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 24-JAN-2024, entry version 233. 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 controls 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; P31947: SFN; NbExp=5; IntAct=EBI-1050865, EBI-476295; CC P40818; P62258: YWHAE; NbExp=4; IntAct=EBI-1050865, EBI-356498; CC P40818; P63104: YWHAZ; NbExp=3; 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. DR RefSeq; XP_011520495.1; XM_011522193.2. 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 PDB; 8ADM; X-ray; 1.70 A; P=715-722. DR PDBsum; 1WHB; -. DR PDBsum; 2A9U; -. DR PDBsum; 2GFO; -. DR PDBsum; 2GWF; -. DR PDBsum; 3N3K; -. DR PDBsum; 6F09; -. DR PDBsum; 8ADM; -. DR AlphaFoldDB; P40818; -. DR SMR; P40818; -. DR BioGRID; 114555; 147. DR DIP; DIP-40365N; -. DR IntAct; P40818; 49. DR MINT; P40818; -. DR STRING; 9606.ENSP00000379721; -. DR BindingDB; P40818; -. DR ChEMBL; CHEMBL2157854; -. DR GuidetoPHARMACOLOGY; 3209; -. DR MEROPS; C19.011; -. DR GlyGen; P40818; 2 sites, 1 O-linked glycan (2 sites). 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; 9606-ENSP00000379721; -. DR PeptideAtlas; P40818; -. DR ProteomicsDB; 4442; -. DR ProteomicsDB; 55380; -. [P40818-1] DR Pumba; P40818; -. DR Antibodypedia; 1385; 298 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 AGR; HGNC:12631; -. 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; TCNKESA; -. DR OrthoDB; 227085at2759; -. 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; 564 hits in 1172 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 195 other cell types or tissues. DR ExpressionAtlas; P40818; baseline and differential. 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:0010008; C:endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0019897; C:extrinsic component of plasma membrane; IBA:GO_Central. 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:1990380; F:K48-linked deubiquitinase activity; IDA:UniProtKB. DR GO; GO:0061578; F:K63-linked deubiquitinase activity; IDA:UniProtKB. 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; IBA:GO_Central. DR GO; GO:0000281; P:mitotic cytokinesis; IMP:MGI. DR GO; GO:1905166; P:negative regulation of lysosomal protein catabolic process; IMP:FlyBase. DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; IMP:FlyBase. 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:0006508; P:proteolysis; IEA:UniProtKB-KW. 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 CDD; cd02674; Peptidase_C19R; 1. DR Gene3D; 3.90.70.10; Cysteine proteinases; 1. DR Gene3D; 1.20.58.80; Phosphotransferase system, lactose/cellobiose-type IIA subunit; 1. DR Gene3D; 3.40.250.10; Rhodanese-like domain; 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 InterPro; IPR048498; WW_USP8. DR PANTHER; PTHR21646; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1. DR PANTHER; PTHR21646:SF27; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 8; 1. DR Pfam; PF00581; Rhodanese; 1. DR Pfam; PF00443; UCH; 1. DR Pfam; PF08969; USP8_dimer; 1. DR Pfam; PF20625; WW_USP8; 1. DR SUPFAM; SSF54001; Cysteine proteinases; 1. DR SUPFAM; SSF52821; Rhodanese/Cell cycle control phosphatase; 1. DR SUPFAM; SSF140856; USP8 N-terminal domain-like; 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. DR Genevisible; P40818; HS. 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 uncertain 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; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:28505279" FT /id="VAR_079717" FT VARIANT 718 FT /note="S -> C (in PITA4; uncertain significance; somatic FT mutation; dbSNP:rs672601308)" FT /evidence="ECO:0000269|PubMed:28505279" FT /id="VAR_079718" FT VARIANT 718 FT /note="S -> P (in PITA4; uncertain significance; somatic FT mutation; localizes to nucleus instead of cytoplasm; FT dbSNP:rs672601307)" FT /evidence="ECO:0000269|PubMed:28505279" FT /id="VAR_079719" FT VARIANT 718 FT /note="Missing (in PITA4; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:28505279" FT /id="VAR_079720" FT VARIANT 720 FT /note="P -> R (in PITA4; uncertain significance; somatic FT mutation; 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 //