OTUB1_HUMAN
ID OTUB1_HUMAN Reviewed; 271 AA.
AC Q96FW1; Q32Q78; Q96II3; Q9NXQ4; Q9P0B8;
DT 01-MAR-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2004, sequence version 2.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Ubiquitin thioesterase OTUB1;
DE EC=3.4.19.12 {ECO:0000269|PubMed:23827681};
DE AltName: Full=Deubiquitinating enzyme OTUB1;
DE AltName: Full=OTU domain-containing ubiquitin aldehyde-binding protein 1;
DE AltName: Full=Otubain-1;
DE Short=hOTU1;
DE AltName: Full=Ubiquitin-specific-processing protease OTUB1;
GN Name=OTUB1; Synonyms=OTB1, OTU1; ORFNames=HSPC263;
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), IDENTIFICATION BY MASS
RP SPECTROMETRY, FUNCTION, TISSUE SPECIFICITY, AND MUTAGENESIS OF ASP-88;
RP CYS-91 AND HIS-265.
RC TISSUE=Cervix carcinoma;
RX PubMed=12704427; DOI=10.1038/sj.embor.embor824;
RA Balakirev M.Y., Tcherniuk S.O., Jaquinod M., Chroboczek J.;
RT "Otubains: a new family of cysteine proteases in the ubiquitin pathway.";
RL EMBO Rep. 4:517-522(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), ALTERNATIVE SPLICING,
RP FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH RNF128 AND USP8, AND
RP MUTAGENESIS OF CYS-91; ARG-176 AND CYS-212.
RX PubMed=14661020; DOI=10.1038/ni1017;
RA Soares L., Seroogy C., Skrenta H., Anandasabapathy N., Lovelace P.,
RA Chung C.D., Engleman E., Fathman C.G.;
RT "Two isoforms of otubain 1 regulate T cell anergy via GRAIL.";
RL Nat. Immunol. 5:45-54(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for 300
RT previously undefined genes expressed in CD34+ hematopoietic stem/progenitor
RT cells.";
RL Genome Res. 10:1546-1560(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon, and Skin;
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 [7]
RP PARTIAL PROTEIN SEQUENCE, AND FUNCTION.
RX PubMed=12401499; DOI=10.1016/s1074-5521(02)00248-x;
RA Borodovsky A., Ovaa H., Kolli N., Gan-Erdene T., Wilkinson K.D.,
RA Ploegh H.L., Kessler B.M.;
RT "Chemistry-based functional proteomics reveals novel members of the
RT deubiquitinating enzyme family.";
RL Chem. Biol. 9:1149-1159(2002).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-16, AND IDENTIFICATION BY
RP 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 [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [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 [10]
RP FUNCTION, INTERACTION WITH ESR1, AND MUTAGENESIS OF CYS-91.
RX PubMed=19383985; DOI=10.1074/jbc.m109.007484;
RA Stanisic V., Malovannaya A., Qin J., Lonard D.M., O'Malley B.W.;
RT "OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1)
RT deubiquitinates estrogen receptor (ER) alpha and affects ERalpha
RT transcriptional activity.";
RL J. Biol. Chem. 284:16135-16145(2009).
RN [11]
RP FUNCTION, UBIQUITIN-BINDING, DOMAIN, AND MUTAGENESIS OF CYS-23; CYS-91 AND
RP CYS-212.
RX PubMed=19211026; DOI=10.1016/j.jmb.2008.12.085;
RA Wang T., Yin L., Cooper E.M., Lai M.-Y., Dickey S., Pickart C.M.,
RA Fushman D., Wilkinson K.D., Cohen R.E., Wolberger C.;
RT "Evidence for bidentate substrate binding as the basis for the K48 linkage
RT specificity of otubain 1.";
RL J. Mol. Biol. 386:1011-1023(2009).
RN [12]
RP FUNCTION IN INHIBITION OF RNF168, INTERACTION WITH UBE2N/UBC13, AND
RP MUTAGENESIS OF ASP-88; CYS-91 AND HIS-265.
RX PubMed=20725033; DOI=10.1038/nature09297;
RA Nakada S., Tai I., Panier S., Al-Hakim A., Iemura S., Juang Y.C.,
RA O'Donnell L., Kumakubo A., Munro M., Sicheri F., Gingras A.C., Natsume T.,
RA Suda T., Durocher D.;
RT "Non-canonical inhibition of DNA damage-dependent ubiquitination by
RT OTUB1.";
RL Nature 466:941-946(2010).
RN [13]
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 [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [15]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=23827681; DOI=10.1016/j.cell.2013.05.046;
RA Mevissen T.E., Hospenthal M.K., Geurink P.P., Elliott P.R., Akutsu M.,
RA Arnaudo N., Ekkebus R., Kulathu Y., Wauer T., El Oualid F., Freund S.M.,
RA Ovaa H., Komander D.;
RT "OTU deubiquitinases reveal mechanisms of linkage specificity and enable
RT ubiquitin chain restriction analysis.";
RL Cell 154:169-184(2013).
RN [16]
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 [17]
RP X-RAY CRYSTALLOGRAPHY (1.69 ANGSTROMS) OF 40-271, FUNCTION, INTERACTION
RP WITH FUS AND RACK1, MUTAGENESIS OF PRO-87 AND CYS-91, AND ACTIVE SITE.
RX PubMed=18954305; DOI=10.1042/bj20081318;
RA Edelmann M.J., Iphoefer A., Akutsu M., Altun M., di Gleria K., Kramer H.B.,
RA Fiebiger E., Dhe-Paganon S., Kessler B.M.;
RT "Structural basis and specificity of human otubain 1-mediated
RT deubiquitination.";
RL Biochem. J. 418:379-390(2009).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 25-271 IN COMPLEX WITH UBE2V2 AND
RP UBE2N, FREE UBIQUITIN-BINDING, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP GLN-33; ILE-37; GLN-39; CYS-91; ALA-116; THR-134; ASP-137; PHE-190; TYR-261
RP AND PRO-263.
RX PubMed=22325355; DOI=10.1016/j.molcel.2012.01.011;
RA Juang Y.C., Landry M.C., Sanches M., Vittal V., Leung C.C.,
RA Ceccarelli D.F., Mateo A.R., Pruneda J.N., Mao D.Y., Szilard R.K.,
RA Orlicky S., Munro M., Brzovic P.S., Klevit R.E., Sicheri F., Durocher D.;
RT "OTUB1 co-opts Lys48-linked ubiquitin recognition to suppress E2 enzyme
RT function.";
RL Mol. Cell 45:384-397(2012).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (3.11 ANGSTROMS) OF 1-45 IN COMPLEX WITH UBE2N AND
RP UBIQUITIN, ACTIVITY REGULATION, AND FREE UBIQUITIN-BINDING.
RX PubMed=22367539; DOI=10.1038/nature10911;
RA Wiener R., Zhang X., Wang T., Wolberger C.;
RT "The mechanism of OTUB1-mediated inhibition of ubiquitination.";
RL Nature 483:618-622(2012).
CC -!- FUNCTION: Hydrolase that can specifically remove 'Lys-48'-linked
CC conjugated ubiquitin from proteins and plays an important regulatory
CC role at the level of protein turnover by preventing degradation.
CC Regulator of T-cell anergy, a phenomenon that occurs when T-cells are
CC rendered unresponsive to antigen rechallenge and no longer respond to
CC their cognate antigen. Acts via its interaction with RNF128/GRAIL, a
CC crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128,
CC leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and
CC promotes anergy. Surprisingly, it regulates RNF128-mediated
CC ubiquitination, but does not deubiquitinate polyubiquitinated RNF128.
CC Deubiquitinates estrogen receptor alpha (ESR1). Mediates
CC deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-
CC 63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also
CC capable of removing NEDD8 from NEDD8 conjugates, but with a much lower
CC preference compared to 'Lys-48'-linked ubiquitin.
CC -!- FUNCTION: Plays a key non-catalytic role in DNA repair regulation by
CC inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that
CC promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA
CC damage sites. Inhibits RNF168 independently of ubiquitin thioesterase
CC activity by binding and inhibiting UBE2N/UBC13, the E2 partner of
CC RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and
CC H2AX marks. Inhibition occurs by binding to free ubiquitin: free
CC ubiquitin acts as an allosteric regulator that increases affinity for
CC UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1-
CC UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a
CC cleaved 'Lys48'-linked di-ubiquitin chain.
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:23827681};
CC -!- ACTIVITY REGULATION: By free ubiquitin: binding of free ubiquitin
CC triggers conformational changes in the OTU domain and formation of a
CC ubiquitin-binding helix in the N-terminus, promoting binding of the
CC conjugated donor ubiquitin in UBE2N/UBC13 to OTUB1.
CC {ECO:0000269|PubMed:22325355, ECO:0000269|PubMed:22367539}.
CC -!- SUBUNIT: Isoform 1 and isoform 2 interact with RNF128. Isoform 1 forms
CC a ternary complex with RNF128 and USP8. Isoform 1 interacts with the C-
CC terminal UCH catalytic domain of USP8. Isoform 2 does not associate
CC with USP8. Interacts with FUS, ESR1 and RACK1. Interacts with
CC UBE2N/UBC13. {ECO:0000269|PubMed:14661020, ECO:0000269|PubMed:18954305,
CC ECO:0000269|PubMed:19383985, ECO:0000269|PubMed:20725033,
CC ECO:0000269|PubMed:22325355, ECO:0000269|PubMed:22367539}.
CC -!- INTERACTION:
CC Q96FW1; P01023: A2M; NbExp=3; IntAct=EBI-1058491, EBI-640741;
CC Q96FW1; P05067: APP; NbExp=3; IntAct=EBI-1058491, EBI-77613;
CC Q96FW1; P54253: ATXN1; NbExp=6; IntAct=EBI-1058491, EBI-930964;
CC Q96FW1; P46379-2: BAG6; NbExp=3; IntAct=EBI-1058491, EBI-10988864;
CC Q96FW1; Q13490: BIRC2; NbExp=3; IntAct=EBI-1058491, EBI-514538;
CC Q96FW1; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-1058491, EBI-2837444;
CC Q96FW1; Q14203-5: DCTN1; NbExp=3; IntAct=EBI-1058491, EBI-25840379;
CC Q96FW1; G5E9A7: DMWD; NbExp=3; IntAct=EBI-1058491, EBI-10976677;
CC Q96FW1; O75190-2: DNAJB6; NbExp=3; IntAct=EBI-1058491, EBI-12593112;
CC Q96FW1; O14645: DNALI1; NbExp=3; IntAct=EBI-1058491, EBI-395638;
CC Q96FW1; P50570-2: DNM2; NbExp=3; IntAct=EBI-1058491, EBI-10968534;
CC Q96FW1; P35637: FUS; NbExp=3; IntAct=EBI-1058491, EBI-400434;
CC Q96FW1; P14136: GFAP; NbExp=3; IntAct=EBI-1058491, EBI-744302;
CC Q96FW1; Q53GS7: GLE1; NbExp=3; IntAct=EBI-1058491, EBI-1955541;
CC Q96FW1; P28799: GRN; NbExp=3; IntAct=EBI-1058491, EBI-747754;
CC Q96FW1; P07686: HEXB; NbExp=3; IntAct=EBI-1058491, EBI-7133736;
CC Q96FW1; Q9NWT6: HIF1AN; NbExp=5; IntAct=EBI-1058491, EBI-745632;
CC Q96FW1; P04792: HSPB1; NbExp=3; IntAct=EBI-1058491, EBI-352682;
CC Q96FW1; O43464: HTRA2; NbExp=3; IntAct=EBI-1058491, EBI-517086;
CC Q96FW1; Q9UMF0: ICAM5; NbExp=3; IntAct=EBI-1058491, EBI-6398041;
CC Q96FW1; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-1058491, EBI-1055254;
CC Q96FW1; O60333-2: KIF1B; NbExp=3; IntAct=EBI-1058491, EBI-10975473;
CC Q96FW1; O14901: KLF11; NbExp=3; IntAct=EBI-1058491, EBI-948266;
CC Q96FW1; Q00987: MDM2; NbExp=5; IntAct=EBI-1058491, EBI-389668;
CC Q96FW1; P51608: MECP2; NbExp=3; IntAct=EBI-1058491, EBI-1189067;
CC Q96FW1; P19404: NDUFV2; NbExp=3; IntAct=EBI-1058491, EBI-713665;
CC Q96FW1; P35240-4: NF2; NbExp=3; IntAct=EBI-1058491, EBI-1014514;
CC Q96FW1; Q99497: PARK7; NbExp=4; IntAct=EBI-1058491, EBI-1164361;
CC Q96FW1; O60260-5: PRKN; NbExp=3; IntAct=EBI-1058491, EBI-21251460;
CC Q96FW1; P60891: PRPS1; NbExp=3; IntAct=EBI-1058491, EBI-749195;
CC Q96FW1; P49768-2: PSEN1; NbExp=3; IntAct=EBI-1058491, EBI-11047108;
CC Q96FW1; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-1058491, EBI-396669;
CC Q96FW1; P37840: SNCA; NbExp=3; IntAct=EBI-1058491, EBI-985879;
CC Q96FW1; P00441: SOD1; NbExp=3; IntAct=EBI-1058491, EBI-990792;
CC Q96FW1; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-1058491, EBI-5235340;
CC Q96FW1; Q13148: TARDBP; NbExp=8; IntAct=EBI-1058491, EBI-372899;
CC Q96FW1; P04637: TP53; NbExp=8; IntAct=EBI-1058491, EBI-366083;
CC Q96FW1; O14773: TPP1; NbExp=3; IntAct=EBI-1058491, EBI-2800203;
CC Q96FW1; Q86WV8: TSC1; NbExp=3; IntAct=EBI-1058491, EBI-12806590;
CC Q96FW1; P02766: TTR; NbExp=4; IntAct=EBI-1058491, EBI-711909;
CC Q96FW1; P22314: UBA1; NbExp=4; IntAct=EBI-1058491, EBI-709688;
CC Q96FW1; P0CG47: UBB; NbExp=3; IntAct=EBI-1058491, EBI-413034;
CC Q96FW1; P51668: UBE2D1; NbExp=14; IntAct=EBI-1058491, EBI-743540;
CC Q96FW1; P62837: UBE2D2; NbExp=16; IntAct=EBI-1058491, EBI-347677;
CC Q96FW1; P61077: UBE2D3; NbExp=14; IntAct=EBI-1058491, EBI-348268;
CC Q96FW1; Q9Y2X8: UBE2D4; NbExp=9; IntAct=EBI-1058491, EBI-745527;
CC Q96FW1; P51965: UBE2E1; NbExp=3; IntAct=EBI-1058491, EBI-348546;
CC Q96FW1; Q96LR5: UBE2E2; NbExp=8; IntAct=EBI-1058491, EBI-2129763;
CC Q96FW1; Q969T4: UBE2E3; NbExp=8; IntAct=EBI-1058491, EBI-348496;
CC Q96FW1; P40337-2: VHL; NbExp=3; IntAct=EBI-1058491, EBI-12157263;
CC Q96FW1; O76024: WFS1; NbExp=3; IntAct=EBI-1058491, EBI-720609;
CC Q96FW1; Q56921: ypkA; Xeno; NbExp=5; IntAct=EBI-1058491, EBI-8022937;
CC Q96FW1; Q9RI12: ypkA; Xeno; NbExp=3; IntAct=EBI-1058491, EBI-2849107;
CC Q96FW1-1; P61088: UBE2N; NbExp=5; IntAct=EBI-15972141, EBI-1052908;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Otubain-1;
CC IsoId=Q96FW1-1; Sequence=Displayed;
CC Name=2; Synonyms=ARF-1;
CC IsoId=Q96FW1-2; Sequence=VSP_009464;
CC -!- TISSUE SPECIFICITY: Isoform 1 is ubiquitous. Isoform 2 is expressed
CC only in lymphoid tissues such as tonsils, lymph nodes and spleen, as
CC well as peripheral blood mononuclear cells.
CC {ECO:0000269|PubMed:12704427, ECO:0000269|PubMed:14661020}.
CC -!- DOMAIN: In addition to ubiquitin-binding at the Cys-91 active site, a
CC proximal ubiquitin-binding site is also present at Cys-23 Occupancy of
CC the active site is needed to enable tight binding to the second site.
CC Distinct binding sites for the ubiquitins may allow to discriminate
CC among different isopeptide linkages (i.e. 'Lys-48'-, 'Lys-63'-linked
CC polyubiquitin) in polyubiquitin substrates and achieve linkage-specific
CC deubiquitination. {ECO:0000269|PubMed:19211026}.
CC -!- MISCELLANEOUS: In the structure described by PubMed:18954305, the His-
CC 265 active site of the catalytic triad is located too far to interact
CC directly with the active site Cys-91. A possible explanation is that
CC OTUB1 is in inactive conformation in absence of ubiquitin and a
CC conformation change may move His-265 in the proximity of Cys-91 in
CC presence of ubiquitin substrate.
CC -!- MISCELLANEOUS: [Isoform 2]: Lacks the catalytic sites for protease
CC activity. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase C65 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF28941.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AY177200; AAO27702.1; -; mRNA.
DR EMBL; AF161381; AAF28941.1; ALT_INIT; mRNA.
DR EMBL; AK000120; BAA90956.1; -; mRNA.
DR EMBL; AP000721; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC007519; AAH07519.1; -; mRNA.
DR EMBL; BC010368; AAH10368.1; -; mRNA.
DR EMBL; BC107701; AAI07702.1; -; mRNA.
DR CCDS; CCDS8055.1; -. [Q96FW1-1]
DR RefSeq; NP_060140.2; NM_017670.2. [Q96FW1-1]
DR PDB; 2ZFY; X-ray; 1.69 A; A=40-271.
DR PDB; 3VON; X-ray; 3.15 A; A/H/O/V/c/j=45-271.
DR PDB; 4DDG; X-ray; 3.30 A; A/B/C/J/K/L=25-271.
DR PDB; 4DDI; X-ray; 3.80 A; A/B/C=25-271.
DR PDB; 4DHZ; X-ray; 3.11 A; A=1-45.
DR PDB; 4I6L; X-ray; 2.49 A; A=45-271.
DR PDB; 4LDT; X-ray; 1.90 A; A=1-45.
DR PDBsum; 2ZFY; -.
DR PDBsum; 3VON; -.
DR PDBsum; 4DDG; -.
DR PDBsum; 4DDI; -.
DR PDBsum; 4DHZ; -.
DR PDBsum; 4I6L; -.
DR PDBsum; 4LDT; -.
DR AlphaFoldDB; Q96FW1; -.
DR SMR; Q96FW1; -.
DR BioGRID; 120751; 264.
DR CORUM; Q96FW1; -.
DR DIP; DIP-41158N; -.
DR IntAct; Q96FW1; 371.
DR MINT; Q96FW1; -.
DR STRING; 9606.ENSP00000444357; -.
DR ChEMBL; CHEMBL4523428; -.
DR MEROPS; C65.001; -.
DR GlyGen; Q96FW1; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96FW1; -.
DR MetOSite; Q96FW1; -.
DR PhosphoSitePlus; Q96FW1; -.
DR SwissPalm; Q96FW1; -.
DR BioMuta; OTUB1; -.
DR DMDM; 44888286; -.
DR CPTAC; CPTAC-244; -.
DR CPTAC; CPTAC-245; -.
DR EPD; Q96FW1; -.
DR jPOST; Q96FW1; -.
DR MassIVE; Q96FW1; -.
DR MaxQB; Q96FW1; -.
DR PaxDb; Q96FW1; -.
DR PeptideAtlas; Q96FW1; -.
DR PRIDE; Q96FW1; -.
DR ProteomicsDB; 76566; -. [Q96FW1-1]
DR ProteomicsDB; 76567; -. [Q96FW1-2]
DR Antibodypedia; 29104; 499 antibodies from 35 providers.
DR CPTC; Q96FW1; 3 antibodies.
DR DNASU; 55611; -.
DR Ensembl; ENST00000428192.6; ENSP00000402551.2; ENSG00000167770.13. [Q96FW1-1]
DR Ensembl; ENST00000538426.6; ENSP00000444357.1; ENSG00000167770.13. [Q96FW1-1]
DR GeneID; 55611; -.
DR KEGG; hsa:55611; -.
DR MANE-Select; ENST00000538426.6; ENSP00000444357.1; NM_017670.3; NP_060140.2.
DR UCSC; uc001nyf.2; human. [Q96FW1-1]
DR CTD; 55611; -.
DR DisGeNET; 55611; -.
DR GeneCards; OTUB1; -.
DR HGNC; HGNC:23077; OTUB1.
DR HPA; ENSG00000167770; Low tissue specificity.
DR MIM; 608337; gene.
DR neXtProt; NX_Q96FW1; -.
DR OpenTargets; ENSG00000167770; -.
DR PharmGKB; PA134988141; -.
DR VEuPathDB; HostDB:ENSG00000167770; -.
DR eggNOG; KOG3991; Eukaryota.
DR GeneTree; ENSGT00390000006979; -.
DR InParanoid; Q96FW1; -.
DR PhylomeDB; Q96FW1; -.
DR TreeFam; TF314145; -.
DR PathwayCommons; Q96FW1; -.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases.
DR SignaLink; Q96FW1; -.
DR SIGNOR; Q96FW1; -.
DR BioGRID-ORCS; 55611; 46 hits in 1092 CRISPR screens.
DR ChiTaRS; OTUB1; human.
DR EvolutionaryTrace; Q96FW1; -.
DR GeneWiki; OTUB1; -.
DR GenomeRNAi; 55611; -.
DR Pharos; Q96FW1; Tbio.
DR PRO; PR:Q96FW1; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q96FW1; protein.
DR Bgee; ENSG00000167770; Expressed in right frontal lobe and 210 other tissues.
DR ExpressionAtlas; Q96FW1; baseline and differential.
DR Genevisible; Q96FW1; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0019784; F:deNEDDylase activity; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:2000780; P:negative regulation of double-strand break repair; IMP:UniProtKB.
DR GO; GO:1901315; P:negative regulation of histone H2A K63-linked ubiquitination; IDA:UniProtKB.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; IDA:UniProtKB.
DR Gene3D; 1.20.1300.20; -; 1.
DR Gene3D; 3.30.200.60; -; 1.
DR InterPro; IPR003323; OTU_dom.
DR InterPro; IPR030298; OTUB1.
DR InterPro; IPR016615; Otubain.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR InterPro; IPR019400; Peptidase_C65_otubain.
DR InterPro; IPR042468; Peptidase_C65_otubain_sub1.
DR InterPro; IPR042467; Peptidase_C65_otubain_sub2.
DR PANTHER; PTHR12931; PTHR12931; 1.
DR PANTHER; PTHR12931:SF19; PTHR12931:SF19; 1.
DR Pfam; PF10275; Peptidase_C65; 1.
DR PIRSF; PIRSF013503; Ubiquitin_thioesterase_Otubain; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS50802; OTU; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Adaptive immunity; Alternative splicing;
KW Cytoplasm; Direct protein sequencing; DNA damage; DNA repair; Hydrolase;
KW Immunity; Phosphoprotein; Protease; Reference proteome; Thiol protease;
KW Ubl conjugation pathway.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..271
FT /note="Ubiquitin thioesterase OTUB1"
FT /id="PRO_0000221008"
FT DOMAIN 80..271
FT /note="OTU"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00139"
FT REGION 130..138
FT /note="Ubiquitin-conjugating enzyme E2 binding"
FT /evidence="ECO:0000269|PubMed:22325355"
FT REGION 169..177
FT /note="Ubiquitin-conjugating enzyme E2 binding"
FT /evidence="ECO:0000269|PubMed:22325355"
FT REGION 189..195
FT /note="Free ubiquitin binding"
FT /evidence="ECO:0000269|PubMed:22325355,
FT ECO:0000269|PubMed:22367539, ECO:0007744|PDB:4DHZ"
FT REGION 206..213
FT /note="Ubiquitin-conjugating enzyme E2 binding"
FT /evidence="ECO:0000269|PubMed:22325355,
FT ECO:0000269|PubMed:22367539, ECO:0007744|PDB:4DHZ"
FT REGION 214..221
FT /note="Free ubiquitin binding"
FT /evidence="ECO:0000269|PubMed:22325355,
FT ECO:0000269|PubMed:22367539, ECO:0007744|PDB:4DHZ"
FT REGION 245..251
FT /note="Free ubiquitin binding"
FT /evidence="ECO:0000269|PubMed:22325355,
FT ECO:0000269|PubMed:22367539, ECO:0007744|PDB:4DHZ"
FT ACT_SITE 88
FT /evidence="ECO:0000269|PubMed:22367539,
FT ECO:0007744|PDB:4DHZ"
FT ACT_SITE 91
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:22325355,
FT ECO:0000305|PubMed:18954305"
FT ACT_SITE 265
FT /evidence="ECO:0000269|PubMed:22325355,
FT ECO:0000305|PubMed:18954305"
FT SITE 23
FT /note="Required for proximal ubiquitin-binding"
FT /evidence="ECO:0000269|PubMed:19211026"
FT SITE 221
FT /note="Interacts with free ubiquitin"
FT /evidence="ECO:0000269|PubMed:22325355"
FT SITE 235
FT /note="Interacts with free ubiquitin"
FT /evidence="ECO:0000269|PubMed:22325355"
FT SITE 237
FT /note="Interacts with free ubiquitin"
FT /evidence="ECO:0000269|PubMed:22325355"
FT SITE 261
FT /note="Interacts with free ubiquitin"
FT /evidence="ECO:0000269|PubMed:22325355"
FT SITE 266
FT /note="Interacts with free ubiquitin"
FT /evidence="ECO:0000269|PubMed:22325355,
FT ECO:0000269|PubMed:22367539, ECO:0007744|PDB:4DHZ"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 16
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT VAR_SEQ 1..112
FT /note="MAAEEPQQQKQEPLGSDSEGVNCLAYDEAIMAQQDRIQQEIAVQNPLVSERL
FT ELSVLYKEYAEDDNIYQQKIKDLHKKYSYIRKTRPDGNCFYRAFGFSHLEALLDDSKEL
FT Q -> MMKPSWLSRTEFSKRLLCRTLWCQSGWSSRSYTRSMLKMTTSINRRSRTSTKST
FT RTSARPGLTATVSIGLSDSPTWRHCWMTARSCSGEKGGHWAPRQVGVYLLPGRVGCVSS
FT RVSPSFPGDGLDSGLARRGSAVSALASGLVEEPMLGPPFHPTP (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14661020"
FT /id="VSP_009464"
FT MUTAGEN 23
FT /note="C->A: Abolishes only ubiquitin-vinylsulfone adduct
FT formation."
FT /evidence="ECO:0000269|PubMed:19211026"
FT MUTAGEN 33
FT /note="Q->R: Impairs inhibition of UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 37
FT /note="I->T: Impairs inhibition of UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 39
FT /note="Q->L: Does not affect activity in DNA repair and
FT ability to inhibit UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 87
FT /note="P->G: Slightly improves ability to cleave 'K63'-
FT linked ubiquitin."
FT /evidence="ECO:0000269|PubMed:18954305"
FT MUTAGEN 88
FT /note="D->E: Abolishes hydrolase activity in vitro.
FT Abolishes ability to inhibit RNF168; when associated with
FT S-91 and A-265."
FT /evidence="ECO:0000269|PubMed:12704427,
FT ECO:0000269|PubMed:20725033"
FT MUTAGEN 91
FT /note="C->A: Prevents RNF128 autoubiquitination, and
FT stabilizes RNF128 in vivo. Abolishes both ubiquitin-binding
FT and adduct formation with ubiquitin-vinylsulfone."
FT /evidence="ECO:0000269|PubMed:12704427,
FT ECO:0000269|PubMed:14661020, ECO:0000269|PubMed:18954305,
FT ECO:0000269|PubMed:19211026, ECO:0000269|PubMed:19383985,
FT ECO:0000269|PubMed:20725033, ECO:0000269|PubMed:22325355"
FT MUTAGEN 91
FT /note="C->S: Abolishes hydrolase activity in vitro. Does
FT not affect ability to inhibit RNF168. Abolishes ability to
FT inhibit RNF168; when associated with A-88 and A-265."
FT /evidence="ECO:0000269|PubMed:12704427,
FT ECO:0000269|PubMed:14661020, ECO:0000269|PubMed:18954305,
FT ECO:0000269|PubMed:19211026, ECO:0000269|PubMed:19383985,
FT ECO:0000269|PubMed:20725033, ECO:0000269|PubMed:22325355"
FT MUTAGEN 116
FT /note="A->T: Does not affect ability to inhibit
FT UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 134
FT /note="T->R: Impairs inhibition of UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 137
FT /note="D->G: Impairs inhibition of UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 176
FT /note="R->L: No effect on RNF128."
FT /evidence="ECO:0000269|PubMed:14661020"
FT MUTAGEN 190
FT /note="F->S: Fails to inhibit ubiquitin conjugation by
FT UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 212
FT /note="C->A: No effect on RNF128."
FT /evidence="ECO:0000269|PubMed:14661020,
FT ECO:0000269|PubMed:19211026"
FT MUTAGEN 261
FT /note="Y->H: Impairs inhibition of UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 263
FT /note="P->L: Fails to inhibit ubiquitin conjugation by
FT UBE2N/UBC13."
FT /evidence="ECO:0000269|PubMed:22325355"
FT MUTAGEN 265
FT /note="H->A: Abolishes ability to inhibit RNF168; when
FT associated with A-88 and S-91."
FT /evidence="ECO:0000269|PubMed:12704427,
FT ECO:0000269|PubMed:20725033"
FT MUTAGEN 265
FT /note="H->R: Abolishes hydrolase activity in vitro."
FT /evidence="ECO:0000269|PubMed:12704427,
FT ECO:0000269|PubMed:20725033"
FT CONFLICT 61
FT /note="Y -> C (in Ref. 6; AAH10368)"
FT /evidence="ECO:0000305"
FT CONFLICT 151
FT /note="K -> R (in Ref. 4; BAA90956)"
FT /evidence="ECO:0000305"
FT HELIX 24..44
FT /evidence="ECO:0007829|PDB:4LDT"
FT STRAND 47..53
FT /evidence="ECO:0007829|PDB:4I6L"
FT HELIX 54..60
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 66..75
FT /evidence="ECO:0007829|PDB:2ZFY"
FT TURN 76..78
FT /evidence="ECO:0007829|PDB:2ZFY"
FT STRAND 81..83
FT /evidence="ECO:0007829|PDB:2ZFY"
FT STRAND 87..89
FT /evidence="ECO:0007829|PDB:4I6L"
FT HELIX 91..104
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 108..127
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 132..150
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 155..162
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 165..185
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 187..190
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 191..193
FT /evidence="ECO:0007829|PDB:2ZFY"
FT STRAND 194..197
FT /evidence="ECO:0007829|PDB:4DDG"
FT HELIX 200..207
FT /evidence="ECO:0007829|PDB:2ZFY"
FT HELIX 217..227
FT /evidence="ECO:0007829|PDB:2ZFY"
FT STRAND 231..235
FT /evidence="ECO:0007829|PDB:2ZFY"
FT STRAND 240..242
FT /evidence="ECO:0007829|PDB:4DDG"
FT STRAND 245..250
FT /evidence="ECO:0007829|PDB:2ZFY"
FT STRAND 256..262
FT /evidence="ECO:0007829|PDB:2ZFY"
FT STRAND 265..270
FT /evidence="ECO:0007829|PDB:2ZFY"
SQ SEQUENCE 271 AA; 31284 MW; 63188EE1DC5FD66F CRC64;
MAAEEPQQQK QEPLGSDSEG VNCLAYDEAI MAQQDRIQQE IAVQNPLVSE RLELSVLYKE
YAEDDNIYQQ KIKDLHKKYS YIRKTRPDGN CFYRAFGFSH LEALLDDSKE LQRFKAVSAK
SKEDLVSQGF TEFTIEDFHN TFMDLIEQVE KQTSVADLLA SFNDQSTSDY LVVYLRLLTS
GYLQRESKFF EHFIEGGRTV KEFCQQEVEP MCKESDHIHI IALAQALSVS IQVEYMDRGE
GGTTNPHIFP EGSEPKVYLL YRPGHYDILY K
