UBP8_HUMAN
ID UBP8_HUMAN Reviewed; 1118 AA.
AC P40818; B4DKA8; Q2TB31; Q7Z3U2; Q86VA0; Q8IWI7;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 225.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 8 {ECO:0000305};
DE EC=3.4.19.12 {ECO:0000269|PubMed:9628861};
DE AltName: Full=Deubiquitinating enzyme 8;
DE AltName: Full=Ubiquitin isopeptidase Y;
DE Short=hUBPy;
DE AltName: Full=Ubiquitin thioesterase 8;
DE AltName: Full=Ubiquitin-specific-processing protease 8;
GN Name=USP8 {ECO:0000312|HGNC:HGNC:12631}; Synonyms=KIAA0055, UBPY;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N.,
RA Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II. The
RT coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, and Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND INDUCTION.
RX PubMed=9628861; DOI=10.1093/emboj/17.12.3241;
RA Naviglio S., Mattecucci C., Matoskova B., Nagase T., Nomura N.,
RA Di Fiore P.P., Draetta G.F.;
RT "UBPY: a growth-regulated human ubiquitin isopeptidase.";
RL EMBO J. 17:3241-3250(1998).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF CYS-786.
RX PubMed=16520378; DOI=10.1074/jbc.m512615200;
RA Row P.E., Prior I.A., McCullough J., Clague M.J., Urbe S.;
RT "The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and
RT is essential for receptor down-regulation.";
RL J. Biol. Chem. 281:12618-12624(2006).
RN [8]
RP IDENTIFICATION BY 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 DOMAIN, INTERACTION WITH CHMP1A; CHMP1B AND CHMP7, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=17711858; DOI=10.1074/jbc.m704009200;
RA Row P.E., Liu H., Hayes S., Welchman R., Charalabous P., Hofmann K.,
RA Clague M.J., Sanderson C.M., Urbe S.;
RT "The MIT domain of UBPY constitutes a CHMP binding and endosomal
RT localization signal required for efficient epidermal growth factor receptor
RT degradation.";
RL J. Biol. Chem. 282:30929-30937(2007).
RN [10]
RP FUNCTION, AND INTERACTION WITH BIRC6/BRUCE AND KIF23/MKLP1.
RX PubMed=18329369; DOI=10.1016/j.cell.2008.01.012;
RA Pohl C., Jentsch S.;
RT "Final stages of cytokinesis and midbody ring formation are controlled by
RT BRUCE.";
RL Cell 132:832-845(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-452; SER-718 AND SER-719, AND
RP 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 [12]
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 [13]
RP INTERACTION WITH NBR1, AND SUBCELLULAR LOCATION.
RX PubMed=19427866; DOI=10.1016/j.febslet.2009.04.049;
RA Waters S., Marchbank K., Solomon E., Whitehouse C., Gautel M.;
RT "Interactions with LC3 and polyubiquitin chains link nbr1 to autophagic
RT protein turnover.";
RL FEBS Lett. 583:1846-1852(2009).
RN [14]
RP INTERACTION WITH IST1.
RX PubMed=19129480; DOI=10.1091/mbc.e08-05-0474;
RA Agromayor M., Carlton J.G., Phelan J.P., Matthews D.R., Carlin L.M.,
RA Ameer-Beg S., Bowers K., Martin-Serrano J.;
RT "Essential role of hIST1 in cytokinesis.";
RL Mol. Biol. Cell 20:1374-1387(2009).
RN [15]
RP IDENTIFICATION BY 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-160 AND SER-718, 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 THR-577 AND SER-718, 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-160; SER-392; SER-400;
RP SER-452; THR-577 AND SER-718, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE 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 FUNCTION.
RX PubMed=27302062; DOI=10.1074/jbc.m116.718023;
RA Yeates E.F., Tesco G.;
RT "The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1
RT Enzyme Ubiquitination and Degradation.";
RL J. Biol. Chem. 291:15753-15766(2016).
RN [22]
RP INTERACTION WITH ZIKA VIRUS NON-STRUCTURAL PROTEIN 1 (MICROBIAL INFECTION).
RX PubMed=30065070; DOI=10.15252/embj.201899347;
RA Zheng Y., Liu Q., Wu Y., Ma L., Zhang Z., Liu T., Jin S., She Y., Li Y.P.,
RA Cui J.;
RT "Zika virus elicits inflammation to evade antiviral response by cleaving
RT cGAS via NS1-caspase-1 axis.";
RL EMBO J. 37:0-0(2018).
RN [23]
RP STRUCTURE BY NMR OF 174-317.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the rhodanese-like domain in human ubiquitin
RT specific protease 8 (UBP8).";
RL Submitted (NOV-2004) to the PDB data bank.
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 181-318 IN COMPLEX WITH RNF41.
RX PubMed=17035239; DOI=10.1074/jbc.m606704200;
RA Avvakumov G.V., Walker J.R., Xue S., Finerty P.J. Jr., Mackenzie F.,
RA Newman E.M., Dhe-Paganon S.;
RT "Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited
RT catalytic domain conformation of the ubiquitin-specific protease 8
RT (USP8).";
RL J. Biol. Chem. 281:38061-38070(2006).
RN [25]
RP VARIANT LYS-310.
RX PubMed=24482476; DOI=10.1126/science.1247363;
RA Novarino G., Fenstermaker A.G., Zaki M.S., Hofree M., Silhavy J.L.,
RA Heiberg A.D., Abdellateef M., Rosti B., Scott E., Mansour L., Masri A.,
RA Kayserili H., Al-Aama J.Y., Abdel-Salam G.M., Karminejad A., Kara M.,
RA Kara B., Bozorgmehri B., Ben-Omran T., Mojahedi F., Mahmoud I.G.,
RA Bouslam N., Bouhouche A., Benomar A., Hanein S., Raymond L., Forlani S.,
RA Mascaro M., Selim L., Shehata N., Al-Allawi N., Bindu P.S., Azam M.,
RA Gunel M., Caglayan A., Bilguvar K., Tolun A., Issa M.Y., Schroth J.,
RA Spencer E.G., Rosti R.O., Akizu N., Vaux K.K., Johansen A., Koh A.A.,
RA Megahed H., Durr A., Brice A., Stevanin G., Gabriel S.B., Ideker T.,
RA Gleeson J.G.;
RT "Exome sequencing links corticospinal motor neuron disease to common
RT neurodegenerative disorders.";
RL Science 343:506-511(2014).
RN [26]
RP VARIANTS PITA4 718-SER--THR-723 DEL; CYS-718; PRO-718; SER-718 DEL AND
RP ARG-720, CHARACTERIZATION OF VARIANT PITA4 PRO-718, AND SUBCELLULAR
RP LOCATION.
RX PubMed=28505279; DOI=10.1210/jc.2017-00161;
RA Faucz F.R., Tirosh A., Tatsi C., Berthon A., Hernandez-Ramirez L.C.,
RA Settas N., Angelousi A., Correa R., Papadakis G.Z., Chittiboina P.,
RA Quezado M., Pankratz N., Lane J., Dimopoulos A., Mills J.L., Lodish M.,
RA Stratakis C.A.;
RT "Somatic USP8 gene mutations are a common cause of pediatric Cushing
RT disease.";
RL J. Clin. Endocrinol. Metab. 102:2836-2843(2017).
CC -!- FUNCTION: Hydrolase that can remove conjugated ubiquitin from proteins
CC and therefore plays an important regulatory role at the level of
CC protein turnover by preventing degradation. Converts both 'Lys-48' an
CC 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the
CC M phase. Involved in cell proliferation. Required to enter into S phase
CC in response to serum stimulation. May regulate T-cell anergy mediated
CC by RNF128 via the formation of a complex containing RNF128 and OTUB1.
CC Probably regulates the stability of STAM2 and RASGRF1. Regulates
CC endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early
CC endosomes, and maintenance of ESCRT-0 stability. The level of protein
CC ubiquitination on endosomes is essential for maintaining the morphology
CC of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase
CC stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR
CC degradation and downstream MAPK signaling. Involved in acrosome
CC biogenesis through interaction with the spermatid ESCRT-0 complex and
CC microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1.
CC Deubiquitinates BACE1 which inhibits BACE1 lysosomal degradation and
CC modulates BACE-mediated APP cleavage and amyloid-beta formation
CC (PubMed:27302062). {ECO:0000269|PubMed:16520378,
CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369,
CC ECO:0000269|PubMed:27302062, ECO:0000269|PubMed:9628861}.
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:9628861};
CC -!- SUBUNIT: Forms a ternary complex with RNF128 and OTUB1. Interacts (via
CC C-terminal UCH catalytic domain) with OTUB1 isoform 1. Interacts with
CC STAM2 (via SH3 domain). Interacts with DNAJB3, EGFR, EPS15, RASGRF1,
CC RNF41, YWHAE, YWHAG and YWHAZ (By similarity). Interacts with NBR1,
CC RASGRF1, RNF41 and IST1. Associates with the ESCRT-0 complex and with
CC microtubules (By similarity). Interacts with BIRC6/bruce and
CC KIF23/MKLP1. {ECO:0000250, ECO:0000269|PubMed:17035239,
CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:18329369,
CC ECO:0000269|PubMed:19129480, ECO:0000269|PubMed:19427866}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Zika virus non-structural
CC protein 1. {ECO:0000269|PubMed:30065070}.
CC -!- INTERACTION:
CC P40818; Q9HD42: CHMP1A; NbExp=3; IntAct=EBI-1050865, EBI-1057156;
CC P40818; Q7LBR1: CHMP1B; NbExp=5; IntAct=EBI-1050865, EBI-2118090;
CC P40818; Q96CF2: CHMP4C; NbExp=2; IntAct=EBI-1050865, EBI-1221015;
CC P40818; Q99814: EPAS1; NbExp=2; IntAct=EBI-1050865, EBI-447470;
CC P40818; Q16665: HIF1A; NbExp=2; IntAct=EBI-1050865, EBI-447269;
CC P40818; Q14596: NBR1; NbExp=3; IntAct=EBI-1050865, EBI-742698;
CC P40818; P63104: YWHAZ; NbExp=2; IntAct=EBI-1050865, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16520378,
CC ECO:0000269|PubMed:17711858, ECO:0000269|PubMed:19427866,
CC ECO:0000269|PubMed:28505279}. Nucleus {ECO:0000250|UniProtKB:Q80U87}.
CC Endosome membrane {ECO:0000269|PubMed:16520378,
CC ECO:0000269|PubMed:17711858}; Peripheral membrane protein
CC {ECO:0000305}. Cell membrane {ECO:0000269|PubMed:16520378}; Peripheral
CC membrane protein {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P40818-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P40818-2; Sequence=VSP_054594, VSP_054595;
CC -!- INDUCTION: Upon growth stimulation in starved human fibroblasts.
CC Decreases in response to growth arrest induced by cell-cell contact.
CC {ECO:0000269|PubMed:9628861}.
CC -!- DOMAIN: The MIT domain is required for endosomal localization, CHMP1B-
CC binding, maintenance of ESCRT-0 stability and EGFR degradation.
CC {ECO:0000269|PubMed:17711858}.
CC -!- DOMAIN: The rhodanese domain is sufficient for RNF41-binding.
CC {ECO:0000250}.
CC -!- PTM: Phosphorylation of Ser-718 is essential for interaction with YWHAE
CC and for cytosol localization. Undergoes dephosphorylation at Ser-718 in
CC the M phase. Tyrosine-phosphorylated in its N-terminal half in an EGFR-
CC dependent manner. {ECO:0000250}.
CC -!- PTM: Ubiquitinated. Inactive form is mostly monoubiquitinated, but
CC polyubiquitination happens too. Ubiquitination is increased in EGF-
CC stimulated cells. Ubiquitination of active form is undetectable,
CC suggesting a possibility that USP8 deubiquitinates itself, thereby
CC regulating its own function (By similarity). {ECO:0000250}.
CC -!- DISEASE: Pituitary adenoma 4, ACTH-secreting (PITA4) [MIM:219090]: A
CC form of pituitary adenoma, a neoplasm of the pituitary gland and one of
CC the most common neuroendocrine tumors. Pituitary adenomas are
CC clinically classified as functional and non-functional tumors, and
CC manifest with a variety of features, including local invasion of
CC surrounding structures and excessive hormone secretion. Functional
CC pituitary adenomas are further classified by the type of hormone they
CC secrete. PITA4 results in excessive production of adrenocorticotropic
CC hormone. This leads to hypersecretion of cortisol by the adrenal glands
CC and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing
CC syndrome include facial and truncal obesity, abdominal striae, muscular
CC weakness, osteoporosis, arterial hypertension, diabetes.
CC {ECO:0000269|PubMed:28505279}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH38801.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC Sequence=AAH51345.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
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DR EMBL; D29956; BAA06225.2; -; mRNA.
DR EMBL; AK296480; BAG59120.1; -; mRNA.
DR EMBL; BX537420; CAD97662.1; -; mRNA.
DR EMBL; AC012170; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC038801; AAH38801.1; ALT_SEQ; mRNA.
DR EMBL; BC051345; AAH51345.1; ALT_SEQ; mRNA.
DR EMBL; BC110590; AAI10591.1; -; mRNA.
DR CCDS; CCDS10137.1; -. [P40818-1]
DR CCDS; CCDS61632.1; -. [P40818-2]
DR RefSeq; NP_001122082.1; NM_001128610.2. [P40818-1]
DR RefSeq; NP_001269978.1; NM_001283049.1. [P40818-2]
DR RefSeq; NP_005145.3; NM_005154.4. [P40818-1]
DR RefSeq; XP_006720824.1; XM_006720761.3. [P40818-1]
DR RefSeq; XP_011520495.1; XM_011522193.2. [P40818-1]
DR PDB; 1WHB; NMR; -; A=174-317.
DR PDB; 2A9U; X-ray; 2.10 A; A/B=1-142.
DR PDB; 2GFO; X-ray; 2.00 A; A=734-1110.
DR PDB; 2GWF; X-ray; 2.30 A; A/C/E=181-318.
DR PDB; 3N3K; X-ray; 2.60 A; A=734-1110.
DR PDB; 6F09; X-ray; 1.59 A; A/B/C/D=712-724.
DR PDBsum; 1WHB; -.
DR PDBsum; 2A9U; -.
DR PDBsum; 2GFO; -.
DR PDBsum; 2GWF; -.
DR PDBsum; 3N3K; -.
DR PDBsum; 6F09; -.
DR AlphaFoldDB; P40818; -.
DR SMR; P40818; -.
DR BioGRID; 114555; 126.
DR DIP; DIP-40365N; -.
DR IntAct; P40818; 37.
DR MINT; P40818; -.
DR STRING; 9606.ENSP00000379721; -.
DR BindingDB; P40818; -.
DR ChEMBL; CHEMBL2157854; -.
DR MEROPS; C19.011; -.
DR iPTMnet; P40818; -.
DR MetOSite; P40818; -.
DR PhosphoSitePlus; P40818; -.
DR BioMuta; USP8; -.
DR DMDM; 731046; -.
DR CPTAC; CPTAC-1733; -.
DR CPTAC; CPTAC-1734; -.
DR EPD; P40818; -.
DR jPOST; P40818; -.
DR MassIVE; P40818; -.
DR MaxQB; P40818; -.
DR PaxDb; P40818; -.
DR PeptideAtlas; P40818; -.
DR PRIDE; P40818; -.
DR ProteomicsDB; 4442; -.
DR ProteomicsDB; 55380; -. [P40818-1]
DR Antibodypedia; 1385; 278 antibodies from 28 providers.
DR DNASU; 9101; -.
DR Ensembl; ENST00000307179.9; ENSP00000302239.4; ENSG00000138592.14. [P40818-1]
DR Ensembl; ENST00000396444.7; ENSP00000379721.3; ENSG00000138592.14. [P40818-1]
DR Ensembl; ENST00000425032.7; ENSP00000412682.3; ENSG00000138592.14. [P40818-2]
DR GeneID; 9101; -.
DR KEGG; hsa:9101; -.
DR MANE-Select; ENST00000307179.9; ENSP00000302239.4; NM_005154.5; NP_005145.3.
DR UCSC; uc001zyl.6; human. [P40818-1]
DR CTD; 9101; -.
DR DisGeNET; 9101; -.
DR GeneCards; USP8; -.
DR HGNC; HGNC:12631; USP8.
DR HPA; ENSG00000138592; Low tissue specificity.
DR MalaCards; USP8; -.
DR MIM; 219090; phenotype.
DR MIM; 603158; gene.
DR neXtProt; NX_P40818; -.
DR OpenTargets; ENSG00000138592; -.
DR Orphanet; 401795; Autosomal recessive spastic paraplegia type 59.
DR Orphanet; 96253; Cushing disease.
DR PharmGKB; PA37256; -.
DR VEuPathDB; HostDB:ENSG00000138592; -.
DR eggNOG; KOG1868; Eukaryota.
DR GeneTree; ENSGT00940000157542; -.
DR HOGENOM; CLU_009980_0_0_1; -.
DR InParanoid; P40818; -.
DR OMA; ENKPACY; -.
DR PhylomeDB; P40818; -.
DR TreeFam; TF106277; -.
DR BRENDA; 3.4.19.12; 2681.
DR PathwayCommons; P40818; -.
DR Reactome; R-HSA-1358803; Downregulation of ERBB2:ERBB3 signaling.
DR Reactome; R-HSA-4641263; Regulation of FZD by ubiquitination.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-6807004; Negative regulation of MET activity.
DR SignaLink; P40818; -.
DR SIGNOR; P40818; -.
DR BioGRID-ORCS; 9101; 547 hits in 1096 CRISPR screens.
DR ChiTaRS; USP8; human.
DR EvolutionaryTrace; P40818; -.
DR GeneWiki; USP8; -.
DR GenomeRNAi; 9101; -.
DR Pharos; P40818; Tchem.
DR PRO; PR:P40818; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; P40818; protein.
DR Bgee; ENSG00000138592; Expressed in calcaneal tendon and 194 other tissues.
DR ExpressionAtlas; P40818; baseline and differential.
DR Genevisible; P40818; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0043197; C:dendritic spine; IBA:GO_Central.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0031313; C:extrinsic component of endosome membrane; IBA:GO_Central.
DR GO; GO:0019897; C:extrinsic component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0030496; C:midbody; IDA:MGI.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0014069; C:postsynaptic density; IBA:GO_Central.
DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
DR GO; GO:0007032; P:endosome organization; IMP:UniProtKB.
DR GO; GO:0000281; P:mitotic cytokinesis; IMP:MGI.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; IMP:FlyBase.
DR GO; GO:0016579; P:protein deubiquitination; IMP:UniProtKB.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; IDA:UniProtKB.
DR GO; GO:0007265; P:Ras protein signal transduction; IBA:GO_Central.
DR GO; GO:0099576; P:regulation of protein catabolic process at postsynapse, modulating synaptic transmission; IEA:Ensembl.
DR GO; GO:0032880; P:regulation of protein localization; IMP:UniProtKB.
DR GO; GO:0031647; P:regulation of protein stability; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 3.40.250.10; -; 1.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR001394; Peptidase_C19_UCH.
DR InterPro; IPR001763; Rhodanese-like_dom.
DR InterPro; IPR036873; Rhodanese-like_dom_sf.
DR InterPro; IPR015063; USP8_dimer.
DR InterPro; IPR018200; USP_CS.
DR InterPro; IPR028889; USP_dom.
DR Pfam; PF00581; Rhodanese; 1.
DR Pfam; PF00443; UCH; 1.
DR Pfam; PF08969; USP8_dimer; 1.
DR SUPFAM; SSF52821; SSF52821; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS50206; RHODANESE_3; 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; Cell cycle; Cell membrane;
KW Cushing syndrome; Cytoplasm; Disease variant; Endosome; Hydrolase;
KW Membrane; Nucleus; Phosphoprotein; Protease; Reference proteome;
KW SH3-binding; Thiol protease; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..1118
FT /note="Ubiquitin carboxyl-terminal hydrolase 8"
FT /id="PRO_0000080627"
FT DOMAIN 33..116
FT /note="MIT"
FT DOMAIN 195..313
FT /note="Rhodanese"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00173"
FT DOMAIN 777..1109
FT /note="USP"
FT REGION 120..177
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 402..447
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 475..648
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 679..746
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 405..413
FT /note="SH3-binding"
FT /evidence="ECO:0000250"
FT COMPBIAS 120..145
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 156..177
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 412..428
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 475..580
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 584..598
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 617..641
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 683..697
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 700..715
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 786
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT ACT_SITE 1067
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT ECO:0000255|PROSITE-ProRule:PRU10093"
FT MOD_RES 160
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 392
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 400
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 452
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 577
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 718
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 719
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 945
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q80U87"
FT VAR_SEQ 35..111
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054594"
FT VAR_SEQ 601..629
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054595"
FT VARIANT 310
FT /note="Q -> K (found in a patient with spastic paraplegia;
FT unknown pathological significance; dbSNP:rs587777201)"
FT /evidence="ECO:0000269|PubMed:24482476"
FT /id="VAR_077850"
FT VARIANT 443
FT /note="D -> G (in dbSNP:rs3743044)"
FT /id="VAR_017796"
FT VARIANT 718..723
FT /note="Missing (in PITA4; somatic mutation; unknown
FT pathological significance)"
FT /evidence="ECO:0000269|PubMed:28505279"
FT /id="VAR_079717"
FT VARIANT 718
FT /note="S -> C (in PITA4; somatic mutation; unknown
FT pathological significance; dbSNP:rs672601308)"
FT /evidence="ECO:0000269|PubMed:28505279"
FT /id="VAR_079718"
FT VARIANT 718
FT /note="S -> P (in PITA4; somatic mutation; unknown
FT pathological significance; localizes to nucleus instead of
FT cytoplasm; dbSNP:rs672601307)"
FT /evidence="ECO:0000269|PubMed:28505279"
FT /id="VAR_079719"
FT VARIANT 718
FT /note="Missing (in PITA4; somatic mutation; unknown
FT pathological significance)"
FT /evidence="ECO:0000269|PubMed:28505279"
FT /id="VAR_079720"
FT VARIANT 720
FT /note="P -> R (in PITA4; somatic mutation; unknown
FT pathological significance; dbSNP:rs672601311)"
FT /evidence="ECO:0000269|PubMed:28505279"
FT /id="VAR_079721"
FT VARIANT 739
FT /note="T -> A (in dbSNP:rs11638390)"
FT /id="VAR_051525"
FT VARIANT 827
FT /note="A -> G (in dbSNP:rs1056577)"
FT /id="VAR_017797"
FT MUTAGEN 786
FT /note="C->S: Impairs deubiquitination activity and leads to
FT endosome membrane accumulation."
FT /evidence="ECO:0000269|PubMed:16520378"
FT CONFLICT 526
FT /note="E -> G (in Ref. 3; CAD97662)"
FT /evidence="ECO:0000305"
FT CONFLICT 717
FT /note="Y -> H (in Ref. 3; CAD97662)"
FT /evidence="ECO:0000305"
FT CONFLICT 945
FT /note="T -> A (in Ref. 3; CAD97662)"
FT /evidence="ECO:0000305"
FT HELIX 17..21
FT /evidence="ECO:0007829|PDB:2A9U"
FT HELIX 22..24
FT /evidence="ECO:0007829|PDB:2A9U"
FT HELIX 28..30
FT /evidence="ECO:0007829|PDB:2A9U"
FT HELIX 33..52
FT /evidence="ECO:0007829|PDB:2A9U"
FT HELIX 56..73
FT /evidence="ECO:0007829|PDB:2A9U"
FT HELIX 77..81
FT /evidence="ECO:0007829|PDB:2A9U"
FT HELIX 83..90
FT /evidence="ECO:0007829|PDB:2A9U"
FT HELIX 92..138
FT /evidence="ECO:0007829|PDB:2A9U"
FT STRAND 181..183
FT /evidence="ECO:0007829|PDB:1WHB"
FT HELIX 185..193
FT /evidence="ECO:0007829|PDB:2GWF"
FT STRAND 195..197
FT /evidence="ECO:0007829|PDB:1WHB"
FT STRAND 199..203
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 207..212
FT /evidence="ECO:0007829|PDB:2GWF"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:1WHB"
FT HELIX 223..225
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 232..237
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 241..248
FT /evidence="ECO:0007829|PDB:2GWF"
FT TURN 249..252
FT /evidence="ECO:0007829|PDB:2GWF"
FT STRAND 253..259
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 265..267
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 273..282
FT /evidence="ECO:0007829|PDB:2GWF"
FT STRAND 295..297
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 300..307
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 309..311
FT /evidence="ECO:0007829|PDB:2GWF"
FT HELIX 763..765
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 782..784
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 786..796
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 799..806
FT /evidence="ECO:0007829|PDB:2GFO"
FT TURN 807..809
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 810..813
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 825..839
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 842..845
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 848..857
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 859..861
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 862..865
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 869..884
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 903..917
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 921..926
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 928..936
FT /evidence="ECO:0007829|PDB:2GFO"
FT TURN 937..939
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 942..954
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 959..963
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 964..971
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 975..977
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 979..981
FT /evidence="ECO:0007829|PDB:3N3K"
FT STRAND 983..985
FT /evidence="ECO:0007829|PDB:2GFO"
FT TURN 986..989
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 990..992
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 994..1002
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1005..1011
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1014..1016
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1018..1023
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1027..1029
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 1038..1040
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1051..1061
FT /evidence="ECO:0007829|PDB:2GFO"
FT TURN 1063..1065
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1067..1074
FT /evidence="ECO:0007829|PDB:2GFO"
FT TURN 1075..1078
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1079..1084
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1087..1090
FT /evidence="ECO:0007829|PDB:2GFO"
FT HELIX 1093..1095
FT /evidence="ECO:0007829|PDB:2GFO"
FT STRAND 1101..1107
FT /evidence="ECO:0007829|PDB:2GFO"
SQ SEQUENCE 1118 AA; 127523 MW; 8B884B7A842F9A9A CRC64;
MPAVASVPKE LYLSSSLKDL NKKTEVKPEK ISTKSYVHSA LKIFKTAEEC RLDRDEERAY
VLYMKYVTVY NLIKKRPDFK QQQDYFHSIL GPGNIKKAVE EAERLSESLK LRYEEAEVRK
KLEEKDRQEE AQRLQQKRQE TGREDGGTLA KGSLENVLDS KDKTQKSNGE KNEKCETKEK
GAITAKELYT MMTDKNISLI IMDARRMQDY QDSCILHSLS VPEEAISPGV TASWIEAHLP
DDSKDTWKKR GNVEYVVLLD WFSSAKDLQI GTTLRSLKDA LFKWESKTVL RNEPLVLEGG
YENWLLCYPQ YTTNAKVTPP PRRQNEEVSI SLDFTYPSLE ESIPSKPAAQ TPPASIEVDE
NIELISGQNE RMGPLNISTP VEPVAASKSD VSPIIQPVPS IKNVPQIDRT KKPAVKLPEE
HRIKSESTNH EQQSPQSGKV IPDRSTKPVV FSPTLMLTDE EKARIHAETA LLMEKNKQEK
ELRERQQEEQ KEKLRKEEQE QKAKKKQEAE ENEITEKQQK AKEEMEKKES EQAKKEDKET
SAKRGKEITG VKRQSKSEHE TSDAKKSVED RGKRCPTPEI QKKSTGDVPH TSVTGDSGSG
KPFKIKGQPE SGILRTGTFR EDTDDTERNK AQREPLTRAR SEEMGRIVPG LPSGWAKFLD
PITGTFRYYH SPTNTVHMYP PEMAPSSAPP STPPTHKAKP QIPAERDREP SKLKRSYSSP
DITQAIQEEE KRKPTVTPTV NRENKPTCYP KAEISRLSAS QIRNLNPVFG GSGPALTGLR
NLGNTCYMNS ILQCLCNAPH LADYFNRNCY QDDINRSNLL GHKGEVAEEF GIIMKALWTG
QYRYISPKDF KITIGKINDQ FAGYSQQDSQ ELLLFLMDGL HEDLNKADNR KRYKEENNDH
LDDFKAAEHA WQKHKQLNES IIVALFQGQF KSTVQCLTCH KKSRTFEAFM YLSLPLASTS
KCTLQDCLRL FSKEEKLTDN NRFYCSHCRA RRDSLKKIEI WKLPPVLLVH LKRFSYDGRW
KQKLQTSVDF PLENLDLSQY VIGPKNNLKK YNLFSVSNHY GGLDGGHYTA YCKNAARQRW
FKFDDHEVSD ISVSSVKSSA AYILFYTSLG PRVTDVAT
