GenomeNet

Database: UniProt
Entry: Q96FW1
LinkDB: Q96FW1
Original site: Q96FW1 
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   07-APR-2021, entry version 180.
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   SMR; Q96FW1; -.
DR   BioGRID; 120751; 241.
DR   CORUM; Q96FW1; -.
DR   DIP; DIP-41158N; -.
DR   IntAct; Q96FW1; 371.
DR   MINT; Q96FW1; -.
DR   STRING; 9606.ENSP00000444357; -.
DR   MEROPS; C65.001; -.
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; 458 antibodies.
DR   CPTC; Q96FW1; 3 antibodies.
DR   DNASU; 55611; -.
DR   Ensembl; ENST00000428192; ENSP00000402551; ENSG00000167770. [Q96FW1-1]
DR   Ensembl; ENST00000538426; ENSP00000444357; ENSG00000167770. [Q96FW1-1]
DR   GeneID; 55611; -.
DR   KEGG; hsa:55611; -.
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:ENSG00000167770.11; -.
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   SIGNOR; Q96FW1; -.
DR   BioGRID-ORCS; 55611; 40 hits in 1002 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 anterior cingulate cortex and 246 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:0019784; F:NEDD8-specific protease activity; IDA:UniProtKB.
DR   GO; GO:0004843; F:thiol-dependent ubiquitin-specific protease 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:0016579; P:protein deubiquitination; TAS:Reactome.
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:0007744|PDB:4LDT"
FT   STRAND          47..53
FT                   /evidence="ECO:0007744|PDB:4I6L"
FT   HELIX           54..60
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           66..75
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   TURN            76..78
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   STRAND          81..83
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   STRAND          87..89
FT                   /evidence="ECO:0007744|PDB:4I6L"
FT   HELIX           91..104
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           108..127
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           132..150
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           155..162
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           165..185
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           187..190
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           191..193
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   STRAND          194..197
FT                   /evidence="ECO:0007744|PDB:4DDG"
FT   HELIX           200..207
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   HELIX           217..227
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   STRAND          231..235
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   STRAND          240..242
FT                   /evidence="ECO:0007744|PDB:4DDG"
FT   STRAND          245..250
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   STRAND          256..262
FT                   /evidence="ECO:0007744|PDB:2ZFY"
FT   STRAND          265..270
FT                   /evidence="ECO:0007744|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
//
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