Patent application title: Vanilloid receptor
Inventors:
Peter Mcintyre (London, GB)
Iain Fraser James (London, GB)
IPC8 Class: AC07K1400FI
USPC Class:
530350
Class name: Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof proteins, i.e., more than 100 amino acid residues
Publication date: 2009-05-21
Patent application number: 20090131637
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Patent application title: Vanilloid receptor
Inventors:
Peter McIntyre
Iain Fraser James
Agents:
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
Assignees:
Origin: CAMBRIDGE, MA US
IPC8 Class: AC07K1400FI
USPC Class:
530350
Abstract:
The isolated nucleic acid encoding human vanilloid receptor, said
receptor, it's preparation, cells expressing said receptor and an assay
for testing compounds for their potential to decrease pain in humans. The
receptor is involved in detection of noxious stimuli in mammalian
organisms.Claims:
1-6. (canceled)
7. A recombinant human vanilloid receptor.
8. The receptor of claim 7 encoded by a nucleic acid wherein the nucleic acid has sequence identity of from more than 85.5% to 100% over the open reading frame of SEQ ID NO:1.
9. (canceled)
10. The receptor of claim 7 wherein when the receptor is expressed in mammalian cells, the receptor can be activated by capsaicin, in the presence of temperatures greater than 42.degree. C. and by pH less than 5.5.
11. The receptor of claim 7 wherein activation by capsaicin, temperatures greater than 42.degree. C. or by pH less than 5.5 is inhibited by the action of the capsaicin antagonist capsazepine.
12-18. (canceled)
19. An isolated human vanilloid receptor.
Description:
[0001]The present invention is directed to an isolated nucleic acid
encoding human vanilloid receptor, said receptor, its preparation, cells
expressing said receptor and an assay for testing compounds for their
potential to decrease pain in humans.
[0002]More particularly the present invention provides in a first aspect, an isolated nucleic acid encoding a human vanilloid receptor.
[0003]Even more particularly the present invention provides an isolated nucleic acid capable of directing expression of a human vanilloid receptor, in particular a cDNA capable of directing expression of said receptor, more particularly a cDNA comprising the nucleotide sequence as depicted in SEQ ID NO:1, most particularly a cDNA capable of directing expression of the predicted protein depicted in SEQ ID NO:2.
[0004]Said isolated nucleic acid may have a nucleotide sequence having sequence identity within a range of from more than 85.5%, preferably more than 97% to 100% over the open reading frame with the nucleotide sequence as described in SEQ ID NO:1. Preferably said isolated nucleic acid comprises a nucleic acid identical over the open reading frame to the sequence as described in SEQ ID NO:1.
[0005]The nucleic acid may be prepared for example by constructing a cDNA library from mRNA derived from human neuronal cells expressing vanilloid receptor. Such cells may be the nociceptive neurones, the cell bodies thereof residing within the dorsal root ganglia. The cDNA may then be expressed in a cell line not normally expressing endogenous vanilloid receptor and by iteratively subdividing and reassaying positive clones an individual clone may be obtained comprising the desired nucleic acid.
[0006]In a further embodiment the present invention is directed to a recombinant human vanilloid receptor. An example for said human vanilloid receptor may be a protein encoded by a nucleic acid having sequence identity within a range of from more than 85.5%, preferably more than 97% to 100% over the open reading frame with the nucleotide sequence as described in SEQ ID NO:1, e.g. a protein comprising an amino acid sequence having sequence identity within a range of from more than 85.7% to 100% with the amino acid sequence as described in SEQ ID NO:2, as calculated using the ALIGN program [Myers and Miller, CABIOS (1989)]. The amino acid differences may occur at a site selected from the N-terminus, the C-terminus and the putative pore region of the channel, i.e. amino acid 597 to amino acid 696 of SEQ ID NO:2. Preferably the human vanilloid receptor comprises an amino acid sequence identical to the sequence as described in SEQ ID NO:2.
[0007]The human vanilloid receptor when expressed in mammalian cells is activated by capsaicin, temperatures greater than 42° C. and by pH less than 5.5. The activation by all these effectors can be blocked substantially or completely by the action of the capsaicin antagonist capsazepine.
[0008]The vanilloid receptor may be prepared by stably transfecting a cell line with an appropriate expression cassette comprising a nucleic acid encoding the receptor, and culturing cells of said cell line under conditions which allow expression of said receptor.
[0009]In a further embodiment the present invention is directed to a cell belonging to a cell line expressing recombinant human vanilloid receptor.
[0010]In a further embodiment the present invention is directed to a cell belonging to a cell line expressing recombinant mammalian vanilloid receptor and aequorin.
[0011]Examples for useful cell lines include any cell line growing well in culture, e.g. human embryonic kidney derived cells, like HEK293 cells and Chinese hamster ovary cells, like CHO-DUKX-B11 cells [Kaufman et al., Mol. Cell biol. 5:1750-1759 (1985)], which have been transformed/transfected with an appropriate expression cassette comprising a nucleic acid encoding human or mammalian vanilloid receptor and optionally a nucleic acid encoding aequorin. The expression cassette may be derived from a vector selected from for example pIRESneo, pBKCMV and pXMT3. A very useful cell line is the CHO-DUKX-B11 cell line.
[0012]Examples for a mammalian vanilloid receptor are the rat receptor and the human receptor. Aequorin is a protein from the jellyfish. In the presence of Ca++ ions the complex of aequorin and coelenterazine gives off light.
[0013]In a further embodiment the present invention is directed to an assay to measure vanilloid receptor activation comprising measuring changes in aequorin luminescence of cells expressing a mammalian vanilloid receptor and aequorin.
[0014]In a further embodiment the present invention is directed to a screening assay for vanilloid receptor channel blockers comprising incubation of a cell expressing a mammalian vanilloid receptor and aequorin with the potential vanilloid receptor channel blocker, adding an activator/agonist, e.g. capsaicin, of the vanilloid receptor channel and measuring changes in aequorin luminescence.
[0015]In a further embodiment the present invention is directed to a screening assay for vanilloid receptor channel agonists comprising incubation of a cell expressing a mammalian vanilloid receptor and aequorin, adding the potential vanilloid receptor channel agonist and measuring changes in aequorin luminescence.
[0016]In a further embodiment the present invention is directed to an assay to measure vanilloid receptor activation comprising measuring changes in the fluorescence of laser activated, calcium sensitive dyes, e.g. fura 2 AM and fluo3.
[0017]In a further embodiment the present invention is directed to a screening assay for vanilloid receptor channel blockers comprising incubation of a cell expressing a mammalian vanilloid receptor and optionally aequorin with the potential vanilloid receptor channel blocker, adding an activator/agonist, e.g. capsaicin, of the vanilloid receptor and measuring changes in the fluorescence of laser activated, calcium sensitive dyes, e.g. fura 2 AM and fluo 3.
[0018]In a further embodiment the present invention is directed to a screening assay for vanilloid receptor channel agonists comprising incubation of a cell expressing a mammalian vanilloid receptor and optionally aequorin with the potential vanilloid receptor channel agonist and measuring changes in the fluorescence of laser activated, calcium sensitive dyes, e.g. fura 2 AM and fluo3.
[0019]The above assay formats allow automation and are suitable for screening.
[0020]In a further embodiment the present invention is directed to a novel vanilloid receptor channel blocker identified by a screening assay for vanilloid receptor channel blockers comprising incubation of a cell expressing a mammalian vanilloid receptor and aequorin with the potential vanilloid receptor channel blocker, adding an activator/agonist, e.g. capsaicin, of the vanilloid receptor and measuring changes in aequorin luminescence.
[0021]In a further embodiment the present invention is directed to a novel vanilloid receptor channel agonist identified by a screening assay for vanilloid receptor channel agonists comprising incubation of a cell expressing a mammalian vanilloid receptor and aequorin with the potential vanilloid receptor channel agonist and measuring changes in aequorin luminescence.
[0022]In a further embodiment the present invention is directed to a novel vanilloid receptor channel blocker identified by a screening assay for vanilloid receptor channel blockers comprising incubation of a cell expressing a mammalian vanilloid receptor and optionally aequorin with the potential vanilloid receptor channel blocker, adding an activator/agonist, e.g. capsaicin, of the vanilloid receptor and measuring changes in the fluorescence of laser activated, calcium sensitive dyes, e.g. fura 2 AM and fluo3.
[0023]In a further embodiment the present invention is directed to a novel vanilloid receptor channel agonist identified by a screening assay for vanilloid receptor channel agonists comprising incubation of a cell expressing a mammalian vanilloid receptor and optionally aequorin with the potential vanilloid receptor channel agonist and measuring changes in the fluorescence of laser activated, calcium sensitive dyes, e.g. fura 2 AM and fluo3.
[0024]In accordance with the foregoing the present invention also provides:
(1) an isolated nucleic acid encoding a human vanilloid receptor;(2) a recombinant human vanilloid receptor;(3) a method of preparation of the receptor of (2);(4) a cell line expressing the receptor of (2) and optionally aequorin;(5) an assay to measure vanilloid receptor activation;(6) a screening assay for vanilloid receptor channel blockers or agonists; and(7) novel vanilloid receptor channel blocker or agonist, e.g. obtained via (6).
[0025]The following examples illustrate the invention without limitation.
[0026]The following abbreviations are used in the examples: DRG: dorsal root ganglion; G418: Geneticin; HBSS: Hanks balanced salt solution; PBS: phosphate buffered saline; RT: room temperature; VR: vanilloid receptor
EXAMPLE A1
Preparation of CHO Cells Expressing Rat VR and Aequorin
[0027](a) Aequorin-pXMT3: The pXMT3 mammalian expression plasmid, SEQ ID NO:3, encodes a cDNA for dihydrofolate reductase. Aequorin-pBk-CMV (SEQ ID NO:4) is linearised with Nhe1 (immediately upstream of the Kozak consensus sequence). The 5'overhang is filled in with Klenow fragment and phosphorylated PstI linker (New England Biolabs) is blunt end ligated to the DNA. The aequorin insert is released with PstI and EcoRI and cloned into pXMT3.
[0028](b) Cloning of rVR1: A rat vanilloid receptor, rVR1, cDNA is cloned by homology cloning from a rat DRG cDNA library in lambda ZAP express using a 969 bp PCR fragment corresponding to nucleotides 1513 to 2482 from the rat VR1 sequence [Caterina et al., Nature 389:816-824 (1997)] as a probe. This probe is derived by RT-PCR using RNA from adult rat DRG [Helliwell et al., Neuroscience Lett. 250:177-180 (1998). The rVR1 insert is then cut out with EcoR1 and Not1 and then subcloned into the pIRESneo expression vector (Accession Number U89673) (Clontech). The rVR1 PCR clone is then subcloned into pcDNA3.1 (Invitrogen) expression vector.
[0029]DNA used for transient and stable transfections is purified using Promega's Wizard plus Maxi or Megaprep DNA purification systems.
[0030](c) Production of rVR1/aequorin CHO cell stable clone: DUKX-CHO-Aequorin cells which have previously been transfected with pXMT3-aequorin are transfected with pIRESneo-rVR1 using LipofectAMINE PLUS reagent. 1,000,000 cells are transfected with 1.25 μg of rVR1 DNA. 2 days following transfection 700 μg/ml G418 is used to select for positive cells. Transfected cells are visible after 5 days and continued to be grown in the presence of G418 after that. 10 days later the G418 selected cells are cloned by limiting dilution in 96 well plates and continue to be grown in G418 after that.
EXAMPLE A2
Preparation of CHO Cells Expressing Human VR and Aequorin
[0031](a) Cloning of hVR1: A human DRG cDNA library of approximately 80,000 clones is made in lambda ZAP express using a Stratagene kit. The library is screened at low stringency (2×SSC, 45° C.) using the rat VR1 probe described in Example A1. Several clones are isolated and the longest full-length one, clone 3D, is chosen for expression studies (SEQ ID NO:1). The insert is cut out with Eco R1 and Not 1 and cloned into pIRESneo (Accession Number U89673) (Clontech).
[0032](b) Production of hVR1/Aequorin CHO cell stable clone: DUKX-CHO-Aequorin cells which have previously been transfected with pXMT3-aequorin are transfected with pIRESneo-hVR1 using LipofectAMINE PLUS reagent. 1,000,000 cells are transfected with 1.25 μg of hVR1 DNA. 2 days following transfection 700 μg/ml G418 is used to select for positive cells. Transfected cells are visible after 5 days and later, the G418 selected cells are cloned by limiting dilution in 96 well plates and continue to be grown in the presence of G418 after that.
EXAMPLE B1
Potency of Capsaicin (Agonist)
[0033](a) Calcium uptake assay: Primary cultures of adult DRG neurones are prepared according to standard protocols [Wood et al., J. Neuroscience 8:3208-3220 (1988)]. Cells are plated at a density of 2000 per well on 96 well view plates pre-coated with poly-ornithine and laminin and cultured in Hams F14 supplemented with 100 ng/ml NGF for four days. On the day of the assay, the cells are washed eight times in a Denley cell washer with calcium/magnesium free HBSS plus 10 mM HEPES, pH7.4. After washing the wells contain approximately 75 μl of buffer.
[0034]To this is added 25 μl of capsaicin with or without capsazepine or ruthenium red in Ca/Mg free buffer containing 370 KBq of 45Ca2+/ml. For negative control, capsaicin is omitted. Samples are incubated at RT for 10 min, then washed four times with HBSS/10 mM HEPES pH 7.4. The remaining buffer is removed from the wells and replaced with 25 μl of 0.1% SDS. After about 10 min 200 μl of Microscint 40 scintillant is added and samples are counted on a Packard Topcount.
[0035](b) Measurement of aequorin activity: Active aequorin is reconstituted by incubating confluent cells resulting from Examples A1 or A2 at 37° C. with 20 μM coelenterazine h [Biochem. J. 261:913-920 (1989)] and 30 μM glutathione (reduced form) in 50 μl of medium per well. All the plates for use in a day are set up at the same time. The first plate is used in the assay after 2.5 h incubation with coelenterazine h. Subsequent plates are used at about 10 min intervals. There is no loss of signal with the longer incubation times. At the start of the assay, the medium containing coelenterazine h is removed and replaced with 100 μl of HBSS buffered to pH 7.4 with 10 mM HEPES containing test compounds where appropriate. Cells are incubated for at least 10 min at RT. They are then placed in the measuring chamber of a luminometer (Wallac Microbeta Jet). Agonist is injected in a volume of 20 μl HBSS and the luminescence signal is collected for 20 sec.
[0036](c) Fluorometric assay using the FLIPR: Cells resulting from Examples A1 or A2 are plated at a density of 50,000 cells/well in Costar Viewplates. The cells are incubated at 37° C. in a humidified atmosphere (5% CO2/95% air) for 24 h. Medium is removed by flicking the plates and replaced with 100 μl HBSS containing 2 μM Fluo-3, AM (Molecular Probes) in the presence of 2.5 mM probenicid (Sigma) and 0.02% pluronic acid (Molecular Probes). The cells are incubated at 37° C. in a humidified atmosphere (5% CO2/95% air) for 1 h. Plates are flicked to remove excess of Fluo-3, AM, washed twice with HBSS and refilled with 100 μl of HBSS containing screening compounds. Incubation in the presence of screening compounds lasts between 10 and 20 min. Plates are then placed in the cell plate stage of the FLIPR (Molecular Devices, Sunnyvale, Calif., USA). A baseline consisting in 5 measurements of 0.4 sec each (laser: excitation 488 nm at 0.6 W, CCD camera opening of 0.4 sec) is recorded. Capsaicin (50 μl at 45 nM) is added from the agonist plate (placed in the agonist plate stage of the FLIPR tower) to the cell plate using the FLIPR 96-tip pipettor simultaneously to fluorescence recording for 3 min according to the following scheme: 0.4 sec measurements each interval of 1 sec for 1 min followed by 0.4 sec measurements each interval of 4 sec for 100 sec. Data are expressed as (Fm-Fb)/Fb where Fm is the fluorescence peak reached following capsaicin injection and Fb is the baseline fluorescence prior to capsaicin injection.
TABLE-US-00001 EC50 (nM) EC50 (nM) EC50 (nM) (aequorin assay) (Ca uptake assay) (Fluo-3 assay) rVR1 in hVR1 in Rat DRG hVR1 in CHO cells CHO cells neurones CHO cells 530 ± 110 480 ± 64 170 ± 19 3.42 ± 0.2
EXAMPLE B2
Capsazepine and Ruthenium Red Activity on Vanilloid Receptors Activated by Capsaicin
[0037](a) Inhibition of capsaicin responses by the competitive antagonist, capsazepine, is measured as described in Example B1. Capsaicin is used at a concentration of 1 μM. The IC50 for capsazepine at hVR1 is comparable to that at rVR1 and slightly lower than that measured in calcium uptake assays with DRG neurones.
[0038](b) Activity of the channel blocker ruthenium red is measured as described in Example B1. The layout and conditions are the same as for (a) above. Ruthenium red is an effective blocker of capsaicin responses. The IC50 at hVR1 is slightly higher than at the cloned rVR1 or that found in the calcium uptake assay with primary cultures of DRG neurones.
TABLE-US-00002 IC50 (nM) IC50 (nM) IC50 (nM) (aequorin assay) (Ca uptake assay) (Fluo-3 assay) Compound rVR1 (CHO) hVR1 (CHO) Rat DRG neurones hVR1 (CHO) Cz 320 ± 110 120 ± 12 800 ± 40 130 ± 32 Rr 18 ± 8.3 220 ± 32 50* *From Wood et al (1988) Cz: Capsazepine; Rr: Ruthenium red; (CHO): in CHO cells
Sequence CWU
1
413463DNAHomo sapiensCDS(359)..(2875) 1CCCCCCAGTT TTACACTTTT ACTTCCCGGT
CGTATATTGT GTGAAATTGT GAGCGGAATA 60CCCATTTTCA CACAAGGAAC CAGTTTATCC
TTTGATTACG CCAAGCTCGA AATTACCCCC 120TCATTAAAAG GGAACAAAAG TTGGAGCTCG
CGCGCCTGCA GGTCGACACT AGTGGATCCA 180AAGAATTCGG CACGAGCCGG GCCCGGGACC
CCACGGAGGC GGGGAGACCA CTCTTCTCCC 240ACACGAGCCC AGCTCTCCCT TCGAGTAGCA
ACCGCCTTCA AGCTCACAAG CACCCGTGGG 300CCTGGGGTGT GCCTGCGTCT AGCTGGTTGC
ACACTGGGCC ACAGAGGATC CAGCAAGG 358ATG AAG AAA TGG AGC AGC ACA GAC
TTG GGG GCA GCT GCG GAC CCA CTC 406Met Lys Lys Trp Ser Ser Thr Asp
Leu Gly Ala Ala Ala Asp Pro Leu1 5 10
15CAA AAG GAC ACC TGC CCA GAC CCC CTG GAT GGA GAC CCT AAC TCC
AGG 454Gln Lys Asp Thr Cys Pro Asp Pro Leu Asp Gly Asp Pro Asn Ser
Arg20 25 30CCA CCT CCA GCC AAG CCC CAG
CTC TCC ACG GCC AAG AGC CGC ACC CGG 502Pro Pro Pro Ala Lys Pro Gln
Leu Ser Thr Ala Lys Ser Arg Thr Arg35 40
45CTC TTT GGG AAG GGT GAC TCG GAG GAG GCT TTC CCG GTG GAT TGC CCT
550Leu Phe Gly Lys Gly Asp Ser Glu Glu Ala Phe Pro Val Asp Cys Pro50
55 60CAC GAG GAA GGT GAG CTG GAC TCC TGC CCG
ACC ATC ACA GTC AGC CCT 598His Glu Glu Gly Glu Leu Asp Ser Cys Pro
Thr Ile Thr Val Ser Pro65 70 75
80GTT ATC ACC ATC CAG AGG CCA GGA GAC GGC CCC ACC GGT GCC AGG
CTG 646Val Ile Thr Ile Gln Arg Pro Gly Asp Gly Pro Thr Gly Ala Arg
Leu85 90 95CTG TCC CAG GAC TCT GTC GCC
GCC AGC ACC GAG AAG ACC CTC AGG CTC 694Leu Ser Gln Asp Ser Val Ala
Ala Ser Thr Glu Lys Thr Leu Arg Leu100 105
110TAT GAT CGC AGG AGT ATC TTT GAA GCC GTT GCT CAG AAT AAC TGC CAG
742Tyr Asp Arg Arg Ser Ile Phe Glu Ala Val Ala Gln Asn Asn Cys Gln115
120 125GAT CTG GAG AGC CTG CTG CTC TTC CTG
CAG AAG AGC AAG AAG CAC CTC 790Asp Leu Glu Ser Leu Leu Leu Phe Leu
Gln Lys Ser Lys Lys His Leu130 135 140ACA
GAC AAC GAG TTC AAA GAC CCT GAG ACA GGG AAG ACC TGT CTG CTG 838Thr
Asp Asn Glu Phe Lys Asp Pro Glu Thr Gly Lys Thr Cys Leu Leu145
150 155 160AAA GCC ATG CTC AAC CTG
CAC GAC GGA CAG AAC ACC ACC ATC CCC CTG 886Lys Ala Met Leu Asn Leu
His Asp Gly Gln Asn Thr Thr Ile Pro Leu165 170
175CTC CTG GAG ATC GCG CGG CAA ACG GAC AGC CTG AAG GAG CTT GTC AAC
934Leu Leu Glu Ile Ala Arg Gln Thr Asp Ser Leu Lys Glu Leu Val Asn180
185 190GCC AGC TAC ACG GAC AGC TAC TAC AAG
GGC CAG ACA GCA CTG CAC ATC 982Ala Ser Tyr Thr Asp Ser Tyr Tyr Lys
Gly Gln Thr Ala Leu His Ile195 200 205GCC
ATC GAG AGA CGC AAC ATG GCC CTG GTG ACC CTC CTG GTG GAG AAC 1030Ala
Ile Glu Arg Arg Asn Met Ala Leu Val Thr Leu Leu Val Glu Asn210
215 220GGA GCA GAC GTC CAG GCT GCG GCC CAT GGG GAC
TTC TTT AAG AAA ACC 1078Gly Ala Asp Val Gln Ala Ala Ala His Gly Asp
Phe Phe Lys Lys Thr225 230 235
240AAA GGG CGG CCT GGA TTC TAC TTC GGT GAA CTG CCC CTG TCC CTG GCC
1126Lys Gly Arg Pro Gly Phe Tyr Phe Gly Glu Leu Pro Leu Ser Leu Ala245
250 255GCG TGC ACC AAC CAG CTG GGC ATC GTG
AAG TTC CTG CTG CAG AAC TCC 1174Ala Cys Thr Asn Gln Leu Gly Ile Val
Lys Phe Leu Leu Gln Asn Ser260 265 270TGG
CAG ACG GCC GAC ATC AGC GCC AGG GAC TCG GTG GGC AAC ACG GTG 1222Trp
Gln Thr Ala Asp Ile Ser Ala Arg Asp Ser Val Gly Asn Thr Val275
280 285CTG CAC GCC CTG GTG GAG GTG GCC GAC AAC ACG
GCC GAC AAC ACG AAG 1270Leu His Ala Leu Val Glu Val Ala Asp Asn Thr
Ala Asp Asn Thr Lys290 295 300TTT GTG ACG
AGC ATG TAC AAT GAG ATT CTG ATC CTG GGG GCC AAA CTG 1318Phe Val Thr
Ser Met Tyr Asn Glu Ile Leu Ile Leu Gly Ala Lys Leu305
310 315 320CAC CCG ACG CTG AAG CTG GAG
GAG CTC ACC AAC AAG AAG GGA ATG ATG 1366His Pro Thr Leu Lys Leu Glu
Glu Leu Thr Asn Lys Lys Gly Met Met325 330
335CCG CTG GCT CTG GCA GCT GGG ACC GGG AAG ATC GGG GTC TTG GCC TAT
1414Pro Leu Ala Leu Ala Ala Gly Thr Gly Lys Ile Gly Val Leu Ala Tyr340
345 350ATT CTC CAG CGG GAG ATC CAG GAG CCC
GAG TGC AGG CAC CTG TCC AGG 1462Ile Leu Gln Arg Glu Ile Gln Glu Pro
Glu Cys Arg His Leu Ser Arg355 360 365AAG
TTC ACC GAG TGG GCC TAC GGG CCC GTG CAC TCC TCG CTG TAC GAC 1510Lys
Phe Thr Glu Trp Ala Tyr Gly Pro Val His Ser Ser Leu Tyr Asp370
375 380CTG TCC TGC ATC GAC ACC TGC GAG AAG AAC TCG
GTG CTG GAG GTG ATC 1558Leu Ser Cys Ile Asp Thr Cys Glu Lys Asn Ser
Val Leu Glu Val Ile385 390 395
400GCC TAC AGC AGC AGC GAG ACC CCT AAT CGC CAC GAC ATG CTC TTG GTG
1606Ala Tyr Ser Ser Ser Glu Thr Pro Asn Arg His Asp Met Leu Leu Val405
410 415GAG CCG CTG AAC CGA CTC CTG CAG GAC
AAG TGG GAC AGA TTC GTC AAG 1654Glu Pro Leu Asn Arg Leu Leu Gln Asp
Lys Trp Asp Arg Phe Val Lys420 425 430CGC
ATC TTC TAC TTC AAC TTC CTG GTC TAC TGC CTG TAC ATG ATC ATC 1702Arg
Ile Phe Tyr Phe Asn Phe Leu Val Tyr Cys Leu Tyr Met Ile Ile435
440 445TTC ACC ATG GCT GCC TAC TAC AGG CCC GTG GAT
GGC TTG CCT CCC TTT 1750Phe Thr Met Ala Ala Tyr Tyr Arg Pro Val Asp
Gly Leu Pro Pro Phe450 455 460AAG ATG GAA
AAA ACT GGA GAC TAT TTC CGA GTT ACT GGA GAG ATC CTG 1798Lys Met Glu
Lys Thr Gly Asp Tyr Phe Arg Val Thr Gly Glu Ile Leu465
470 475 480TCT GTG TTA GGA GGA GTC TAC
TTC TTT TTC CGA GGG ATT CAG TAT TTC 1846Ser Val Leu Gly Gly Val Tyr
Phe Phe Phe Arg Gly Ile Gln Tyr Phe485 490
495CTG CAG AGG CGG CCG TCG ATG AAG ACC CTG TTT GTG GAC AGC TAC AGT
1894Leu Gln Arg Arg Pro Ser Met Lys Thr Leu Phe Val Asp Ser Tyr Ser500
505 510GAG ATG CTT TTC TTT CTG CAG TCA CTG
TTC ATG CTG GCC ACC GTG GTG 1942Glu Met Leu Phe Phe Leu Gln Ser Leu
Phe Met Leu Ala Thr Val Val515 520 525CTG
TAC TTC AGC CAC CTC AAG GAG TAT GTG GCT TCC ATG GTA TTC TCC 1990Leu
Tyr Phe Ser His Leu Lys Glu Tyr Val Ala Ser Met Val Phe Ser530
535 540CTG GCC TTG GGC TGG ACC AAC ATG CTC TAC TAC
ACC CGC GGT TTC CAG 2038Leu Ala Leu Gly Trp Thr Asn Met Leu Tyr Tyr
Thr Arg Gly Phe Gln545 550 555
560CAG ATG GGC ATC TAT GCC GTC ATG ATA GAG AAG ATG ATC CTG AGA GAC
2086Gln Met Gly Ile Tyr Ala Val Met Ile Glu Lys Met Ile Leu Arg Asp565
570 575CTG TGC CGT TTC ATG TTT GTC TAC ATC
GTC TTC TTG TTC GGG TTT TCC 2134Leu Cys Arg Phe Met Phe Val Tyr Ile
Val Phe Leu Phe Gly Phe Ser580 585 590ACA
GCG GTG GTG ACG CTG ATT GAA GAC GGG AAG AAT GAC TCC CTG CCG 2182Thr
Ala Val Val Thr Leu Ile Glu Asp Gly Lys Asn Asp Ser Leu Pro595
600 605TCT GAG TCC ACG TCG CAC AGG TGG CGG GGG CCT
GCC TGC AGG CCC CCC 2230Ser Glu Ser Thr Ser His Arg Trp Arg Gly Pro
Ala Cys Arg Pro Pro610 615 620GAT AGC TCC
TAC AAC AGC CTG TAC TCC ACC TGC CTG GAG CTG TTC AAG 2278Asp Ser Ser
Tyr Asn Ser Leu Tyr Ser Thr Cys Leu Glu Leu Phe Lys625
630 635 640TTC ACC ATC GGC ATG GGC GAC
CTG GAG TTC ACT GAG AAC TAT GAC TTC 2326Phe Thr Ile Gly Met Gly Asp
Leu Glu Phe Thr Glu Asn Tyr Asp Phe645 650
655AAG GCT GTC TTC ATC ATC CTG CTG CTG GCC TAT GTA ATT CTC ACC TAC
2374Lys Ala Val Phe Ile Ile Leu Leu Leu Ala Tyr Val Ile Leu Thr Tyr660
665 670ATC CTC CTG CTC AAC ATG CTC ATC GCC
CTC ATG GGT GAG ACT GTC AAC 2422Ile Leu Leu Leu Asn Met Leu Ile Ala
Leu Met Gly Glu Thr Val Asn675 680 685AAG
ATC GCA CAG GAG AGC AAG AAC ATC TGG AAG CTG CAG AGA GCC ATC 2470Lys
Ile Ala Gln Glu Ser Lys Asn Ile Trp Lys Leu Gln Arg Ala Ile690
695 700ACC ATC CTG GAC ACG GAG AAG AGC TTC CTT AAG
TGC ATG AGG AAG GCC 2518Thr Ile Leu Asp Thr Glu Lys Ser Phe Leu Lys
Cys Met Arg Lys Ala705 710 715
720TTC CGC TCA GGC AAG CTG CTG CAG GTG GGG TAC ACA CCT GAT GGC AAG
2566Phe Arg Ser Gly Lys Leu Leu Gln Val Gly Tyr Thr Pro Asp Gly Lys725
730 735GAC GAC TAC CGG TGG TGC TTC AGG GTG
GAC GAG GTG AAC TGG ACC ACC 2614Asp Asp Tyr Arg Trp Cys Phe Arg Val
Asp Glu Val Asn Trp Thr Thr740 745 750TGG
AAC ACC AAC GTG GGC ATC ATC AAC GAA GAC CCG GGC AAC TGT GAG 2662Trp
Asn Thr Asn Val Gly Ile Ile Asn Glu Asp Pro Gly Asn Cys Glu755
760 765GGC GTC AAG CGC ACC CTG AGC TTC TCC CTG CGG
TCA AGC AGA GTT TCA 2710Gly Val Lys Arg Thr Leu Ser Phe Ser Leu Arg
Ser Ser Arg Val Ser770 775 780GGC AGA CAC
TGG AAG AAC TTT GCC CTG GTC CCC CTT TTA AGA GAG GCA 2758Gly Arg His
Trp Lys Asn Phe Ala Leu Val Pro Leu Leu Arg Glu Ala785
790 795 800AGT GCT CGA GAT AGG CAG TCT
GCT CAG CCC GAG GAA GTT TAT CTG CGA 2806Ser Ala Arg Asp Arg Gln Ser
Ala Gln Pro Glu Glu Val Tyr Leu Arg805 810
815CAG TTT TCA GGG TCT CTG AAG CCA GAG GAC GCT GAG GTC TTC AAG AGT
2854Gln Phe Ser Gly Ser Leu Lys Pro Glu Asp Ala Glu Val Phe Lys Ser820
825 830CCT GCC GCT TCC GGG GAG AAG
TGAGGACGTC ACGCAGACAG CACTGTCAAC 2905Pro Ala Ala Ser Gly Glu
Lys835ACTGGGCCTT AGGAGACCCC GTTGCCACGG GGGGCTGCTG AGGGAACACC AGTGCTCTGT
2965CAGCAGCCTG GCCTGGTCTG TGCCTGCCCA GCATGTTCCC AAATCTGTGC TGGACAAACT
3025GTGGGAAAGC GTTCTTGGAA GCATGGGGAG TGATGTACAT CCAACCGTCA CTGTCCCCAA
3085GTGAATCTCC TAACAGACTT TCAGGTTTTT ACTCACTTTA CTAAACAGTG TGGATGGTCA
3145GTCTCTACTG GGACATGTTA GGCCCTTGTT TTCTTTGATT TTATTCTTTT TTTTGAGACA
3205GAATTTCACT CTTCTCGCCC AGGCTGGAAT GCAGTGGCAC AATTTTGGCT CCCTGCAACC
3265TCCGCCTCCT GGATTCCAGC AATTCTCCTG CCTCGGCTTC CCAAGTAGCT GGGATTACAG
3325GCACGTGCCA CCATGTCTGG CTAATTTTTT GGATTTTTTT AATAAAAATG GGGGTTCGCC
3385ATGTTGGCCA GGCTGGTCTC GAACTCCTGA CCTTAGGGGA TCCCCCCACC TTGGGCCTCC
3445CAAAGGGCTG GGAATACA
34632839PRTHomo sapiens 2Met Lys Lys Trp Ser Ser Thr Asp Leu Gly Ala Ala
Ala Asp Pro Leu1 5 10
15Gln Lys Asp Thr Cys Pro Asp Pro Leu Asp Gly Asp Pro Asn Ser Arg20
25 30Pro Pro Pro Ala Lys Pro Gln Leu Ser Thr
Ala Lys Ser Arg Thr Arg35 40 45Leu Phe
Gly Lys Gly Asp Ser Glu Glu Ala Phe Pro Val Asp Cys Pro50
55 60His Glu Glu Gly Glu Leu Asp Ser Cys Pro Thr Ile
Thr Val Ser Pro65 70 75
80Val Ile Thr Ile Gln Arg Pro Gly Asp Gly Pro Thr Gly Ala Arg Leu85
90 95Leu Ser Gln Asp Ser Val Ala Ala Ser Thr
Glu Lys Thr Leu Arg Leu100 105 110Tyr Asp
Arg Arg Ser Ile Phe Glu Ala Val Ala Gln Asn Asn Cys Gln115
120 125Asp Leu Glu Ser Leu Leu Leu Phe Leu Gln Lys Ser
Lys Lys His Leu130 135 140Thr Asp Asn Glu
Phe Lys Asp Pro Glu Thr Gly Lys Thr Cys Leu Leu145 150
155 160Lys Ala Met Leu Asn Leu His Asp Gly
Gln Asn Thr Thr Ile Pro Leu165 170 175Leu
Leu Glu Ile Ala Arg Gln Thr Asp Ser Leu Lys Glu Leu Val Asn180
185 190Ala Ser Tyr Thr Asp Ser Tyr Tyr Lys Gly Gln
Thr Ala Leu His Ile195 200 205Ala Ile Glu
Arg Arg Asn Met Ala Leu Val Thr Leu Leu Val Glu Asn210
215 220Gly Ala Asp Val Gln Ala Ala Ala His Gly Asp Phe
Phe Lys Lys Thr225 230 235
240Lys Gly Arg Pro Gly Phe Tyr Phe Gly Glu Leu Pro Leu Ser Leu Ala245
250 255Ala Cys Thr Asn Gln Leu Gly Ile Val
Lys Phe Leu Leu Gln Asn Ser260 265 270Trp
Gln Thr Ala Asp Ile Ser Ala Arg Asp Ser Val Gly Asn Thr Val275
280 285Leu His Ala Leu Val Glu Val Ala Asp Asn Thr
Ala Asp Asn Thr Lys290 295 300Phe Val Thr
Ser Met Tyr Asn Glu Ile Leu Ile Leu Gly Ala Lys Leu305
310 315 320His Pro Thr Leu Lys Leu Glu
Glu Leu Thr Asn Lys Lys Gly Met Met325 330
335Pro Leu Ala Leu Ala Ala Gly Thr Gly Lys Ile Gly Val Leu Ala Tyr340
345 350Ile Leu Gln Arg Glu Ile Gln Glu Pro
Glu Cys Arg His Leu Ser Arg355 360 365Lys
Phe Thr Glu Trp Ala Tyr Gly Pro Val His Ser Ser Leu Tyr Asp370
375 380Leu Ser Cys Ile Asp Thr Cys Glu Lys Asn Ser
Val Leu Glu Val Ile385 390 395
400Ala Tyr Ser Ser Ser Glu Thr Pro Asn Arg His Asp Met Leu Leu
Val405 410 415Glu Pro Leu Asn Arg Leu Leu
Gln Asp Lys Trp Asp Arg Phe Val Lys420 425
430Arg Ile Phe Tyr Phe Asn Phe Leu Val Tyr Cys Leu Tyr Met Ile Ile435
440 445Phe Thr Met Ala Ala Tyr Tyr Arg Pro
Val Asp Gly Leu Pro Pro Phe450 455 460Lys
Met Glu Lys Thr Gly Asp Tyr Phe Arg Val Thr Gly Glu Ile Leu465
470 475 480Ser Val Leu Gly Gly Val
Tyr Phe Phe Phe Arg Gly Ile Gln Tyr Phe485 490
495Leu Gln Arg Arg Pro Ser Met Lys Thr Leu Phe Val Asp Ser Tyr
Ser500 505 510Glu Met Leu Phe Phe Leu Gln
Ser Leu Phe Met Leu Ala Thr Val Val515 520
525Leu Tyr Phe Ser His Leu Lys Glu Tyr Val Ala Ser Met Val Phe Ser530
535 540Leu Ala Leu Gly Trp Thr Asn Met Leu
Tyr Tyr Thr Arg Gly Phe Gln545 550 555
560Gln Met Gly Ile Tyr Ala Val Met Ile Glu Lys Met Ile Leu
Arg Asp565 570 575Leu Cys Arg Phe Met Phe
Val Tyr Ile Val Phe Leu Phe Gly Phe Ser580 585
590Thr Ala Val Val Thr Leu Ile Glu Asp Gly Lys Asn Asp Ser Leu
Pro595 600 605Ser Glu Ser Thr Ser His Arg
Trp Arg Gly Pro Ala Cys Arg Pro Pro610 615
620Asp Ser Ser Tyr Asn Ser Leu Tyr Ser Thr Cys Leu Glu Leu Phe Lys625
630 635 640Phe Thr Ile Gly
Met Gly Asp Leu Glu Phe Thr Glu Asn Tyr Asp Phe645 650
655Lys Ala Val Phe Ile Ile Leu Leu Leu Ala Tyr Val Ile Leu
Thr Tyr660 665 670Ile Leu Leu Leu Asn Met
Leu Ile Ala Leu Met Gly Glu Thr Val Asn675 680
685Lys Ile Ala Gln Glu Ser Lys Asn Ile Trp Lys Leu Gln Arg Ala
Ile690 695 700Thr Ile Leu Asp Thr Glu Lys
Ser Phe Leu Lys Cys Met Arg Lys Ala705 710
715 720Phe Arg Ser Gly Lys Leu Leu Gln Val Gly Tyr Thr
Pro Asp Gly Lys725 730 735Asp Asp Tyr Arg
Trp Cys Phe Arg Val Asp Glu Val Asn Trp Thr Thr740 745
750Trp Asn Thr Asn Val Gly Ile Ile Asn Glu Asp Pro Gly Asn
Cys Glu755 760 765Gly Val Lys Arg Thr Leu
Ser Phe Ser Leu Arg Ser Ser Arg Val Ser770 775
780Gly Arg His Trp Lys Asn Phe Ala Leu Val Pro Leu Leu Arg Glu
Ala785 790 795 800Ser Ala
Arg Asp Arg Gln Ser Ala Gln Pro Glu Glu Val Tyr Leu Arg805
810 815Gln Phe Ser Gly Ser Leu Lys Pro Glu Asp Ala Glu
Val Phe Lys Ser820 825 830Pro Ala Ala Ser
Gly Glu Lys83535155DNAHomo sapiens 3AAGCTTTTTG CAAAAGCCTA GGAAAAAAGC
CTCCTCACTA CTTCTGGAAT AGCTCAGAGG 60CCGAGGCGGC CTCGGCCTCT GCATAAATAA
AAAAAATTAG TCAGCCATGG GGCGGAGAAT 120GGGCGGAACT GGGCGGAGTT AGGGGCGGGA
TGGGCGGAGT TAGGGGCGGG ACTATGGTTG 180CTGACTAATT GAGATGCATG CTTTGCATAC
TTCTGCCTGC TGGGGAGCCT GGGGACTTTC 240CACACCTGGT TGCTGACTAA TTGAGATGCA
TGCTTTGCAT ACTTCTGCCT GCTGGGGAGC 300CTGGGGACTT TCCACACCCT AACTGACACA
CATTCCACAG GATCCGGTCG CGCGAATTTC 360GAGCGGTGTT CCGCGGTCCT CCTCGTATAG
AAACTCGGAC CACTCTGAGA CGAAGGCTCG 420CGTCCAGGCC AGCACGAAGG AGGCTAAGTG
GGAGGGGTAG CGGTCGTTGT CCACTAGGGG 480GTCCACTCGC TCCAGGGTGT GAAGACACAT
GTCGCCCTCT TCGGCATCAA GGAAGGTGAT 540TGGTTTATAG GTGTAGGCCA CGTGACCGGG
TGTTCCTGAA GGGGGGCTAT AAAAGGGGGT 600GGGGGCGCGT TCGTCCTCAC TCTCTTCCGC
ATCGCTGTCT GCGAGGGCCA GCTGTTGGGC 660TCGCGGTTGA GGACAAACTC TTCGCGGTCT
TTCCAGTACT CTTGGATCGG AAACCCGTCG 720GCCTCCGAAC GGTACTCCGC CACCGAGGGA
CCTGAGCGAG TCCGCATCGA CCGGATCGGA 780AAACCTCTCG ACTGTTGGGG TGAGTACTCC
CTCTCAAAAG CGGGCATGAC TTCTGCGCTA 840AGATTGTCAG TTTCCAAAAA CGAGGAGGAT
TTGATATTCA CCTGGCCCGC GGTGATGCCT 900TTGAGGGTGG CCGCGTCCAT CTGGTCAGAA
AAGACAATCT TTTTGTTGTC AAGCTTGAGG 960TGTGGCAGGC TTGAGATCTG GCCATACACT
TGAGTGACAA TGACATCCAC TTTGCCTTTC 1020TCTCCACAGG TGTCCACTCC CAGGTCCAAC
TGCAGGTCGA CTCTAGAGGA TCCCCGGGTA 1080CCGAGCTCGA ATTCCGGGGG GGGGGGGGGG
GGGGACAGCT CAGGGCTGCG ATTTCGCGCC 1140AAACTTGACG GCAATCCTAG CGTGAAGGCT
GGTAGGATTT TATCCCCGCT GCCATCATGG 1200TTCGACCATT GAACTGCATC GTCGCCGTGT
CCCAAAATAT GGGGATTGGC AAGAACGGAG 1260ACCTACCCTG GCCTCCGCTC AGGAACGAGT
TCAAGTACTT CCAAAGAATG ACCACAACCT 1320CTTCAGTGGA AGGTAAACAG AATCTGGTGA
TTATGGGTAG GAAAACCTGG TTCTCCATTC 1380CTGAGAAGAA TCGACCTTTA AAGGACAGAA
TTAATATAGT TCTCAGTAGA GAACTCAAAG 1440AACCACCACG AGGAGCTCAT TTTCTTGCCA
AAAGTTTGGA TGATGCCTTA AGACTTATTG 1500AACAACCGGA ATTGGCAAGT AAAGTAGACA
TGGTTTGGAT AGTCGGAGGC AGTTCTGTTT 1560ACCAGGAAGC CATGAATCAA CCAGGCCACC
TCAGACTCTT TGTGACAAGG ATCATGCAGG 1620AATTTGAAAG TGACACGTTT TTCCCAGAAA
TTGATTTGGG GAAATATAAA CTTCTCCCAG 1680AATACCCAGG CGTCCTCTCT GAGGTCCAGG
AGGAAAAAGG CATCAAGTAT AAGTTTGAAG 1740TCTACGAGAA GAAAGACTAA CAGGAAGATG
CTTTCAAGTT CTCTGCTCCC CTCCTAAAGC 1800TATGCATTTT TTATAAGACC ATGGGACTTT
TGCTGGCTTT AGATCATAAT CAGCCATACC 1860ACATTTGTAG AGGTTTTACT TGCTTTAAAA
AACCTCCCAC ACCTCCCCCT GAACCTGAAA 1920CATAAAATGA ATGCAATTGT TGTTGTTAAC
TTGTTTATTG CAGCTTATAA TGGTTACAAA 1980TAAAGCAATA GCATCACAAA TTTCACAAAT
AAAGCATTTT TTTCACTGCA TTCTAGTTGT 2040GGTTTGTCCA AACTCATCAA TGTATCTTAT
CATGTCTGGA TCCCCGGCCA ACGGTCTGGT 2100GACCCGGCTG CGAGAGCTCG GTGTACCTGA
GACGCGAGTA AGCCCTTGAG TCAAAGACGT 2160AGTCGTTGCA AGTCCGCACC AGGTACTGAT
ATCCCACCAA AAAGTGCGGC GGCGGCTGGC 2220GGTAGAGGGG CCAGCGTAGG GTGGCCGGGG
CTCCGGGGGC GAGGTCTTCC AACATAAGGC 2280GATGATATCC GTAGATGTAC CTGGACATCC
AGGTGATGCC GGCGGCGGTG GTGGAGGCGC 2340GCGGAAAGTC GCGGACGCGG TTCCAGATGT
TGCGCAGCGG CAAAAAGTGC TCCATGGTCG 2400GGACGCTCTG GCCGGTGAGG CGTGCGCAGT
CGTTGACGCT CTAGACCGTG CAAAAGGAGA 2460GCCTGTAAGC GGGCACTCTT CCGTGGTCTG
GTGGATAAAT TCGCAAGGGT ATCATGGCGG 2520ACGACCGGGG TTCGAACCCC GGATCCGGCC
GTCCGCCGTG ATCCATCCGG TTACCGCCCG 2580CGTGTCGAAC CCAGGTGTGC GACGTCAGAC
AACGGGGGAG CGCTCCTTTT GGCTTCCTTC 2640CAGGCGCGGC GGCTGCTGCG CTAGCTTTTT
TGGCGAGCTC GAATTAATTC TGCATTAATG 2700AATCGGCCAA CGCGCGGGGA GAGGCGGTTT
GCGTATTGGG CGCTCTTCCG CTTCCTCGCT 2760CACTGACTCG CTGCGCTCGG TCGTTCGGCT
GCGGCGAGCG GTATCAGCTC ACTCAAAGGC 2820GGTAATACGG TTATCCACAG AATCAGGGGA
TAACGCAGGA AAGAACATGT GAGCAAAAGG 2880CCAGCAAAAG GCCAGGAACC GTAAAAAGGC
CGCGTTGCTG GCGTTTTTCC ATAGGCTCCG 2940CCCCCCTGAC GAGCATCACA AAAATCGACG
CTCAAGTCAG AGGTGGCGAA ACCCGACAGG 3000ACTATAAAGA TACCAGGCGT TTCCCCCTGG
AAGCTCCCTC GTGCGCTCTC CTGTTCCGAC 3060CCTGCCGCTT ACCGGATACC TGTCCGCCTT
TCTCCCTTCG GGAAGCGTGG CGCTTTCTCA 3120ATGCTCACGC TGTAGGTATC TCAGTTCGGT
GTAGGTCGTT CGCTCCAAGC TGGGCTGTGT 3180GCACGAACCC CCCGTTCAGC CCGACCGCTG
CGCCTTATCC GGTAACTATC GTCTTGAGTC 3240CAACCCGGTA AGACACGACT TATCGCCACT
GGCAGCAGCC ACTGGTAACA GGATTAGCAG 3300AGCGAGGTAT GTAGGCGGTG CTACAGAGTT
CTTGAAGTGG TGGCCTAACT ACGGCTACAC 3360TAGAAGGACA GTATTTGGTA TCTGCGCTCT
GCTGAAGCCA GTTACCTTCG GAAAAAGAGT 3420TGGTAGCTCT TGATCCGGCA AACAAACCAC
CGCTGGTAGC GGTGGTTTTT TTGTTTGCAA 3480GCAGCAGATT ACGCGCAGAA AAAAAGGATC
TCAAGAAGAT CCTTTGATCT TTTCTACGGG 3540GTCTGACGCT CAGTGGAACG AAAACTCACG
TTAAGGGATT TTGGTCATGA GATTATCAAA 3600AAGGATCTTC ACCTAGATCC TTTTAAATTA
AAAATGAAGT TTTAAATCAA TCTAAAGTAT 3660ATATGAGTAA ACTTGGTCTG ACAGTTACCA
ATGCTTAATC AGTGAGGCAC CTATCTCAGC 3720GATCTGTCTA TTTCGTTCAT CCATAGTTGC
CTGACTCCCC GTCGTGTAGA TAACTACGAT 3780ACGGGAGGGC TTACCATCTG GCCCCAGTGC
TGCAATGATA CCGCGAGACC CACGCTCACC 3840GGCTCCAGAT TTATCAGCAA TAAACCAGCC
AGCCGGAAGG GCCGAGCGCA GAAGTGGTCC 3900TGCAACTTTA TCCGCCTCCA TCCAGTCTAT
TAATTGTTGC CGGGAAGCTA GAGTAAGTAG 3960TTCGCCAGTT AATAGTTTGC GCAACGTTGT
TGCCATTGCT ACAGGCATCG TGGTGTCACG 4020CTCGTCGTTT GGTATGGCTT CATTCAGCTC
CGGTTCCCAA CGATCAAGGC GAGTTACATG 4080ATCCCCCATG TTGTGCAAAA AAGCGGTTAG
CTCCTTCGGT CCTCCGATCG TTGTCAGAAG 4140TAAGTTGGCC GCAGTGTTAT CACTCATGGT
TATGGCAGCA CTGCATAATT CTCTTACTGT 4200CATGCCATCC GTAAGATGCT TTTCTGTGAC
TGGTGAGTAC TCAACCAAGT CATTCTGAGA 4260ATAGTGTATG CGGCGACCGA GTTGCTCTTG
CCCGGCGTCA ATACGGGATA ATACCGCGCC 4320ACATAGCAGA ACTTTAAAAG TGCTCATCAT
TGGAAAACGT TCTTCGGGGC GAAAACTCTC 4380AAGGATCTTA CCGCTGTTGA GATCCAGTTC
GATGTAACCC ACTCGTGCAC CCAACTGATC 4440TTCAGCATCT TTTACTTTCA CCAGCGTTTC
TGGGTGAGCA AAAACAGGAA GGCAAAATGC 4500CGCAAAAAAG GGAATAAGGG CGACACGGAA
ATGTTGAATA CTCATACTCT TCCTTTTTCA 4560ATATTATTGA AGCATTTATC AGGGTTATTG
TCTCATGAGC GGATACATAT TTGAATGTAT 4620TTAGAAAAAT AAACAAATAG GGGTTCCGCG
CACATTTCCC CGAAAAGTGC CACCTGACGT 4680CTAAGAAACC ATTATTATCA TGACATTAAC
CTATAAAAAT AGGCGTATCA CGAGGCCCTT 4740TCGTCTCGCG CGTTTCGGTG ATGACGGTGA
AAACCTCTGA CACATGCAGC TCCCGGAGAC 4800GGTCACAGCT TGTCTGTAAG CGGATGCCGG
GAGCAGACAA GCCCGTCAGG GCGCGTCAGC 4860GGGTGTTGGC GGGTGTCGGG GCTGGCTTAA
CTATGCGGCA TCAGAGCAGA TTGTACTGAG 4920AGTGCACCAT ATGCGGTGCG AAATACCGCA
CAGATGCGTA AGGAGAAAAT ACCGCATCAG 4980GCGCCATTCG CCATTCAGGC TGCGCAACTG
TTGGGAAGGG CGATCGGTGC GGGCCTCTTC 5040GCTATTACGC CAGCTGGCGA AAGGGGGATG
TGCTGCAAGG CGATTAAGTT GGGTAACGCC 5100AGGGTTTTCC CAGTCACGAC GTTGTAAAAC
GACGGCCAGT GCCAAGCTTT TTGCA 515544886DNAHomo sapiens 4CTAGCATGCA
GTCAAGCTTA CATCAGACTT CGACAACCCA AGATGGATTG GACGACACAA 60GCATATGTTC
AATTTCCTTG ATGTCAACCA CAATGGAAAA ATCTCTCTTG ACGAGATGGT 120CTACAAGGCA
TCTGATATTG TCATCAATAA CCTTGGAGCA ACACCTGAGC AAGCCAAACG 180ACACAAAGAT
GCTGTAGAAG CCTTCTTCGG AGGAGCTGGA ATGAAATATG GTGTGGAAAC 240TGATTGGCCT
GCATATATTG AAGGATGGAA AAAATTGGCT ACTGATGAAT TGGAGAAATA 300CGCCAAAAAC
GAACCAACGC TCATCCGTAT ATGGGGTGAT GCTTTGTTTG ATATCGTTGA 360CAAAGATCAA
AATGGAGCCA TTACACTGGA TGAATGGAAA GCATACACCA AAGCTGCTGG 420TATCATCCAA
TCATCAGAAG ATTGCGAGGA AACATTCAGA GTGTGCGATA TTGATGAAAG 480TGGACAACTC
GATGTTGATG AGATGACAAG ACAACATTTA GGATTTTGGT ACACCATGGA 540TCCTGCTTGC
GAAAAGCTCT ACGGTGGAGC TGTCCCCTAA GAAGAATTCA AAAAGCTTCT 600CGAGAGTACT
TCTAGAGCGG CCGCGGGCCC ATCGATTTTC CACCCGGGTG GGGTACCAGG 660TAAGTGTACC
CAATTCGCCC TATAGTGAGT CGTATTACAA TTCACTGGCC GTCGTTTTAC 720AACGTCGTGA
CTGGGAAAAC CCTGGCGTTA CCCAACTTAA TCGCCTTGCA GCACATCCCC 780CTTTCGCCAG
CTGGCGTAAT AGCGAAGAGG CCCGCACCGA TCGCCCTTCC CAACAGTTGC 840GCAGCCTGAA
TGGCGAATGG AGATCCAATT TTTAAGTGTA TAATGTGTTA AACTACTGAT 900TCTAATTGTT
TGTGTATTTT AGATTCACAG TCCCAAGGCT CATTTCAGGC CCCTCAGTCC 960TCACAGTCTG
TTCATGATCA TAATCAGCCA TACCACATTT GTAGAGGTTT TACTTGCTTT 1020AAAAAACCTC
CCACACCTCC CCCTGAACCT GAAACATAAA ATGAATGCAA TTGTTGTTGT 1080TAACTTGTTT
ATTGCAGCTT ATAATGGTTA CAAATAAAGC AATAGCATCA CAAATTTCAC 1140AAATAAAGCA
TTTTTTTCAC TGCATTCTAG TTGTGGTTTG TCCAAACTCA TCAATGTATC 1200TTAACGCGTA
AATTGTAAGC GTTAATATTT TGTTAAAATT CGCGTTAAAT TTTTGTTAAA 1260TCAGCTCATT
TTTTAACCAA TAGGCCGAAA TCGGCAAAAT CCCTTATAAA TCAAAAGAAT 1320AGACCGAGAT
AGGGTTGAGT GTTGTTCCAG TTTGGAACAA GAGTCCACTA TTAAAGAACG 1380TGGACTCCAA
CGTCAAAGGG CGAAAAACCG TCTATCAGGG CGATGGCCCA CTACGTGAAC 1440CATCACCCTA
ATCAAGTTTT TTGGGGTCGA GGTGCCGTAA AGCACTAAAT CGGAACCCTA 1500AAGGGAGCCC
CCGATTTAGA GCTTGACGGG GAAAGCCGGC GAACGTGGCG AGAAAGGAAG 1560GGAAGAAAGC
GAAAGGAGCG GGCGCTAGGG CGCTGGCAAG TGTAGCGGTC ACGCTGCGCG 1620TAACCACCAC
ACCCGCCGCG CTTAATGCGC CGCTACAGGG CGCGTCAGGT GGCACTTTTC 1680GGGGAAATGT
GCGCGGAACC CCTATTTGTT TATTTTTCTA AATACATTCA AATATGTATC 1740CGCTCATGAG
ACAATAACCC TGATAAATGC TTCAATAATA TTGAAAAAGG AAGAGTCCTG 1800AGGCGGAAAG
AACCAGCTGT GGAATGTGTG TCAGTTAGGG TGTGGAAAGT CCCCAGGCTC 1860CCCAGCAGGC
AGAAGTATGC AAAGCATGCA TCTCAATTAG TCAGCAACCA GGTGTGGAAA 1920GTCCCCAGGC
TCCCCAGCAG GCAGAAGTAT GCAAAGCATG CATCTCAATT AGTCAGCAAC 1980CATAGTCCCG
CCCCTAACTC CGCCCATCCC GCCCCTAACT CCGCCCAGTT CCGCCCATTC 2040TCCGCCCCAT
GGCTGACTAA TTTTTTTTAT TTATGCAGAG GCCGAGGCCG CCTCGGCCTC 2100TGAGCTATTC
CAGAAGTAGT GAGGAGGCTT TTTTGGAGGC CTAGGCTTTT GCAAAGATCG 2160ATCAAGAGAC
AGGATGAGGA TCGTTTCGCA TGATTGAACA AGATGGATTG CACGCAGGTT 2220CTCCGGCCGC
TTGGGTGGAG AGGCTATTCG GCTATGACTG GGCACAACAG ACAATCGGCT 2280GCTCTGATGC
CGCCGTGTTC CGGCTGTCAG CGCAGGGGCG CCCGGTTCTT TTTGTCAAGA 2340CCGACCTGTC
CGGTGCCCTG AATGAACTGC AAGACGAGGC AGCGCGGCTA TCGTGGCTGG 2400CCACGACGGG
CGTTCCTTGC GCAGCTGTGC TCGACGTTGT CACTGAAGCG GGAAGGGACT 2460GGCTGCTATT
GGGCGAAGTG CCGGGGCAGG ATCTCCTGTC ATCTCACCTT GCTCCTGCCG 2520AGAAAGTATC
CATCATGGCT GATGCAATGC GGCGGCTGCA TACGCTTGAT CCGGCTACCT 2580GCCCATTCGA
CCACCAAGCG AAACATCGCA TCGAGCGAGC ACGTACTCGG ATGGAAGCCG 2640GTCTTGTCGA
TCAGGATGAT CTGGACGAAG AGCATCAGGG GCTCGCGCCA GCCGAACTGT 2700TCGCCAGGCT
CAAGGCGAGC ATGCCCGACG GCGAGGATCT CGTCGTGACC CATGGCGATG 2760CCTGCTTGCC
GAATATCATG GTGGAAAATG GCCGCTTTTC TGGATTCATC GACTGTGGCC 2820GGCTGGGTGT
GGCGGACCGC TATCAGGACA TAGCGTTGGC TACCCGTGAT ATTGCTGAAG 2880AGCTTGGCGG
CGAATGGGCT GACCGCTTCC TCGTGCTTTA CGGTATCGCC GCTCCCGATT 2940CGCAGCGCAT
CGCCTTCTAT CGCCTTCTTG ACGAGTTCTT CTGAGCGGGA CTCTGGGGTT 3000CGAAATGACC
GACCAAGCGA CGCCCAACCT GCCATCACGA GATTTCGATT CCACCGCCGC 3060CTTCTATGAA
AGGTTGGGCT TCGGAATCGT TTTCCGGGAC GCCGGCTGGA TGATCCTCCA 3120GCGCGGGGAT
CTCATGCTGG AGTTCTTCGC CCACCCTAGG GGGAGGCTAA CTGAAACACG 3180GAAGGAGACA
ATACCGGAAG GAACCCGCGC TATGACGGCA ATAAAAAGAC AGAATAAAAC 3240GCACGGTGTT
GGGTCGTTTG TTCATAAACG CGGGGTTCGG TCCCAGGGCT GGCACTCTGT 3300CGATACCCCA
CCGAGACCCC ATTGGGGCCA ATACGCCCGC GTTTCTTCCT TTTCCCCACC 3360CCACCCCCCA
AGTTCGGGTG AAGGCCCAGG GCTCGCAGCC AACGTCGGGG CGGCAGGCCC 3420TGCCATAGCC
TCAGGTTACT CATATATACT TTAGATTGAT TTAAAACTTC ATTTTTAATT 3480TAAAAGGATC
TAGGTGAAGA TCCTTTTTGA TAATCTCATG ACCAAAATCC CTTAACGTGA 3540GTTTTCGTTC
CACTGAGCGT CAGACCCCGT AGAAAAGATC AAAGGATCTT CTTGAGATCC 3600TTTTTTTCTG
CGCGTAATCT GCTGCTTGCA AACAAAAAAA CCACCGCTAC CAGCGGTGGT 3660TTGTTTGCCG
GATCAAGAGC TACCAACTCT TTTTCCGAAG GTAACTGGCT TCAGCAGAGC 3720GCAGATACCA
AATACTGTCC TTCTAGTGTA GCCGTAGTTA GGCCACCACT TCAAGAACTC 3780TGTAGCACCG
CCTACATACC TCGCTCTGCT AATCCTGTTA CCAGTGGCTG CTGCCAGTGG 3840CGATAAGTCG
TGTCTTACCG GGTTGGACTC AAGACGATAG TTACCGGATA AGGCGCAGCG 3900GTCGGGCTGA
ACGGGGGGTT CGTGCACACA GCCCAGCTTG GAGCGAACGA CCTACACCGA 3960ACTGAGATAC
CTACAGCGTG AGCTATGAGA AAGCGCCACG CTTCCCGAAG GGAGAAAGGC 4020GGACAGGTAT
CCGGTAAGCG GCAGGGTCGG AACAGGAGAG CGCACGAGGG AGCTTCCAGG 4080GGGAAACGCC
TGGTATCTTT ATAGTCCTGT CGGGTTTCGC CACCTCTGAC TTGAGCGTCG 4140ATTTTTGTGA
TGCTCGTCAG GGGGGCGGAG CCTATGGAAA AACGCCAGCA ACGCGGCCTT 4200TTTACGGTTC
CTGGCCTTTT GCTGGCCTTT TGCTCACATG TTCTTTCCTG CGTTATCCCC 4260TGATTCTGTG
GATAACCGTA TTACCGCCAT GCATTAGTTA TTAATAGTAA TCAATTACGG 4320GGTCATTAGT
TCATAGCCCA TATATGGAGT TCCGCGTTAC ATAACTTACG GTAAATGGCC 4380CGCCTGGCTG
ACCGCCCAAC GACCCCCGCC CATTGACGTC AATAATGACG TATGTTCCCA 4440TAGTAACGCC
AATAGGGACT TTCCATTGAC GTCAATGGGT GGAGTATTTA CGGTAAACTG 4500CCCACTTGGC
AGTACATCAA GTGTATCATA TGCCAAGTAC GCCCCCTATT GACGTCAATG 4560ACGGTAAATG
GCCCGCCTGG CATTATGCCC AGTACATGAC CTTATGGGAC TTTCCTACTT 4620GGCAGTACAT
CTACGTATTA GTCATCGCTA TTACCATGGT GATGCGGTTT TGGCAGTACA 4680TCAATGGGCG
TGGATAGCGG TTTGACTCAC GGGGATTTCC AAGTCTCCAC CCCATTGACG 4740TCAATGGGAG
TTTGTTTTGG CACCAAAATC AACGGGACTT TCCAAAATGT CGTAACAACT 4800CCGCCCCATT
GACGCAAATG GGCGGTAGGC GTGTACGGTG GGAGGTCTAT ATAAGCAGAG 4860CTGGTTTAGT
GAACCGTCAG ATCCGA 4886
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