Tyr Glu Lys Arg Leu Tyr
595442981DNAHomo sapiens 44gctgggtaaa tcccagagtc tcagccgcct aagtgtcttc
cccggaggtg agattatctc 60cgcctgtgct ggacacctcc ctttctcctg cagccatgga
tgccgctctg ctcctgaacg 120tggaaggggt caagaaaacc attctgcacg ggggcacggg
cgagctccca aacttcatca 180ccggatcccg agtgatcttt catttccgca ccatgaaatg
tgatgaggag cggacagtca 240ttgacgacag tcggcaggtg ggccagccca tgcacatcat
catcggaaac atgttcaagc 300tcgaggtctg ggagatcctg cttacctcca tgcgggtgca
cgaggtggcc gagttctggt 360gcgacaccat ccacacgggg gtctacccca tcctatcccg
gagcctgagg cagatggccc 420agggcaagga ccccacagag tggcacgtgc acacgtgcgg
gctggccaac atgttcgcct 480accacacgct gggctacgag gacctggacg agctgcagaa
ggagcctcag cctctggtct 540ttgtgatcga gctgctgcag gttgatgccc cgagtgatta
ccagagggag acctggaacc 600tgagcaatca tgagaagatg aaggcggtgc ccgtcctcca
cggagaggga aatcggctct 660tcaagctggg ccgctacgag gaggcctctt ccaagtacca
ggaggccatc atctgcctaa 720ggaacctgca gaccaaggag aagccatggg aggtgcagtg
gctgaagctg gagaagatga 780tcaatactct gatcctcaac tactgccagt gcctgctgaa
gaaggaggag tactatgagg 840tgctggagca caccagtgat attctccggc accacccagg
catcgtgaag gcctactacg 900tgcgtgcccg ggctcacgca gaggtgtgga atgaggccga
ggccaaggcg gacctccaga 960aagtgctgga gctggagccg tccatgcaga aggcggtgcg
cagggagctg aggctgctgg 1020agaaccgcat ggcggagaag caggaggagg agcggctgcg
ctgccggaac atgctgagcc 1080agggtgccac gcagcctccc gcagagccac ccacagagcc
acccgcacag tcatccacag 1140agccacctgc agagccaccc acagcaccat ctgcagagct
gtccgcaggg ccccctgcag 1200agccagccac agagccaccc ccgtccccag ggcactcgct
gcagcactga gccccctgag 1260gcccacagcc acccaggcag ggagcaagtg gcctggtcac
ttctggttcg attgaccagg 1320atcgtggtgt cactttttaa aatttaaaat taatttttga
aatcaaagtc agacacaccc 1380atggtaaaaa aaaaaaaaaa aacaatccca agggtacaga
agagcttatg aataaaagta 1440gttttctcct ctacccctct cattccttcc gtgccatggt
tttaattgac cctgttttta 1500attcttctgg tagttttctc tatttccaag taatctgttt
aaatcagttt ctagatttta 1560ccccatgtca atgacaaatg aggatttgat gctctgatcc
tttctcatgc ctgatacccc 1620tccctgtctc cccattttgg atagttacat ttgggggtca
tctcggtgat ttttgtaact 1680ttacgcagga cacttagagc tctctagaat cccactgact
ttagtgggtc ttgatgtagg 1740gtgggcaagc cccgacactg gagcttagcc tgagagggtt
cttggcctcc cccaggaaag 1800atttcaaagg caagcgccag tggtagggta gaagaaaaca
gctgtggtcg ggcacggtgg 1860ctcacgccta taatcccagc actttgggag gccgaggcgg
gtggatcacc tgaggtcagg 1920agttccagac cagcctggcc aacatggtga aacctcatct
ctactaaaaa tacaaaaaaa 1980ctagctgggc gtggtggcgg gcgcctataa tcccagctac
ttgggaggct gaggcaggag 2040aattgattga acctgggagg cggaggttgc agtgagccaa
gatcacgtca ttgcactcca 2100gcctggtcaa caagagtaaa acttcatctc aaaaaacaaa
acaaaacaaa aacaacaaca 2160aaaaacaaaa gaaaaacaaa caaaaccaaa accaaaacag
ctgtattgaa gctgcagtgt 2220tgcagctctg tgactgccct gcagagcagg gctaccccat
aggcagcgag cagcagctca 2280gggcagttct gcagtcagat ttatacccac ttttaattac
atgtagatta aggagctgca 2340tatacaaaga tttctaggga aggagtagta acttctgggt
cctggggtct ttgccacgga 2400acagggcagt atgccagggt gttgccacgg caatggtaaa
ctgacatggc accctggggg 2460tcatgcctta gggaaagccg cttccactcg cccctgtttt
agctcatctt caagttagtc 2520tggtgtccaa gctccaccgc ctgcctcagt ctggtgacct
ccttctgtgt ctgatgagca 2580tggcagcgtt gggaccttcc ccttccaact ctctccctcc
tcttcgtcct ccctaaagga 2640cgggtacgag gaggggctat cacgccagcg acatcctcta
gcaccaccca ggtgtgtggg 2700gtggggcagg ggggcgacga agtatccagc ccagggccac
gtagtcaact gccaagggct 2760tcctgggctt ctcttctgcc ccagagcttg tctccaccca
gcaggggttc ccccagcgct 2820aactgtatcc ctaaagttct gatgtacttt acttttccat
cttccttgtt gttaacatct 2880accttctgct ctgtaagcaa aactaaatct tctgtgcttt
gtccataggt tgattctaca 2940atctgaaaat caataaacag catttgcatg aaaaaaaaaa a
298145384PRTHomo sapiens 45Met Asp Ala Ala Leu Leu
Leu Asn Val Glu Gly Val Lys Lys Thr Ile1 5
10 15Leu His Gly Gly Thr Gly Glu Leu Pro Asn Phe Ile
Thr Gly Ser Arg 20 25 30Val
Ile Phe His Phe Arg Thr Met Lys Cys Asp Glu Glu Arg Thr Val 35
40 45Ile Asp Asp Ser Arg Gln Val Gly Gln
Pro Met His Ile Ile Ile Gly 50 55
60Asn Met Phe Lys Leu Glu Val Trp Glu Ile Leu Leu Thr Ser Met Arg65
70 75 80Val His Glu Val Ala
Glu Phe Trp Cys Asp Thr Ile His Thr Gly Val 85
90 95Tyr Pro Ile Leu Ser Arg Ser Leu Arg Gln Met
Ala Gln Gly Lys Asp 100 105
110Pro Thr Glu Trp His Val His Thr Cys Gly Leu Ala Asn Met Phe Ala
115 120 125Tyr His Thr Leu Gly Tyr Glu
Asp Leu Asp Glu Leu Gln Lys Glu Pro 130 135
140Gln Pro Leu Val Phe Val Ile Glu Leu Leu Gln Val Asp Ala Pro
Ser145 150 155 160Asp Tyr
Gln Arg Glu Thr Trp Asn Leu Ser Asn His Glu Lys Met Lys
165 170 175Ala Val Pro Val Leu His Gly
Glu Gly Asn Arg Leu Phe Lys Leu Gly 180 185
190Arg Tyr Glu Glu Ala Ser Ser Lys Tyr Gln Glu Ala Ile Ile
Cys Leu 195 200 205Arg Asn Leu Gln
Thr Lys Glu Lys Pro Trp Glu Val Gln Trp Leu Lys 210
215 220Leu Glu Lys Met Ile Asn Thr Leu Ile Leu Asn Tyr
Cys Gln Cys Leu225 230 235
240Leu Lys Lys Glu Glu Tyr Tyr Glu Val Leu Glu His Thr Ser Asp Ile
245 250 255Leu Arg His His Pro
Gly Ile Val Lys Ala Tyr Tyr Val Arg Ala Arg 260
265 270Ala His Ala Glu Val Trp Asn Glu Ala Glu Ala Lys
Ala Asp Leu Gln 275 280 285Lys Val
Leu Glu Leu Glu Pro Ser Met Gln Lys Ala Val Arg Arg Glu 290
295 300Leu Arg Leu Leu Glu Asn Arg Met Ala Glu Lys
Gln Glu Glu Glu Arg305 310 315
320Leu Arg Cys Arg Asn Met Leu Ser Gln Gly Ala Thr Gln Pro Pro Ala
325 330 335Glu Pro Pro Thr
Glu Pro Pro Ala Gln Ser Ser Thr Glu Pro Pro Ala 340
345 350Glu Pro Pro Thr Ala Pro Ser Ala Glu Leu Ser
Ala Gly Pro Pro Ala 355 360 365Glu
Pro Ala Thr Glu Pro Pro Pro Ser Pro Gly His Ser Leu Gln His 370
375 380461934DNAHomo sapiens 46gggcacaagc
aatcctccct tctcagcttc ctgagtggcc aggactacag aggactgtat 60gctgttctta
aggactctct gcttcctgga caagctcaag ctaaggacta catctcccag 120caggctgtgc
tctgacagct cttggattta aataggattc tgggctctgc tcagagtcag 180gctgctgctc
agcacccagg acggagagga gcagagaagc agcagaagca gccaagagct 240ggagccagac
caggaacctg agccagagct ggggttgaag ctggagcagc agcaaaagca 300acagcagcta
cagaagttgg aacgatgctg gtcaccttgg gactgctcac ctccttcttc 360tcgttcctgt
atatggtagc tccatccatc aggaagttct ttgctggtgg agtgtgtaga 420acaaatgtgc
agcttcctgg caaggtagtg gtgatcactg gcgccaacac gggcattggc 480aaggagacgg
ccagagagct cgctagccga ggagcccgag tctatattgc ctgcagagat 540gtactgaagg
gggagtctgc tgccagtgaa atccgagtgg atacaaagaa ctcccaggtg 600ctggtgcgga
aattggacct atccgacacc aaatctatcc gagcctttgc tgagggcttt 660ctggcagagg
aaaagcagct ccatattctg atcaacaatg cgggagtaat gatgtgtcca 720tattccaaga
cagctgatgg ctttgaaacc cacctgggag tcaaccacct gggccacttc 780ctcctcacct
acctgctcct ggagcggcta aaggtgtctg cccctgcacg ggtggttaat 840gtgtcctcgg
tggctcacca cattggcaag attcccttcc acgacctcca gagcgagaag 900cgctacagca
ggggttttgc ctattgccac agcaagctgg ccaatgtgct ttttactcgt 960gagctggcca
agaggctcca aggcaccggg gtcaccacct acgcagtgca cccaggcgtc 1020gtccgctctg
agctggtccg gcactcctcc ctgctctgcc tgctctggcg gctcttctcc 1080ccctttgtca
agacggcacg ggagggggcg cagaccagcc tgcactgcgc cctggctgag 1140ggcctggagc
ccctgagtgg caagtacttc agtgactgca agaggacctg ggtgtctcca 1200agggcccgaa
ataacaaaac agctgagcgc ctatggaatg tcagctgtga gcttctagga 1260atccggtggg
agtagctggt ggaagagctg cagctttatc aggcccaatc catgccataa 1320tgaacaggga
ccaaggagaa ggccaaccct aaaggattgt cctcttggcc agctggtgct 1380gcgaatcctg
cctgctctga tcctcttgac ccttctggga atgtttgcac acctgacact 1440cttgtgagac
tggcttatgg catgagttgt ggacacctat agagtgttct tctctaagac 1500ctggaaagtc
agcaaccctc tgggggcagc aggactgggc agatcccagg ctgggcatgg 1560gggtggcaga
agagcccgag aaattgggtc agttccctca tcagcaccag aggctcagct 1620gaggcaagaa
gagcaccatc actgcctatt tctaggggct atacactcca actcttggtt 1680gatctctttc
tttttaaaaa tatttgccac caccctggag tctagaccaa cacacaaaga 1740tcctggctaa
ccctggccta tttagattcc ttcctctcac ctggaccttc ccatttcaat 1800catgcagatg
gtttcttttt gtaaagagtt ccgtttgcct ttcaattttt agagaaaata 1860aagactgcat
tcatctcaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1920aaaaaaaaaa
aaaa 193447316PRTHomo
sapiens 47Met Leu Val Thr Leu Gly Leu Leu Thr Ser Phe Phe Ser Phe Leu
Tyr1 5 10 15Met Val Ala
Pro Ser Ile Arg Lys Phe Phe Ala Gly Gly Val Cys Arg 20
25 30Thr Asn Val Gln Leu Pro Gly Lys Val Val
Val Ile Thr Gly Ala Asn 35 40
45Thr Gly Ile Gly Lys Glu Thr Ala Arg Glu Leu Ala Ser Arg Gly Ala 50
55 60Arg Val Tyr Ile Ala Cys Arg Asp Val
Leu Lys Gly Glu Ser Ala Ala65 70 75
80Ser Glu Ile Arg Val Asp Thr Lys Asn Ser Gln Val Leu Val
Arg Lys 85 90 95Leu Asp
Leu Ser Asp Thr Lys Ser Ile Arg Ala Phe Ala Glu Gly Phe 100
105 110Leu Ala Glu Glu Lys Gln Leu His Ile
Leu Ile Asn Asn Ala Gly Val 115 120
125Met Met Cys Pro Tyr Ser Lys Thr Ala Asp Gly Phe Glu Thr His Leu
130 135 140Gly Val Asn His Leu Gly His
Phe Leu Leu Thr Tyr Leu Leu Leu Glu145 150
155 160Arg Leu Lys Val Ser Ala Pro Ala Arg Val Val Asn
Val Ser Ser Val 165 170
175Ala His His Ile Gly Lys Ile Pro Phe His Asp Leu Gln Ser Glu Lys
180 185 190Arg Tyr Ser Arg Gly Phe
Ala Tyr Cys His Ser Lys Leu Ala Asn Val 195 200
205Leu Phe Thr Arg Glu Leu Ala Lys Arg Leu Gln Gly Thr Gly
Val Thr 210 215 220Thr Tyr Ala Val His
Pro Gly Val Val Arg Ser Glu Leu Val Arg His225 230
235 240Ser Ser Leu Leu Cys Leu Leu Trp Arg Leu
Phe Ser Pro Phe Val Lys 245 250
255Thr Ala Arg Glu Gly Ala Gln Thr Ser Leu His Cys Ala Leu Ala Glu
260 265 270Gly Leu Glu Pro Leu
Ser Gly Lys Tyr Phe Ser Asp Cys Lys Arg Thr 275
280 285Trp Val Ser Pro Arg Ala Arg Asn Asn Lys Thr Ala
Glu Arg Leu Trp 290 295 300Asn Val Ser
Cys Glu Leu Leu Gly Ile Arg Trp Glu305 310
315484729DNAHomo sapiens 48agtctaggcc tccgcctccg ttaccctgga gcccaggtta
ccgccgctgc cacccaggag 60ccccgatcct cgcctctgtc ccatccttgt gttcaaacct
cccgcatctc ggcaacctcg 120gcacccgccc ggcagcctcc gcaggaacca ggcacccgct
ctttggcggt cagacgccga 180ggccccagct gggagtttgg tcctaagagg gaaggcaagg
aggcgggacg ccgcatcggc 240tctgctgaag agcctgcggg ttggaggtgg gctttgaagt
gggcgtggag acggcggggg 300aggtggaggt gcgagtataa atgatcaacc agaaattatc
ttcaaaggaa taaaaccaga 360agtatgtaaa taaaaagccc aagataaaga aacagaaaag
ctgacactac atgaagcaga 420gggcaaaaaa gtttatcttc tggatgccaa tgtgaattgt
ggtctacaaa tacattgtgg 480agaaaataga ttgcacagaa atgaatatta tcaggatctg
aagactgtga aaatgttttt 540cagtattgtc atagtctcct ctggagaaaa taatctgtga
aattatgtga atagagacca 600tttttcaaaa caatggggga aagagcagga agtccaggta
ctgatcaaga aagaaaggca 660ggcaaacacc attattctta cttatctgat tttgaaacgc
cacagtcttc tggccgatca 720tcgctggtca gttcttcacc tgcaagtgtt aggagaaaaa
atcctaaaag acaaacttca 780gatggccaag tacatcacca agcccctcgg aaaccaagcc
ctaagggtct accaaacaga 840aagggagtcc gagtgggatt tcgctcccag agcctcaata
gagagccact tcggaaagat 900actgatcttg ttacaaaacg gattctgtct gcaagactgc
taaaaatcaa tgagttgcag 960aatgaagtat ctgaactcca ggtcaagtta gctgagctgc
taaaagaaaa taaatctttg 1020aaaaggcttc agtacagaca ggagaaagcc ctgaataagt
ttgaagatgc cgaaaatgaa 1080atctcacaac ttatatttcg tcataacaat gagattacag
cactcaaaga acgcttaaga 1140aaatctcaag agaaagaacg ggcaactgag aaaagggtaa
aagatacaga aagtgaacta 1200tttaggacaa aattttcctt acagaaactg aaagagatct
ctgaagctag acacctacct 1260gaacgagatg atttggcaaa gaaactagtt tcagcagagt
taaagttaga tgacaccgag 1320agaagaatta aggagctatc gaaaaacctt gaactgagta
ctaacagttt ccaacgacag 1380ttgcttgctg aaaggaaaag ggcatatgag gctcatgatg
aaaataaagt tcttcaaaag 1440gaggtacagc gactatatca caaattaaag gaaaaggaga
gagaactgga tataaaaaat 1500atatattcta atcgtctgcc aaagtcctct ccaaataaag
agaaagaact tgcattaaga 1560aaaaatgctg catgccagag tgattttgca gacctgtgta
caaaaggagt acaaaccatg 1620gaagacttca agccagaaga atatccttta actccagaaa
caattatgtg ttacgaaaac 1680aaatgggaag aaccaggaca tcttactttg gacttgcaat
ctcaaaagca agacaggcat 1740ggagaagcag ggattctaaa cccaattatg gaaagagaag
aaaaatttgt tacagatgaa 1800gaactccatg tcgtaaaaca ggaggttgaa aagctggagg
atgaatggga aagagaagaa 1860cttgataaaa agcaaaaaga aaaggcatct ttactggaaa
gagaagaaaa gccagagtgg 1920gaaactggaa ggtaccaact aggaatgtat ccaattcaga
atatggataa attgcaagga 1980gaggaagaag aaagactgaa gagagaaatg ctacttgcta
aactgaatga aattgacaga 2040gaactccaag attctcgaaa tctaaaatac cctgttttgc
cattgttacc tgattttgaa 2100tcaaaactac actccccaga gagaagcccc aaaacataca
ggttctctga atcctcagag 2160agattattta atgggcatca tttgcaagac atcagtttct
caactccaaa aggagaaggt 2220cagaattcag gaaatgttag aagtccagcc tcccctaatg
agttcgcatt tggtagctac 2280gtgccttcgt ttgcaaaaac atcagagagg tcaaatccat
ttagtcaaaa aagtagtttt 2340ttggatttcc aaagaaacag tatggaaaaa cttagtaaag
atggtgtaga tttaattaca 2400agaaaagaga aaaaagctaa tttgatggaa cagttatttg
gtgccagtgg tagcagcacc 2460atttcctcca aaagcagtga cccaaattct gtggcttcca
gtaaaggaga cattgaccct 2520ctaaattttc tccctgggaa taaaggcagc agagatcaag
aacatgatga agatgaaggc 2580tttttcctca gtgaaggaag aagttttaat ccaaataggc
accgattaaa acatgcagac 2640gataaaccag cagtaaaagc agctgattct gtagaagatg
aaattgaaga agtagcactg 2700agatgactga ctagagtata cattttttct aattgtaaat
attgaaatat tttaatacag 2760tatttattat aaacatttag actttttaat gctaaaatgt
ccttattaag gaatgatttt 2820taatagctaa atacaatgca gttaaaaaga agtagatcat
acatacacca catagatagt 2880ttgccaagaa tgaaggaggc ttttttgaat gaaaccaaaa
ataaaaatat gtcttgaaaa 2940atgaaataga ttttaactct tcatccagtg ctatggcaag
tttaactgca ctggaggtgg 3000tattcctttt ctacttttat tcctatttat gtatttattt
ttaatcatat tctcactgtg 3060ctaaatacag tcttcccact aattgttgaa tgaaaattaa
gggtgaaagt ctgtgttggg 3120aagtgtagct ccggatggtg gagaaccagt gcttcttagg
agcccttccc tttatggata 3180gggccagggg tccctatctt acgtggcagt cctaagctac
tcttgagtga tagcagtcac 3240aacattggga tttcccattc ctctgaaagt acccacagct
aaacactact catttcccaa 3300tttcagtatt tactgaaatc acttacctac aattctgtta
gaatattatg ttgagttcgg 3360aagacatttc tctgtttgca aggacagtta gttgctctct
gtcatagccc gcagaagctt 3420ggctacagtg taattcctct ccttgttctc ctacactctt
tgtatctcag tgactgggtg 3480taagatttca tgccaaatgc aaggaatagt ggaaatacat
accaactgca aagaatagaa 3540aaactttatc ccaatatatt atagaaagat cttcagttca
attatgtcca gagtaatata 3600atttggcaat gttaatgctt ttaagatttg aacttgtcct
caaaccaagg agacaacaat 3660agtgtaatac tattggactt acaggattag ttttaaagca
actttgaata gaagtgtttc 3720agacatagga cttctgcctt gttgactaga gtggatagtt
ttctgtttaa atgcattggt 3780cttttggctg tttgtaattc acttcagctt atagagaagt
tgatgacctt ggatcatgct 3840gggtatgatt ggtctttaaa aagcagtaat ataccaccag
cccaaggaga aaacattgtt 3900aaaatgaaga gtggtggaaa tagtgtgttg ggaagaataa
aaaatttaga ttggcactta 3960ttctaaagtg agctgttttt ttcaagaatt tactagcatt
tgctcgtagt atgatttctg 4020acgccagtca tatatactga tgaggggaag gagttactgt
gttattctga gttcttataa 4080atgcatatta ttgaatttca ttgcatgact atttgtcaag
acttacctgg ttaggtctcc 4140aattaaaaga tgtaccacct gtcatcttct aaattgtgtt
cctttcattt attgggaaca 4200gaatctctca aaagtgctaa actatattaa aaagttttct
taatagattt gtatgtctga 4260tatgtataac catttactat aatatgttgc aaatcattct
aatatatgta aaacaatatt 4320atttgtaatg cagttattgg taaaatatta tgtaatgtta
attttgttcc tagctgctaa 4380tttttctgcc aaaagtattc taattttcag gttgttttaa
aggcttttaa aactttttag 4440ttaagttttt tattcacgtc atttaaatta gttttttgct
ttttttctac ctgataatct 4500ctttaacaag atgcaacaag acagaattat taaaattaaa
cctaaagtta agttacagat 4560ttaaaggcat tatgatatta agcattaaaa ttggagatta
aaatgtacaa aacagggttt 4620tccttatgaa caaaccttac agggtaaatt gttttttttt
ctaaatgtca ttaaatttat 4680ttgtactcag aactgttact aataaaaatt aaaaatgcaa
aaaaaaaaa 472949697PRTHomo sapiens 49Met Gly Glu Arg Ala
Gly Ser Pro Gly Thr Asp Gln Glu Arg Lys Ala1 5
10 15Gly Lys His His Tyr Ser Tyr Leu Ser Asp Phe
Glu Thr Pro Gln Ser 20 25
30Ser Gly Arg Ser Ser Leu Val Ser Ser Ser Pro Ala Ser Val Arg Arg
35 40 45Lys Asn Pro Lys Arg Gln Thr Ser
Asp Gly Gln Val His His Gln Ala 50 55
60Pro Arg Lys Pro Ser Pro Lys Gly Leu Pro Asn Arg Lys Gly Val Arg65
70 75 80Val Gly Phe Arg Ser
Gln Ser Leu Asn Arg Glu Pro Leu Arg Lys Asp 85
90 95Thr Asp Leu Val Thr Lys Arg Ile Leu Ser Ala
Arg Leu Leu Lys Ile 100 105
110Asn Glu Leu Gln Asn Glu Val Ser Glu Leu Gln Val Lys Leu Ala Glu
115 120 125Leu Leu Lys Glu Asn Lys Ser
Leu Lys Arg Leu Gln Tyr Arg Gln Glu 130 135
140Lys Ala Leu Asn Lys Phe Glu Asp Ala Glu Asn Glu Ile Ser Gln
Leu145 150 155 160Ile Phe
Arg His Asn Asn Glu Ile Thr Ala Leu Lys Glu Arg Leu Arg
165 170 175Lys Ser Gln Glu Lys Glu Arg
Ala Thr Glu Lys Arg Val Lys Asp Thr 180 185
190Glu Ser Glu Leu Phe Arg Thr Lys Phe Ser Leu Gln Lys Leu
Lys Glu 195 200 205Ile Ser Glu Ala
Arg His Leu Pro Glu Arg Asp Asp Leu Ala Lys Lys 210
215 220Leu Val Ser Ala Glu Leu Lys Leu Asp Asp Thr Glu
Arg Arg Ile Lys225 230 235
240Glu Leu Ser Lys Asn Leu Glu Leu Ser Thr Asn Ser Phe Gln Arg Gln
245 250 255Leu Leu Ala Glu Arg
Lys Arg Ala Tyr Glu Ala His Asp Glu Asn Lys 260
265 270Val Leu Gln Lys Glu Val Gln Arg Leu Tyr His Lys
Leu Lys Glu Lys 275 280 285Glu Arg
Glu Leu Asp Ile Lys Asn Ile Tyr Ser Asn Arg Leu Pro Lys 290
295 300Ser Ser Pro Asn Lys Glu Lys Glu Leu Ala Leu
Arg Lys Asn Ala Ala305 310 315
320Cys Gln Ser Asp Phe Ala Asp Leu Cys Thr Lys Gly Val Gln Thr Met
325 330 335Glu Asp Phe Lys
Pro Glu Glu Tyr Pro Leu Thr Pro Glu Thr Ile Met 340
345 350Cys Tyr Glu Asn Lys Trp Glu Glu Pro Gly His
Leu Thr Leu Asp Leu 355 360 365Gln
Ser Gln Lys Gln Asp Arg His Gly Glu Ala Gly Ile Leu Asn Pro 370
375 380Ile Met Glu Arg Glu Glu Lys Phe Val Thr
Asp Glu Glu Leu His Val385 390 395
400Val Lys Gln Glu Val Glu Lys Leu Glu Asp Glu Trp Glu Arg Glu
Glu 405 410 415Leu Asp Lys
Lys Gln Lys Glu Lys Ala Ser Leu Leu Glu Arg Glu Glu 420
425 430Lys Pro Glu Trp Glu Thr Gly Arg Tyr Gln
Leu Gly Met Tyr Pro Ile 435 440
445Gln Asn Met Asp Lys Leu Gln Gly Glu Glu Glu Glu Arg Leu Lys Arg 450
455 460Glu Met Leu Leu Ala Lys Leu Asn
Glu Ile Asp Arg Glu Leu Gln Asp465 470
475 480Ser Arg Asn Leu Lys Tyr Pro Val Leu Pro Leu Leu
Pro Asp Phe Glu 485 490
495Ser Lys Leu His Ser Pro Glu Arg Ser Pro Lys Thr Tyr Arg Phe Ser
500 505 510Glu Ser Ser Glu Arg Leu
Phe Asn Gly His His Leu Gln Asp Ile Ser 515 520
525Phe Ser Thr Pro Lys Gly Glu Gly Gln Asn Ser Gly Asn Val
Arg Ser 530 535 540Pro Ala Ser Pro Asn
Glu Phe Ala Phe Gly Ser Tyr Val Pro Ser Phe545 550
555 560Ala Lys Thr Ser Glu Arg Ser Asn Pro Phe
Ser Gln Lys Ser Ser Phe 565 570
575Leu Asp Phe Gln Arg Asn Ser Met Glu Lys Leu Ser Lys Asp Gly Val
580 585 590Asp Leu Ile Thr Arg
Lys Glu Lys Lys Ala Asn Leu Met Glu Gln Leu 595
600 605Phe Gly Ala Ser Gly Ser Ser Thr Ile Ser Ser Lys
Ser Ser Asp Pro 610 615 620Asn Ser Val
Ala Ser Ser Lys Gly Asp Ile Asp Pro Leu Asn Phe Leu625
630 635 640Pro Gly Asn Lys Gly Ser Arg
Asp Gln Glu His Asp Glu Asp Glu Gly 645
650 655Phe Phe Leu Ser Glu Gly Arg Ser Phe Asn Pro Asn
Arg His Arg Leu 660 665 670Lys
His Ala Asp Asp Lys Pro Ala Val Lys Ala Ala Asp Ser Val Glu 675
680 685Asp Glu Ile Glu Glu Val Ala Leu Arg
690 695503771DNAHomo sapiens 50ccagggtgag attatgaggc
tgagctgaga atatcaagac tgtaccgagt agggggcctt 60ggcaagtgtg gagagcccgg
cagctggggc agagggcgga gtacggtgtg cgtttacgga 120cctcttcaaa cgaggtagga
aggtcagaag tcaaaaaggg aacaaatgat gtttaaccac 180acaaaaatga aaatccaatg
gttggatatc cattccaaat acacaaaggc aacggataag 240tgatccgggc caggcacaga
aggccatgca cccgtaggat tgcactcaga gctcccaaat 300gcataggaat agaagggtgg
gtgcaggagg ctgaggggtg gggaaagggc atgggtgttt 360catgaggaca gagcttccgt
ttcatgcaat gaaaagagtt tggagacgga tggtggtgac 420tggactatac acttacacac
ggtagcgatg gtacactttg tattatgtat attttaccac 480gatcttttta aagtgtcaaa
ggcaaatggc caaatggttc cttgtcctat agctgtagca 540gccatcggct gttagtgaca
aagcccctga gtcaagatga cagcagcccc cataactcct 600aatcggctct cccgcgtgga
gtcatttagg agtagtcgca ttagagacaa gtccaacatc 660taatcttcca ccctggccag
ggccccagct ggcagcgagg gtgggagact ccgggcagag 720cagagggcgc tgacattggg
gcccggcctg gcttgggtcc ctctggcctt tccccagggg 780ccctctttcc ttggggcttt
cttgggccgc cactgctccc gctcctctcc ccccatccca 840ccccctcacc ccctcgttct
tcatatcctt ctctagtgct ccctccactt tcatccaccc 900ttctgcaaga gtgtgggacc
acaaatgagt tttcacctgg cctggggaca cacgtgcccc 960cacaggtgct gagtgacttt
ctaggacagt aatctgcttt aggctaaaat gggacttgat 1020cttctgttag ccctaatcat
caattagcag agccggtgaa ggtgcagaac ctaccgcctt 1080tccaggcctc ctcccacctc
tgccacctcc actctccttc ctgggatgtg ggggctggca 1140cacgtgtggc ccagggcatt
ggtgggattg cactgagctg ggtcattagc gtaatcctgg 1200acaagggcag acagggcgag
cggagggcca gctccggggc tcaggcaagg ctgggggctt 1260cccccagaca ccccactcct
cctctgctgg acccccactt catagggcac ttcgtgttct 1320caaagggctt ccaaatagca
tggtggcctt ggatgcccag ggaagcctca gagttgctta 1380tctccctcta gacagaaggg
gaatctcggt caagagggag aggtcgccct gttcaaggcc 1440acccagccag ctcatggcgg
taatgggaca aggctggcca gccatcccac cctcagaagg 1500gacccggtgg ggcaggtgat
ctcagaggag gctcacttct gggtctcaca ttcttggatc 1560cggttccagg cctcggccct
aaatagtctc cctgggcttt caagagaacc acatgagaaa 1620ggaggattcg ggctctgagc
agtttcacca cccacccccc agtctgcaaa tcctgacccg 1680tgggtccacc tgccccaaag
gcggacgcag gacagtagaa gggaacagag aacacataaa 1740cacagagagg gccacagcgg
ctcccacagt caccgccacc ttcctggcgg ggatgggtgg 1800ggcgtctgag tttggttccc
agcaaatccc tctgagccgc ccttgcgggc tcgcctcagg 1860agcaggggag caagaggtgg
gaggaggagg tctaagtccc aggcccaatt aagagatcag 1920gtagtgtagg gtttgggagc
ttttaaggtg aagaggcccg ggctgatccc acaggccagt 1980ataaagcgcc gtgaccctca
ggtgatgcgc cagggccggc tgccgtcggg gacagggctt 2040tccatagcca tgctagagga
tccggtactc gaggaactga aaaaccagaa agttaactgg 2100taagtttagt ctttttgtct
tttatttcag gtcccggatc cggtggtggt gcaaatcaaa 2160gaactgctcc tcagtggatg
ttgcctttac ttctaggcct gtacggaagt gttacttctg 2220ctctaaaagc tgcggaattg
tacccgcggc cgcgggacag ggctttccat agccatggcc 2280cagcagtgga gcctccaaag
gctcgcaggc cgccatccgc aggacagcta tgaggacagc 2340acccagtcca gcatcttcac
ctacaccaac agcaactcca ccagaggccc cttcgaaggc 2400ccgaattacc acatcgctcc
cagatgggtg taccacctca ccagtgtctg gatgatcttt 2460gtggtcactg catccgtctt
cacaaatggg cttgtgctgg cggccaccat gaagttcaag 2520aagctgcgcc acccgctgaa
ctggatcctg gtgaacctgg cggtcgctga cctagcagag 2580accgtcatcg ccagcactat
cagcattgtg aaccaggtct ctggctactt cgtgctgggc 2640caccctatgt gtgtcctgga
gggctacacc gtctccctgt gtgggatcac aggtctctgg 2700tctctggcca tcatttcctg
ggagagatgg atggtggtct gcaagccctt tggcaatgtg 2760agatttgatg ccaagctggc
catcgtgggc attgccttct cctggatctg gtctgctgtg 2820tggacagccc cgcccatctt
tggttggagc aggtactggc cccacggcct gaagacttca 2880tgcggcccag acgtgttcag
cggcagctcg taccccgggg tgcagtctta catgattgtc 2940ctcatggtca cctgctgcat
catcccactc gctatcatca tgctctgcta cctccaagtg 3000tggctggcca tccgagcggt
ggcaaagcag cagaaagagt ctgaatccac ccagaaggca 3060gagaaggaag tgacgcgcat
ggtggtggtg atgatctttg cgtactgcgt ctgctgggga 3120ccctacacct tcttcgcatg
ctttgctgct gccaaccctg gttacgcctt ccaccctttg 3180atggctgccc tgccggccta
ctttgccaaa agtgccacta tctacaaccc cgttatctat 3240gtctttatga accggcagtt
tcgaaactgc atcttgcagc ttttcgggaa gaaggttgac 3300gatggctctg aactctccag
cgcctccaaa acggaggtct caactgtgtc ctcgacccag 3360gtagggccta actgaggtct
gcctcctacc catcccgccc accggggctt tggccacctc 3420tcctttcccc ctccttctcc
atccctgtaa aataaatgta atttatcttt gccaaaacca 3480aaaaaaacgg aattcgtaat
catgtcatag ctgtttcctg tgtgaaattg ttatccgctc 3540acaattccac acaacatacg
aggcggccgc gcggatccag acatgataag atacattgat 3600gagtttggac aaaccacaac
tagaatgcag tgaaaaaaat gctttatttg tgaaatttgt 3660gatgctattg ctttatttgt
aaccattata agctgcaata aacaagttaa caacaacaat 3720tgcattcatt ttatgtttca
ggttcagggg gaggtgtggg aggtttttta g 37715136DNAArtificial
SequenceSynthetic 51gacttgatct tctgttagcc ctaatcatca attagc
36
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