USP9X_HUMAN
ID USP9X_HUMAN Reviewed; 2554 AA.
AC Q93008; O75550; Q8WWT3; Q8WX12;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 07-OCT-2020, sequence version 4.
DT 03-AUG-2022, entry version 215.
DE RecName: Full=Probable ubiquitin carboxyl-terminal hydrolase FAF-X;
DE EC=3.4.19.12 {ECO:0000269|PubMed:18254724, ECO:0000269|PubMed:19135894, ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29626158};
DE AltName: Full=Deubiquitinating enzyme FAF-X;
DE AltName: Full=Fat facets in mammals;
DE Short=hFAM;
DE AltName: Full=Fat facets protein-related, X-linked;
DE AltName: Full=Ubiquitin thioesterase FAF-X;
DE AltName: Full=Ubiquitin-specific protease 9, X chromosome;
DE AltName: Full=Ubiquitin-specific-processing protease FAF-X;
GN Name=USP9X {ECO:0000312|HGNC:HGNC:12632}; Synonyms=DFFRX, FAM, USP9;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Fetal brain, Retina, and Testis;
RX PubMed=8922996; DOI=10.1093/hmg/5.11.1695;
RA Jones M.H., Furlong R.A., Burkin H., Chalmers I.J., Brown G.M., Khwaja O.,
RA Affara N.A.;
RT "The Drosophila developmental gene fat facets has a human homologue in
RT Xp11.4 which escapes X-inactivation and has related sequences on Yq11.2.";
RL Hum. Mol. Genet. 5:1695-1701(1996).
RN [2]
RP ERRATUM OF PUBMED:8922996.
RA Jones M.H., Furlong R.A., Burkin H., Chalmers I.J., Brown G.M., Khwaja O.,
RA Affara N.A.;
RL Hum. Mol. Genet. 6:334-335(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L.,
RA Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C.,
RA Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A.,
RA Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P.,
RA Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D.,
RA Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D.,
RA Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L.,
RA Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P.,
RA Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G.,
RA Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J.,
RA Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D.,
RA Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L.,
RA Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z.,
RA Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O.,
RA Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H.,
RA Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T.,
RA Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L.,
RA Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R.,
RA Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y.,
RA Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K.,
RA Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J.,
RA Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L.,
RA Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S.,
RA Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A.,
RA Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L.,
RA Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S.,
RA Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C.,
RA Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S.,
RA Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V.,
RA Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K.,
RA Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B.,
RA Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C.,
RA d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q.,
RA Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N.,
RA Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A.,
RA Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J.,
RA Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A.,
RA Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L.,
RA Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S.,
RA Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2226-2554 (ISOFORM 2).
RC TISSUE=Brain;
RA Yu W., Gibbs R.A.;
RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-2540, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [6]
RP FUNCTION, AND INTERACTION WITH BIRC5.
RX PubMed=16322459; DOI=10.1126/science.1120160;
RA Vong Q.P., Cao K., Li H.Y., Iglesias P.A., Zheng Y.;
RT "Chromosome alignment and segregation regulated by ubiquitination of
RT survivin.";
RL Science 310:1499-1504(2005).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1600, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2547, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2443, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17693683; DOI=10.1074/mcp.m700120-mcp200;
RA Tang L.-Y., Deng N., Wang L.-S., Dai J., Wang Z.-L., Jiang X.-S., Li S.-J.,
RA Li L., Sheng Q.-H., Wu D.-Q., Li L., Zeng R.;
RT "Quantitative phosphoproteome profiling of Wnt3a-mediated signaling
RT network: indicating the involvement of ribonucleoside-diphosphate reductase
RT M2 subunit phosphorylation at residue serine 20 in canonical Wnt signal
RT transduction.";
RL Mol. Cell. Proteomics 6:1952-1967(2007).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH MARK4 AND NUAK1.
RX PubMed=18254724; DOI=10.1042/bj20080067;
RA Al-Hakim A.K., Zagorska A., Chapman L., Deak M., Peggie M., Alessi D.R.;
RT "Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-
RT linked polyubiquitin chains.";
RL Biochem. J. 411:249-260(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1600, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1600; SER-2443 AND SER-2547,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH SMAD4, AND SUBCELLULAR
RP LOCATION.
RX PubMed=19135894; DOI=10.1016/j.cell.2008.10.051;
RA Dupont S., Mamidi A., Cordenonsi M., Montagner M., Zacchigna L., Adorno M.,
RA Martello G., Stinchfield M.J., Soligo S., Morsut L., Inui M., Moro S.,
RA Modena N., Argenton F., Newfeld S.J., Piccolo S.;
RT "FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling,
RT controls Smad4 monoubiquitination.";
RL Cell 136:123-135(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1600, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2547 AND THR-2551, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1600 AND SER-2443, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-588; THR-590; SER-1600;
RP SER-2443 AND SER-2547, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [21]
RP INTERACTION WITH OTUD4; ALKBH3 AND USP7, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=25944111; DOI=10.15252/embj.201490497;
RA Zhao Y., Majid M.C., Soll J.M., Brickner J.R., Dango S., Mosammaparast N.;
RT "Noncanonical regulation of alkylation damage resistance by the OTUD4
RT deubiquitinase.";
RL EMBO J. 34:1687-1703(2015).
RN [22]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH ARNTL, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RX PubMed=29626158; DOI=10.1042/bcj20180005;
RA Zhang Y., Duan C., Yang J., Chen S., Liu Q., Zhou L., Huang Z., Xu Y.,
RA Xu G.;
RT "Deubiquitinating enzyme USP9X regulates cellular clock function by
RT modulating the ubiquitination and degradation of a core circadian protein
RT BMAL1.";
RL Biochem. J. 475:1507-1522(2018).
RN [23]
RP FUNCTION, INTERACTION WITH RICTOR, INDUCTION, AND MUTAGENESIS OF CYS-1566.
RX PubMed=33378666; DOI=10.1016/j.celrep.2020.108564;
RA Wrobel L., Siddiqi F.H., Hill S.M., Son S.M., Karabiyik C., Kim H.,
RA Rubinsztein D.C.;
RT "mTORC2 Assembly Is Regulated by USP9X-Mediated Deubiquitination of
RT RICTOR.";
RL Cell Rep. 33:108564-108564(2020).
RN [24]
RP INVOLVEMENT IN XLID99, VARIANTS XLID99 HIS-2093 AND ILE-2157,
RP CHARACTERIZATION OF VARIANTS XLID99 HIS-2093 AND ILE-2157, FUNCTION,
RP INTERACTION WITH DCX, AND SUBCELLULAR LOCATION.
RX PubMed=24607389; DOI=10.1016/j.ajhg.2014.02.004;
RA Homan C.C., Kumar R., Nguyen L.S., Haan E., Raymond F.L., Abidi F.,
RA Raynaud M., Schwartz C.E., Wood S.A., Gecz J., Jolly L.A.;
RT "Mutations in USP9X are associated with X-linked intellectual disability
RT and disrupt neuronal cell migration and growth.";
RL Am. J. Hum. Genet. 94:470-478(2014).
RN [25]
RP INVOLVEMENT IN MRXS99F, SUBCELLULAR LOCATION, VARIANTS MRXS99F
RP 371-ARG--GLN-2554 DEL; 852-ARG--GLN-2554 DEL; 1255-GLN--GLN-2554 DEL;
RP 1268-TYR--GLN-2554 DEL; 2483-ASP--GLU-2487 DEL AND TRP-1693, AND
RP CHARACTERIZATION OF VARIANT MRXS99F 852-ARG--GLN-2554 DEL.
RX PubMed=26833328; DOI=10.1016/j.ajhg.2015.12.015;
RA Reijnders M.R., Zachariadis V., Latour B., Jolly L., Mancini G.M.,
RA Pfundt R., Wu K.M., van Ravenswaaij-Arts C.M., Veenstra-Knol H.E.,
RA Anderlid B.M., Wood S.A., Cheung S.W., Barnicoat A., Probst F.,
RA Magoulas P., Brooks A.S., Malmgren H., Harila-Saari A., Marcelis C.M.,
RA Vreeburg M., Hobson E., Sutton V.R., Stark Z., Vogt J., Cooper N.,
RA Lim J.Y., Price S., Lai A.H., Domingo D., Reversade B., Gecz J.,
RA Gilissen C., Brunner H.G., Kini U., Roepman R., Nordgren A., Kleefstra T.;
RT "De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific
RT Recognizable Syndrome with Developmental Delay and Congenital
RT Malformations.";
RL Am. J. Hum. Genet. 98:373-381(2016).
CC -!- FUNCTION: Deubiquitinase involved both in the processing of ubiquitin
CC precursors and of ubiquitinated proteins (PubMed:19135894,
CC PubMed:25944111, PubMed:18254724, PubMed:29626158). May therefore play
CC an important regulatory role at the level of protein turnover by
CC preventing degradation of proteins through the removal of conjugated
CC ubiquitin (PubMed:19135894, PubMed:25944111, PubMed:18254724,
CC PubMed:29626158). Specifically hydrolyzes 'Lys-63'-, 'Lys-48'-, 'Lys-
CC 29'- and 'Lys-33'-linked polyubiquitins chains (PubMed:25944111,
CC PubMed:18254724, PubMed:33378666). Essential component of TGF-beta/BMP
CC signaling cascade (PubMed:19135894). Specifically deubiquitinates
CC monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein
CC ligase TRIM33 (PubMed:19135894). Deubiquitinates alkylation repair
CC enzyme ALKBH3 (PubMed:25944111). OTUD4 recruits USP7 and USP9X to
CC stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions
CC (PubMed:25944111). Deubiquitinates mTORC2 complex component RICTOR at
CC 'Lys-294' by removing 'Lys-63'-linked polyubiquitin chains, stabilizing
CC RICTOR and enhancing its binding to MTOR, thus promoting mTORC2 complex
CC assembly (PubMed:33378666). Regulates chromosome alignment and
CC segregation in mitosis by regulating the localization of BIRC5/survivin
CC to mitotic centromeres (PubMed:16322459). Involved in axonal growth and
CC neuronal cell migration (PubMed:24607389). Regulates cellular clock
CC function by enhancing the protein stability and transcriptional
CC activity of the core circadian protein ARNTL/BMAL1 via its
CC deubiquitinating activity (PubMed:29626158). Deubiquitinates PEG10 (By
CC similarity). {ECO:0000250|UniProtKB:P70398,
CC ECO:0000269|PubMed:16322459, ECO:0000269|PubMed:18254724,
CC ECO:0000269|PubMed:19135894, ECO:0000269|PubMed:24607389,
CC ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29626158,
CC ECO:0000269|PubMed:33378666}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:18254724,
CC ECO:0000269|PubMed:19135894, ECO:0000269|PubMed:25944111,
CC ECO:0000269|PubMed:29626158};
CC -!- SUBUNIT: Interacts with SMAD4, MARK4, NUAK1 and BIRC5/survivin.
CC Interacts with DCX. Interacts with OTUD4 and USP7; the interaction is
CC direct (PubMed:25944111). Interacts with ARNTL/BMAL1 (PubMed:29626158).
CC Interacts with RICTOR; the interaction results in deubiquitination of
CC RICTOR and protection from proteasomal degradation (PubMed:33378666).
CC {ECO:0000269|PubMed:16322459, ECO:0000269|PubMed:18254724,
CC ECO:0000269|PubMed:19135894, ECO:0000269|PubMed:24607389,
CC ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:29626158,
CC ECO:0000269|PubMed:33378666}.
CC -!- INTERACTION:
CC Q93008; P42858: HTT; NbExp=8; IntAct=EBI-302524, EBI-466029;
CC Q93008; Q07820: MCL1; NbExp=10; IntAct=EBI-302524, EBI-1003422;
CC Q93008; O60285: NUAK1; NbExp=2; IntAct=EBI-302524, EBI-1046789;
CC Q93008; Q13485: SMAD4; NbExp=2; IntAct=EBI-302524, EBI-347263;
CC Q93008; P08393: ICP0; Xeno; NbExp=3; IntAct=EBI-302524, EBI-6148881;
CC Q93008; P0DTC9: N; Xeno; NbExp=3; IntAct=EBI-302524, EBI-25475856;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19135894,
CC ECO:0000269|PubMed:26833328}. Cell projection, growth cone
CC {ECO:0000269|PubMed:24607389}. Cytoplasm, cytoskeleton, cilium axoneme
CC {ECO:0000269|PubMed:26833328}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Short;
CC IsoId=Q93008-1; Sequence=Displayed;
CC Name=2; Synonyms=Long;
CC IsoId=Q93008-3; Sequence=VSP_060711;
CC -!- TISSUE SPECIFICITY: Widely expressed in embryonic and adult tissues.
CC {ECO:0000269|PubMed:8922996}.
CC -!- INDUCTION: By growth factors. {ECO:0000269|PubMed:33378666}.
CC -!- DISEASE: Intellectual developmental disorder, X-linked 99 (XLID99)
CC [MIM:300919]: A disorder characterized by significantly below average
CC general intellectual functioning associated with impairments in
CC adaptive behavior and manifested during the developmental period.
CC Intellectual deficiency is the only primary symptom of non-syndromic X-
CC linked forms, while syndromic forms present with associated physical,
CC neurological and/or psychiatric manifestations.
CC {ECO:0000269|PubMed:24607389}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry.
CC -!- DISEASE: Intellectual developmental disorder, X-linked 99, syndromic,
CC female-restricted (MRXS99F) [MIM:300968]: A form of intellectual
CC disability, a disorder characterized by significantly below average
CC general intellectual functioning, associated with impairments in
CC adaptive behavior and manifested during the developmental period.
CC MRXS99F affected females manifest intellectual disability,
CC developmental delay, facial dysmorphism, short stature, and distinct
CC congenital malformations comprising choanal atresia, anal
CC abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft
CC palate/bifid uvula, progressive scoliosis, and structural brain
CC abnormalities. Inheritance is X-linked dominant.
CC {ECO:0000269|PubMed:26833328}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Escapes X-inactivation. {ECO:0000269|PubMed:8922996}.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
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DR EMBL; X98296; CAA66942.1; -; mRNA.
DR EMBL; AL109797; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL391259; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF070645; AAC25395.1; -; mRNA.
DR CCDS; CCDS43930.1; -. [Q93008-3]
DR CCDS; CCDS55403.1; -. [Q93008-1]
DR RefSeq; NP_001034679.2; NM_001039590.2. [Q93008-3]
DR RefSeq; NP_001034680.2; NM_001039591.2. [Q93008-1]
DR PDB; 5VBD; X-ray; 1.50 A; A=880-970.
DR PDB; 5WCH; X-ray; 2.50 A; A/B/C/D=1551-1970.
DR PDB; 7YXX; EM; 3.30 A; A/B/C=1-2554.
DR PDB; 7YXY; EM; 3.10 A; A=1-2554.
DR PDBsum; 5VBD; -.
DR PDBsum; 5WCH; -.
DR PDBsum; 7YXX; -.
DR PDBsum; 7YXY; -.
DR AlphaFoldDB; Q93008; -.
DR SMR; Q93008; -.
DR BioGRID; 113867; 310.
DR CORUM; Q93008; -.
DR DIP; DIP-27562N; -.
DR IntAct; Q93008; 99.
DR MINT; Q93008; -.
DR STRING; 9606.ENSP00000316357; -.
DR BindingDB; Q93008; -.
DR ChEMBL; CHEMBL2406899; -.
DR MEROPS; C19.017; -.
DR GlyGen; Q93008; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q93008; -.
DR MetOSite; Q93008; -.
DR PhosphoSitePlus; Q93008; -.
DR SwissPalm; Q93008; -.
DR BioMuta; USP9X; -.
DR DMDM; 317373496; -.
DR EPD; Q93008; -.
DR jPOST; Q93008; -.
DR MassIVE; Q93008; -.
DR MaxQB; Q93008; -.
DR PaxDb; Q93008; -.
DR PeptideAtlas; Q93008; -.
DR PRIDE; Q93008; -.
DR ProteomicsDB; 75667; -. [Q93008-3]
DR ProteomicsDB; 75668; -. [Q93008-1]
DR Antibodypedia; 25013; 371 antibodies from 31 providers.
DR DNASU; 8239; -.
DR Ensembl; ENST00000324545.9; ENSP00000316357.6; ENSG00000124486.14. [Q93008-3]
DR Ensembl; ENST00000378308.7; ENSP00000367558.2; ENSG00000124486.14. [Q93008-1]
DR GeneID; 8239; -.
DR KEGG; hsa:8239; -.
DR MANE-Select; ENST00000378308.7; ENSP00000367558.2; NM_001039591.3; NP_001034680.2.
DR UCSC; uc004dfb.3; human. [Q93008-1]
DR CTD; 8239; -.
DR DisGeNET; 8239; -.
DR GeneCards; USP9X; -.
DR HGNC; HGNC:12632; USP9X.
DR HPA; ENSG00000124486; Low tissue specificity.
DR MalaCards; USP9X; -.
DR MIM; 300072; gene.
DR MIM; 300919; phenotype.
DR MIM; 300968; phenotype.
DR neXtProt; NX_Q93008; -.
DR OpenTargets; ENSG00000124486; -.
DR Orphanet; 480880; X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability.
DR Orphanet; 777; X-linked non-syndromic intellectual disability.
DR PharmGKB; PA37257; -.
DR VEuPathDB; HostDB:ENSG00000124486; -.
DR eggNOG; KOG1866; Eukaryota.
DR GeneTree; ENSGT00940000155375; -.
DR HOGENOM; CLU_000331_1_0_1; -.
DR InParanoid; Q93008; -.
DR OMA; CCDVSSK; -.
DR OrthoDB; 625455at2759; -.
DR PhylomeDB; Q93008; -.
DR TreeFam; TF323966; -.
DR PathwayCommons; Q93008; -.
DR Reactome; R-HSA-2173795; Downregulation of SMAD2/3:SMAD4 transcriptional activity.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-8866652; Synthesis of active ubiquitin: roles of E1 and E2 enzymes.
DR Reactome; R-HSA-9013420; RHOU GTPase cycle.
DR Reactome; R-HSA-9013424; RHOV GTPase cycle.
DR Reactome; R-HSA-9033241; Peroxisomal protein import.
DR Reactome; R-HSA-977225; Amyloid fiber formation.
DR SignaLink; Q93008; -.
DR SIGNOR; Q93008; -.
DR BioGRID-ORCS; 8239; 76 hits in 717 CRISPR screens.
DR ChiTaRS; USP9X; human.
DR GeneWiki; USP9X; -.
DR GenomeRNAi; 8239; -.
DR Pharos; Q93008; Tbio.
DR PRO; PR:Q93008; -.
DR Proteomes; UP000005640; Chromosome X.
DR RNAct; Q93008; protein.
DR Bgee; ENSG00000124486; Expressed in endometrium epithelium and 210 other tissues.
DR Genevisible; Q93008; HS.
DR GO; GO:0005929; C:cilium; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0070410; F:co-SMAD binding; IPI:BHF-UCL.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; EXP:Reactome.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0008234; F:cysteine-type peptidase activity; TAS:Reactome.
DR GO; GO:0101005; F:deubiquitinase activity; ISS:UniProtKB.
DR GO; GO:1990380; F:Lys48-specific deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0061578; F:Lys63-specific deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:1990000; P:amyloid fibril formation; TAS:Reactome.
DR GO; GO:0048675; P:axon extension; IMP:UniProtKB.
DR GO; GO:0030509; P:BMP signaling pathway; IDA:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0016477; P:cell migration; IBA:GO_Central.
DR GO; GO:0007059; P:chromosome segregation; IEA:UniProtKB-KW.
DR GO; GO:0007292; P:female gamete generation; TAS:ProtInc.
DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; TAS:Reactome.
DR GO; GO:0001764; P:neuron migration; IMP:UniProtKB.
DR GO; GO:1901537; P:positive regulation of DNA demethylation; IDA:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; IMP:UniProtKB.
DR GO; GO:1904515; P:positive regulation of TORC2 signaling; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0071947; P:protein deubiquitination involved in ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:0008104; P:protein localization; TAS:Reactome.
DR GO; GO:0050821; P:protein stabilization; IMP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; TAS:Reactome.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IMP:UniProtKB.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR021905; DUF3517.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001394; Peptidase_C19_UCH.
DR InterPro; IPR031226; USP9X.
DR InterPro; IPR018200; USP_CS.
DR InterPro; IPR028889; USP_dom.
DR PANTHER; PTHR24006:SF777; PTHR24006:SF777; 1.
DR Pfam; PF12030; DUF3517; 1.
DR Pfam; PF00443; UCH; 1.
DR SUPFAM; SSF48371; SSF48371; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS00972; USP_1; 1.
DR PROSITE; PS00973; USP_2; 1.
DR PROSITE; PS50235; USP_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Biological rhythms; Cell cycle;
KW Cell division; Cell projection; Chromosome partition; Cytoplasm;
KW Cytoskeleton; Disease variant; Hydrolase; Intellectual disability; Mitosis;
KW Phosphoprotein; Protease; Reference proteome; Thiol protease;
KW Ubl conjugation pathway.
FT CHAIN 1..2554
FT /note="Probable ubiquitin carboxyl-terminal hydrolase FAF-
FT X"
FT /id="PRO_0000080689"
FT DOMAIN 1557..1956
FT /note="USP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01035"
FT REGION 1..65
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 967..999
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1592..1621
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2475..2554
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..49
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 967..993
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2502..2516
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2523..2547
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 1566
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT ACT_SITE 1879
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT MOD_RES 588
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 590
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1600
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 2443
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17693683,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 2540
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:15592455"
FT MOD_RES 2547
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 2551
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:20068231"
FT VAR_SEQ 2477
FT /note="E -> EVKKATSVQQIEMEESK (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_060711"
FT VARIANT 371..2554
FT /note="Missing (in MRXS99F; dbSNP:rs869025592)"
FT /evidence="ECO:0000269|PubMed:26833328"
FT /id="VAR_086077"
FT VARIANT 852..2554
FT /note="Missing (in MRXS99F; decreased expression levels;
FT dbSNP:rs869025588)"
FT /evidence="ECO:0000269|PubMed:26833328"
FT /id="VAR_086078"
FT VARIANT 1255..2554
FT /note="Missing (in MRXS99F; dbSNP:rs869025591)"
FT /evidence="ECO:0000269|PubMed:26833328"
FT /id="VAR_086079"
FT VARIANT 1268..2554
FT /note="Missing (in MRXS99F)"
FT /evidence="ECO:0000269|PubMed:26833328"
FT /id="VAR_086080"
FT VARIANT 1693
FT /note="L -> W (in MRXS99F)"
FT /evidence="ECO:0000269|PubMed:26833328"
FT /id="VAR_086081"
FT VARIANT 2093
FT /note="L -> H (in XLID99; unknown pathological
FT significance; does not affect interaction with DCX; reduced
FT subcellular localization in the axonal growth cones;
FT dbSNP:rs587777317)"
FT /evidence="ECO:0000269|PubMed:24607389"
FT /id="VAR_071131"
FT VARIANT 2157
FT /note="L -> I (in XLID99; unknown pathological
FT significance; does not affect interaction with DCX; reduced
FT subcellular localization in the axonal growth cones;
FT dbSNP:rs587777319)"
FT /evidence="ECO:0000269|PubMed:24607389"
FT /id="VAR_071132"
FT VARIANT 2483..2487
FT /note="Missing (in MRXS99F)"
FT /evidence="ECO:0000269|PubMed:26833328"
FT /id="VAR_086082"
FT MUTAGEN 1566
FT /note="C->A: Does not restore RICTOR expression levels when
FT introduced into cells where endogenous USP9X has been
FT silenced."
FT /evidence="ECO:0000269|PubMed:33378666"
FT CONFLICT 25
FT /note="Q -> L (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 148..154
FT /note="Missing (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 468
FT /note="L -> P (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 476
FT /note="W -> R (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 506
FT /note="K -> R (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 621
FT /note="A -> V (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 1400
FT /note="L -> F (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 1951
FT /note="L -> P (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT CONFLICT 2330
FT /note="T -> P (in Ref. 1; CAA66942)"
FT /evidence="ECO:0000305"
FT STRAND 889..891
FT /evidence="ECO:0007829|PDB:5VBD"
FT HELIX 912..928
FT /evidence="ECO:0007829|PDB:5VBD"
FT STRAND 930..936
FT /evidence="ECO:0007829|PDB:5VBD"
FT HELIX 943..945
FT /evidence="ECO:0007829|PDB:5VBD"
FT HELIX 950..952
FT /evidence="ECO:0007829|PDB:5VBD"
FT STRAND 960..967
FT /evidence="ECO:0007829|PDB:5VBD"
FT HELIX 1566..1576
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1579..1586
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1634..1656
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1659..1662
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1665..1670
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1686..1703
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1709..1714
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1716..1728
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1730..1742
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1744..1746
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1750..1759
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1761..1763
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1765..1767
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1769..1771
FT /evidence="ECO:0007829|PDB:5WCH"
FT TURN 1772..1775
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1776..1778
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1780..1788
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1791..1797
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1800..1803
FT /evidence="ECO:0007829|PDB:5WCH"
FT TURN 1804..1807
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1808..1811
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1820..1823
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1825..1827
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1829..1836
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1862..1873
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1875..1877
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1879..1885
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1897..1901
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1904..1907
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1913..1920
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1924..1931
FT /evidence="ECO:0007829|PDB:5WCH"
FT TURN 1932..1935
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1936..1943
FT /evidence="ECO:0007829|PDB:5WCH"
FT STRAND 1946..1955
FT /evidence="ECO:0007829|PDB:5WCH"
FT HELIX 1963..1965
FT /evidence="ECO:0007829|PDB:5WCH"
SQ SEQUENCE 2554 AA; 290463 MW; 16B87B7FCC1428AF CRC64;
MTATTRGSPV GGNDNQGQAP DGQSQPPLQQ NQTSSPDSSN ENSPATPPDE QGQGDAPPQL
EDEEPAFPHT DLAKLDDMIN RPRWVVPVLP KGELEVLLEA AIDLSKKGLD VKSEACQRFF
RDGLTISFTK ILTDEAVSGW KFEIHRCIIN NTHRLVELCV AKLSQDWFPL LELLAMALNP
HCKFHIYNGT RPCESVSSSV QLPEDELFAR SPDPRSPKGW LVDLLNKFGT LNGFQILHDR
FINGSALNVQ IIAALIKPFG QCYEFLTLHT VKKYFLPIIE MVPQFLENLT DEELKKEAKN
EAKNDALSMI IKSLKNLASR VPGQEETVKN LEIFRLKMIL RLLQISSFNG KMNALNEVNK
VISSVSYYTH RHGNPEEEEW LTAERMAEWI QQNNILSIVL RDSLHQPQYV EKLEKILRFV
IKEKALTLQD LDNIWAAQAG KHEAIVKNVH DLLAKLAWDF SPEQLDHLFD CFKASWTNAS
KKQREKLLEL IRRLAEDDKD GVMAHKVLNL LWNLAHSDDV PVDIMDLALS AHIKILDYSC
SQDRDTQKIQ WIDRFIEELR TNDKWVIPAL KQIREICSLF GEAPQNLSQT QRSPHVFYRH
DLINQLQHNH ALVTLVAENL ATYMESMRLY ARDHEDYDPQ TVRLGSRYSH VQEVQERLNF
LRFLLKDGQL WLCAPQAKQI WKCLAENAVY LCDREACFKW YSKLMGDEPD LDPDINKDFF
ESNVLQLDPS LLTENGMKCF ERFFKAVNCR EGKLVAKRRA YMMDDLELIG LDYLWRVVIQ
SNDDIASRAI DLLKEIYTNL GPRLQVNQVV IHEDFIQSCF DRLKASYDTL CVLDGDKDSV
NCARQEAVRM VRVLTVLREY INECDSDYHE ERTILPMSRA FRGKHLSFVV RFPNQGRQVD
DLEVWSHTND TIGSVRRCIL NRIKANVAHT KIELFVGGEL IDPADDRKLI GQLNLKDKSL
ITAKLTQISS NMPSSPDSSS DSSTGSPGNH GNHYSDGPNP EVESCLPGVI MSLHPRYISF
LWQVADLGSS LNMPPLRDGA RVLMKLMPPD STTIEKLRAI CLDHAKLGES SLSPSLDSLF
FGPSASQVLY LTEVVYALLM PAGAPLADDS SDFQFHFLKS GGLPLVLSML TRNNFLPNAD
METRRGAYLN ALKIAKLLLT AIGYGHVRAV AEACQPGVEG VNPMTQINQV THDQAVVLQS
ALQSIPNPSS ECMLRNVSVR LAQQISDEAS RYMPDICVIR AIQKIIWASG CGSLQLVFSP
NEEITKIYEK TNAGNEPDLE DEQVCCEALE VMTLCFALIP TALDALSKEK AWQTFIIDLL
LHCHSKTVRQ VAQEQFFLMC TRCCMGHRPL LFFITLLFTV LGSTARERAK HSGDYFTLLR
HLLNYAYNSN INVPNAEVLL NNEIDWLKRI RDDVKRTGET GIEETILEGH LGVTKELLAF
QTSEKKFHIG CEKGGANLIK ELIDDFIFPA SNVYLQYMRN GELPAEQAIP VCGSPPTINA
GFELLVALAV GCVRNLKQIV DSLTEMYYIG TAITTCEALT EWEYLPPVGP RPPKGFVGLK
NAGATCYMNS VIQQLYMIPS IRNGILAIEG TGSDVDDDMS GDEKQDNESN VDPRDDVFGY
PQQFEDKPAL SKTEDRKEYN IGVLRHLQVI FGHLAASRLQ YYVPRGFWKQ FRLWGEPVNL
REQHDALEFF NSLVDSLDEA LKALGHPAML SKVLGGSFAD QKICQGCPHR YECEESFTTL
NVDIRNHQNL LDSLEQYVKG DLLEGANAYH CEKCNKKVDT VKRLLIKKLP PVLAIQLKRF
DYDWERECAI KFNDYFEFPR ELDMEPYTVA GVAKLEGDNV NPESQLIQQS EQSESETAGS
TKYRLVGVLV HSGQASGGHY YSYIIQRNGG DGERNRWYKF DDGDVTECKM DDDEEMKNQC
FGGEYMGEVF DHMMKRMSYR RQKRWWNAYI LFYERMDTID QDDELIRYIS ELAITTRPHQ
IIMPSAIERS VRKQNVQFMH NRMQYSMEYF QFMKKLLTCN GVYLNPPPGQ DHLLPEAEEI
TMISIQLAAR FLFTTGFHTK KVVRGSASDW YDALCILLRH SKNVRFWFAH NVLFNVSNRF
SEYLLECPSA EVRGAFAKLI VFIAHFSLQD GPCPSPFASP GPSSQAYDNL SLSDHLLRAV
LNLLRREVSE HGRHLQQYFN LFVMYANLGV AEKTQLLKLS VPATFMLVSL DEGPGPPIKY
QYAELGKLYS VVSQLIRCCN VSSRMQSSIN GNPPLPNPFG DPNLSQPIMP IQQNVADILF
VRTSYVKKII EDCSNSEETV KLLRFCCWEN PQFSSTVLSE LLWQVAYSYT YELRPYLDLL
LQILLIEDSW QTHRIHNALK GIPDDRDGLF DTIQRSKNHY QKRAYQCIKC MVALFSNCPV
AYQILQGNGD LKRKWTWAVE WLGDELERRP YTGNPQYTYN NWSPPVQSNE TSNGYFLERS
HSARMTLAKA CELCPEEEPD DQDAPDEHES PPPEDAPLYP HSPGSQYQQN NHVHGQPYTG
PAAHHMNNPQ RTGQRAQENY EGSEEVSPPQ TKDQ
