ID   OTUD3_HUMAN             Reviewed;         398 AA.
AC   Q5T2D3; O75047;
DT   30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT   21-DEC-2004, sequence version 1.
DT   24-JAN-2024, entry version 130.
DE   RecName: Full=OTU domain-containing protein 3 {ECO:0000305};
DE            EC=3.4.19.12 {ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:32011234, ECO:0000269|PubMed:35675826};
GN   Name=OTUD3 {ECO:0000312|HGNC:HGNC:29038};
GN   Synonyms=KIAA0459 {ECO:0000303|PubMed:9455484};
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].
RC   TISSUE=Brain;
RX   PubMed=9455484; DOI=10.1093/dnares/4.5.345;
RA   Seki N., Ohira M., Nagase T., Ishikawa K., Miyajima N., Nakajima D.,
RA   Nomura N., Ohara O.;
RT   "Characterization of cDNA clones in size-fractionated cDNA libraries from
RT   human brain.";
RL   DNA Res. 4:345-349(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [3]
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   [4]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-224, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [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   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF CYS-76.
RX   PubMed=32011234; DOI=10.7554/elife.54023;
RA   Garshott D.M., Sundaramoorthy E., Leonard M., Bennett E.J.;
RT   "Distinct regulatory ribosomal ubiquitylation events are reversible and
RT   hierarchically organized.";
RL   Elife 9:0-0(2020).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 52-209, FUNCTION, CATALYTIC
RP   ACTIVITY, AND MUTAGENESIS OF 178-ARG--GLU-181.
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   [7]
RP   VARIANT ASP-288, CHARACTERIZATION OF VARIANT ASP-288, FUNCTION, SUBCELLULAR
RP   LOCATION, AND ACETYLATION AT LYS-66; LYS-105; LYS-122; LYS-129; LYS-220;
RP   LYS-292 AND LYS-322.
RX   PubMed=35675826; DOI=10.1016/j.cmet.2022.05.005;
RA   Zhou N., Qi H., Liu J., Zhang G., Liu J., Liu N., Zhu M., Zhao X., Song C.,
RA   Zhou Z., Gong J., Li R., Bai X., Jin Y., Song Y., Yin Y.;
RT   "Deubiquitinase OTUD3 regulates metabolism homeostasis in response to
RT   nutritional stresses.";
RL   Cell Metab. 34:1023-1041.e8(2022).
CC   -!- FUNCTION: Deubiquitinating enzyme that hydrolyzes 'Lys-6'- and 'Lys-
CC       11'-linked polyubiquitin. Also hydrolyzes heterotypic (mixed and
CC       branched) and homotypic chains (PubMed:23827681, PubMed:32011234,
CC       PubMed:35675826). Important regulator of energy metabolism
CC       (PubMed:35675826). Glucose and fatty acids trigger its nuclear
CC       translocation by CBP-dependent acetylation (PubMed:35675826). In the
CC       nucleus, deubiquitinates and stabilizes the nuclear receptor PPARD
CC       regulating the expression of various genes involved in glucose and
CC       lipid metabolism and oxidative phosphorylation (PubMed:35675826). Also
CC       acts as a negative regulator of the ribosome quality control (RQC) by
CC       mediating deubiquitination of 40S ribosomal proteins RPS10/eS10 and
CC       RPS20/uS10, thereby antagonizing ZNF598-mediated 40S ubiquitination
CC       (PubMed:32011234). {ECO:0000269|PubMed:23827681,
CC       ECO:0000269|PubMed:32011234, ECO:0000269|PubMed:35675826}.
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         ECO:0000269|PubMed:32011234, ECO:0000269|PubMed:35675826};
CC   -!- INTERACTION:
CC       Q5T2D3; Q9BPX1: HSD17B14; NbExp=3; IntAct=EBI-16170539, EBI-742664;
CC       Q5T2D3; P60484-1: PTEN; NbExp=9; IntAct=EBI-16170539, EBI-15722967;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:35675826}. Nucleus
CC       {ECO:0000269|PubMed:35675826}. Note=Glucose or fatty acid promote
CC       nuclear translocation upon acetylation. {ECO:0000269|PubMed:35675826}.
CC   -!- DOMAIN: The UBA-like domain has no influence on ubiquitin hydrolysis.
CC       {ECO:0000269|PubMed:23827681}.
CC   -!- DOMAIN: Specificity is given by the S1' ubiquitin-binding site within
CC       the OTU domain composed of the Cys-, His- and Variable-loops.
CC       {ECO:0000269|PubMed:23827681}.
CC   -!- PTM: Glucose and fatty acids stimulate CREBBP-dependent acetylation,
CC       promoting its nuclear translocation. {ECO:0000269|PubMed:35675826}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAA32304.2; Type=Erroneous initiation; Note=Extended N-terminus.; 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; AB007928; BAA32304.2; ALT_INIT; mRNA.
DR   EMBL; AL391883; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS41279.1; -.
DR   RefSeq; NP_056022.1; NM_015207.1.
DR   PDB; 4BOU; X-ray; 1.55 A; A=52-209.
DR   PDBsum; 4BOU; -.
DR   AlphaFoldDB; Q5T2D3; -.
DR   SMR; Q5T2D3; -.
DR   BioGRID; 116856; 49.
DR   DIP; DIP-61702N; -.
DR   IntAct; Q5T2D3; 2.
DR   STRING; 9606.ENSP00000364261; -.
DR   BindingDB; Q5T2D3; -.
DR   ChEMBL; CHEMBL4630831; -.
DR   MEROPS; C85.003; -.
DR   iPTMnet; Q5T2D3; -.
DR   PhosphoSitePlus; Q5T2D3; -.
DR   BioMuta; OTUD3; -.
DR   EPD; Q5T2D3; -.
DR   jPOST; Q5T2D3; -.
DR   MassIVE; Q5T2D3; -.
DR   MaxQB; Q5T2D3; -.
DR   PaxDb; 9606-ENSP00000364261; -.
DR   PeptideAtlas; Q5T2D3; -.
DR   ProteomicsDB; 64331; -.
DR   Pumba; Q5T2D3; -.
DR   Antibodypedia; 29739; 92 antibodies from 18 providers.
DR   DNASU; 23252; -.
DR   Ensembl; ENST00000375120.4; ENSP00000364261.3; ENSG00000169914.6.
DR   GeneID; 23252; -.
DR   KEGG; hsa:23252; -.
DR   MANE-Select; ENST00000375120.4; ENSP00000364261.3; NM_015207.2; NP_056022.1.
DR   UCSC; uc001bcs.5; human.
DR   AGR; HGNC:29038; -.
DR   CTD; 23252; -.
DR   DisGeNET; 23252; -.
DR   GeneCards; OTUD3; -.
DR   HGNC; HGNC:29038; OTUD3.
DR   HPA; ENSG00000169914; Low tissue specificity.
DR   MIM; 611758; gene.
DR   neXtProt; NX_Q5T2D3; -.
DR   OpenTargets; ENSG00000169914; -.
DR   PharmGKB; PA142671215; -.
DR   VEuPathDB; HostDB:ENSG00000169914; -.
DR   eggNOG; ENOG502QUTD; Eukaryota.
DR   GeneTree; ENSGT00390000016392; -.
DR   HOGENOM; CLU_056188_0_0_1; -.
DR   InParanoid; Q5T2D3; -.
DR   OMA; TDFQILH; -.
DR   OrthoDB; 597214at2759; -.
DR   PhylomeDB; Q5T2D3; -.
DR   TreeFam; TF329594; -.
DR   PathwayCommons; Q5T2D3; -.
DR   Reactome; R-HSA-5689896; Ovarian tumor domain proteases.
DR   Reactome; R-HSA-8948751; Regulation of PTEN stability and activity.
DR   SignaLink; Q5T2D3; -.
DR   BioGRID-ORCS; 23252; 18 hits in 1193 CRISPR screens.
DR   ChiTaRS; OTUD3; human.
DR   GenomeRNAi; 23252; -.
DR   Pharos; Q5T2D3; Tbio.
DR   PRO; PR:Q5T2D3; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; Q5T2D3; Protein.
DR   Bgee; ENSG00000169914; Expressed in oocyte and 138 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005634; C:nucleus; IDA:UniProt.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR   GO; GO:0031669; P:cellular response to nutrient levels; IDA:UniProt.
DR   GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IDA:MGI.
DR   GO; GO:0035871; P:protein K11-linked deubiquitination; IDA:UniProtKB.
DR   GO; GO:1990167; P:protein K27-linked deubiquitination; IDA:MGI.
DR   GO; GO:0071108; P:protein K48-linked deubiquitination; IDA:MGI.
DR   GO; GO:0044313; P:protein K6-linked deubiquitination; IDA:UniProtKB.
DR   GO; GO:0050821; P:protein stabilization; IDA:MGI.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   CDD; cd22770; OTU_OTUD3; 1.
DR   Gene3D; 3.90.70.80; -; 1.
DR   InterPro; IPR003323; OTU_dom.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   PANTHER; PTHR12419; OTU DOMAIN CONTAINING PROTEIN; 1.
DR   PANTHER; PTHR12419:SF7; OTU DOMAIN-CONTAINING PROTEIN 3; 1.
DR   Pfam; PF02338; OTU; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   PROSITE; PS50802; OTU; 1.
DR   Genevisible; Q5T2D3; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Cytoplasm; Hydrolase; Nucleus; Phosphoprotein;
KW   Protease; Reference proteome; Thiol protease; Ubl conjugation pathway.
FT   CHAIN           1..398
FT                   /note="OTU domain-containing protein 3"
FT                   /id="PRO_0000058103"
FT   DOMAIN          65..189
FT                   /note="OTU"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00139"
FT   DOMAIN          230..270
FT                   /note="UBA-like"
FT   REGION          1..50
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          70..76
FT                   /note="Cys-loop"
FT   REGION          127..137
FT                   /note="Variable-loop"
FT   REGION          177..182
FT                   /note="His-loop"
FT   REGION          305..383
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        14..45
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        313..345
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        346..380
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        73
FT                   /evidence="ECO:0000250|UniProtKB:Q96FW1"
FT   ACT_SITE        76
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000305|PubMed:32011234"
FT   ACT_SITE        182
FT                   /evidence="ECO:0000250|UniProtKB:Q5VVQ6"
FT   MOD_RES         66
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT   MOD_RES         105
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT   MOD_RES         122
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT   MOD_RES         129
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT   MOD_RES         220
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT   MOD_RES         224
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   MOD_RES         292
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT   MOD_RES         322
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT   VARIANT         288
FT                   /note="G -> D (found in a family with an early age of onset
FT                   of diabetes; uncertain significance; reduced the stability
FT                   and catalytic activity)"
FT                   /evidence="ECO:0000269|PubMed:35675826"
FT                   /id="VAR_087061"
FT   VARIANT         321
FT                   /note="N -> S (in dbSNP:rs2298110)"
FT                   /id="VAR_051258"
FT   VARIANT         333
FT                   /note="A -> T (in dbSNP:rs10916668)"
FT                   /id="VAR_051259"
FT   MUTAGEN         76
FT                   /note="C->S: Abolished deubiquitinase activity."
FT                   /evidence="ECO:0000269|PubMed:32011234"
FT   MUTAGEN         178..181
FT                   /note="RYGE->LSNG: Impaired activity."
FT                   /evidence="ECO:0000269|PubMed:23827681"
FT   HELIX           56..62
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   STRAND          65..68
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   HELIX           76..86
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   STRAND          87..89
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   HELIX           92..105
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   HELIX           107..110
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   HELIX           111..113
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   HELIX           120..128
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   HELIX           136..145
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   STRAND          149..153
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   STRAND          160..166
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   STRAND          172..178
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   TURN            179..181
FT                   /evidence="ECO:0007829|PDB:4BOU"
FT   STRAND          182..188
FT                   /evidence="ECO:0007829|PDB:4BOU"
SQ   SEQUENCE   398 AA;  45124 MW;  9C16E610CF1E3C5A CRC64;
     MSRKQAAKSR PGSGSRKAEA ERKRDERAAR RALAKERRNR PESGGGGGCE EEFVSFANQL
     QALGLKLREV PGDGNCLFRA LGDQLEGHSR NHLKHRQETV DYMIKQREDF EPFVEDDIPF
     EKHVASLAKP GTFAGNDAIV AFARNHQLNV VIHQLNAPLW QIRGTEKSSV RELHIAYRYG
     EHYDSVRRIN DNSEAPAHLQ TDFQMLHQDE SNKREKIKTK GMDSEDDLRD EVEDAVQKVC
     NATGCSDFNL IVQNLEAENY NIESAIIAVL RMNQGKRNNA EENLEPSGRV LKQCGPLWEE
     GGSGARIFGN QGLNEGRTEN NKAQASPSEE NKANKNQLAK VTNKQRREQQ WMEKKKRQEE
     RHRHKALESR GSHRDNNRSE AEANTQVTLV KTFAALNI
//