OTU6B_HUMAN
ID OTU6B_HUMAN Reviewed; 293 AA.
AC Q8N6M0; A8K6I1; B4DEY0; Q9NTA4; Q9Y387;
DT 24-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Deubiquitinase OTUD6B {ECO:0000305};
DE EC=3.4.19.12 {ECO:0000269|PubMed:21267069};
DE AltName: Full=DUBA-5;
DE AltName: Full=OTU domain-containing protein 6B {ECO:0000312|HGNC:HGNC:24281};
GN Name=OTUD6B {ECO:0000312|HGNC:HGNC:24281}; Synonyms=DUBA5;
GN ORFNames=CGI-77 {ECO:0000303|PubMed:10810093};
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).
RX PubMed=10810093; DOI=10.1101/gr.10.5.703;
RA Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.;
RT "Identification of novel human genes evolutionarily conserved in
RT Caenorhabditis elegans by comparative proteomics.";
RL Genome Res. 10:703-713(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Cerebellum, and Placenta;
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 GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 67-293 (ISOFORM 1), AND VARIANT
RP GLN-283.
RC TISSUE=Amygdala;
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 [6]
RP IDENTIFICATION.
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 ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP 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 [8]
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 [9]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF CYS-158.
RX PubMed=21267069; DOI=10.1371/journal.pone.0014514;
RA Xu Z., Zheng Y., Zhu Y., Kong X., Hu L.;
RT "Evidence for OTUD-6B participation in B lymphocytes cell cycle after
RT cytokine stimulation.";
RL PLoS ONE 6:E14514-E14514(2011).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [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 [11]
RP FUNCTION, INVOLVEMENT IN IDDFSDA, AND VARIANTS IDDFSDA 145-ARG--SER-293 DEL
RP AND CYS-186.
RX PubMed=28343629; DOI=10.1016/j.ajhg.2017.03.001;
RG EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan;
RA Santiago-Sim T., Burrage L.C., Ebstein F., Tokita M.J., Miller M., Bi W.,
RA Braxton A.A., Rosenfeld J.A., Shahrour M., Lehmann A., Cogne B., Kuery S.,
RA Besnard T., Isidor B., Bezieau S., Hazart I., Nagakura H., Immken L.L.,
RA Littlejohn R.O., Roeder E., Kara B., Hardies K., Weckhuysen S., May P.,
RA Lemke J.R., Elpeleg O., Abu-Libdeh B., James K.N., Silhavy J.L., Issa M.Y.,
RA Zaki M.S., Gleeson J.G., Seavitt J.R., Dickinson M.E., Ljungberg M.C.,
RA Wells S., Johnson S.J., Teboul L., Eng C.M., Yang Y., Kloetzel P.M.,
RA Heaney J.D., Walkiewicz M.A.;
RT "Biallelic variants in OTUD6B cause an intellectual disability syndrome
RT associated with seizures and dysmorphic features.";
RL Am. J. Hum. Genet. 100:676-688(2017).
RN [12]
RP FUNCTION IN PROTEIN SYNTHESIS, AND INTERACTION WITH THE EUKARYOTIC
RP TRANSLATION INITIATION FACTOR 4F COMPLEX.
RX PubMed=27864334; DOI=10.1158/1541-7786.mcr-16-0281-t;
RA Sobol A., Askonas C., Alani S., Weber M.J., Ananthanarayanan V., Osipo C.,
RA Bocchetta M.;
RT "Deubiquitinase OTUD6B isoforms are important regulators of growth and
RT proliferation.";
RL Mol. Cancer Res. 15:117-127(2017).
CC -!- FUNCTION: [Isoform 1]: Deubiquitinating enzyme that may play a role in
CC the ubiquitin-dependent regulation of protein synthesis, downstream of
CC mTORC1 (PubMed:21267069, PubMed:27864334). May associate with the
CC protein synthesis initiation complex and modify its ubiquitination to
CC repress translation (PubMed:27864334). May also repress DNA synthesis
CC and modify different cellular targets thereby regulating cell growth
CC and proliferation (PubMed:27864334). May also play a role in proteasome
CC assembly and function (PubMed:28343629). {ECO:0000269|PubMed:21267069,
CC ECO:0000269|PubMed:27864334, ECO:0000269|PubMed:28343629}.
CC -!- FUNCTION: [Isoform 2]: Stimulates protein synthesis. Influences the
CC expression of CCND1/cyclin D1 by promoting its translation and
CC regulates MYC/c-Myc protein stability. {ECO:0000269|PubMed:27864334}.
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:21267069};
CC -!- SUBUNIT: Interacts with the eukaryotic translation initiation factor 4F
CC complex. {ECO:0000269|PubMed:27864334}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=OTUD6B-1 {ECO:0000303|PubMed:27864334};
CC IsoId=Q8N6M0-1; Sequence=Displayed;
CC Name=2; Synonyms=OTUD6B-2 {ECO:0000303|PubMed:27864334};
CC IsoId=Q8N6M0-2; Sequence=VSP_055378;
CC -!- DISEASE: Intellectual developmental disorder with dysmorphic facies,
CC seizures, and distal limb anomalies (IDDFSDA) [MIM:617452]: An
CC autosomal recessive severe multisystem disorder characterized by poor
CC overall growth, developmental delay, early-onset seizures, intellectual
CC disability, and dysmorphic features. Additional features include
CC microcephaly, absent speech, hypotonia, feeding difficulties,
CC structural brain abnormalities, congenital malformations including
CC congenital heart disease, and musculoskeletal features.
CC {ECO:0000269|PubMed:28343629}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- CAUTION: Initially, no deubiquitinase activity could be detected when
CC tested (PubMed:23827681). Other studies, show an obvious deubiquitinase
CC activity (PubMed:21267069, PubMed:28343629, PubMed:27864334).
CC {ECO:0000269|PubMed:21267069, ECO:0000269|PubMed:23827681,
CC ECO:0000269|PubMed:27864334, ECO:0000269|PubMed:28343629}.
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; AF151836; AAD34073.1; -; mRNA.
DR EMBL; AK291646; BAF84335.1; -; mRNA.
DR EMBL; AK293843; BAG57241.1; -; mRNA.
DR EMBL; AC087439; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC029760; AAH29760.1; -; mRNA.
DR EMBL; AL137441; CAB70738.1; -; mRNA.
DR CCDS; CCDS6253.2; -. [Q8N6M0-1]
DR CCDS; CCDS69513.1; -. [Q8N6M0-2]
DR PIR; T46264; T46264.
DR RefSeq; NP_001273674.1; NM_001286745.1. [Q8N6M0-2]
DR RefSeq; NP_057107.3; NM_016023.3. [Q8N6M0-1]
DR RefSeq; XP_011515431.2; XM_011517129.2. [Q8N6M0-2]
DR AlphaFoldDB; Q8N6M0; -.
DR SMR; Q8N6M0; -.
DR BioGRID; 119647; 48.
DR IntAct; Q8N6M0; 17.
DR STRING; 9606.ENSP00000285420; -.
DR BindingDB; Q8N6M0; -.
DR ChEMBL; CHEMBL4630843; -.
DR MEROPS; C85.009; -.
DR GlyGen; Q8N6M0; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q8N6M0; -.
DR PhosphoSitePlus; Q8N6M0; -.
DR BioMuta; OTUD6B; -.
DR DMDM; 74729149; -.
DR EPD; Q8N6M0; -.
DR jPOST; Q8N6M0; -.
DR MassIVE; Q8N6M0; -.
DR MaxQB; Q8N6M0; -.
DR PaxDb; Q8N6M0; -.
DR PeptideAtlas; Q8N6M0; -.
DR PRIDE; Q8N6M0; -.
DR ProteomicsDB; 72191; -. [Q8N6M0-1]
DR Antibodypedia; 12759; 160 antibodies from 24 providers.
DR DNASU; 51633; -.
DR Ensembl; ENST00000404789.8; ENSP00000384190.4; ENSG00000155100.11. [Q8N6M0-1]
DR Ensembl; ENST00000615618.1; ENSP00000481196.1; ENSG00000155100.11. [Q8N6M0-2]
DR GeneID; 51633; -.
DR KEGG; hsa:51633; -.
DR MANE-Select; ENST00000404789.8; ENSP00000384190.4; NM_016023.5; NP_057107.4.
DR UCSC; uc011lgh.3; human. [Q8N6M0-1]
DR CTD; 51633; -.
DR DisGeNET; 51633; -.
DR GeneCards; OTUD6B; -.
DR HGNC; HGNC:24281; OTUD6B.
DR HPA; ENSG00000155100; Low tissue specificity.
DR MalaCards; OTUD6B; -.
DR MIM; 612021; gene.
DR MIM; 617452; phenotype.
DR neXtProt; NX_Q8N6M0; -.
DR OpenTargets; ENSG00000155100; -.
DR Orphanet; 505237; Early-onset seizures-distal limb anomalies-facial dysmorphism-global developmental delay syndrome.
DR PharmGKB; PA142671219; -.
DR VEuPathDB; HostDB:ENSG00000155100; -.
DR eggNOG; KOG2606; Eukaryota.
DR GeneTree; ENSGT00390000012840; -.
DR HOGENOM; CLU_034963_0_1_1; -.
DR InParanoid; Q8N6M0; -.
DR OrthoDB; 1541668at2759; -.
DR PhylomeDB; Q8N6M0; -.
DR TreeFam; TF315010; -.
DR PathwayCommons; Q8N6M0; -.
DR SignaLink; Q8N6M0; -.
DR BioGRID-ORCS; 51633; 32 hits in 1119 CRISPR screens.
DR GeneWiki; OTUD6B; -.
DR GenomeRNAi; 51633; -.
DR Pharos; Q8N6M0; Tbio.
DR PRO; PR:Q8N6M0; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q8N6M0; protein.
DR Bgee; ENSG00000155100; Expressed in sural nerve and 177 other tissues.
DR ExpressionAtlas; Q8N6M0; baseline and differential.
DR Genevisible; Q8N6M0; HS.
DR GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0008283; P:cell population proliferation; IDA:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; IMP:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; IMP:UniProtKB.
DR GO; GO:0043248; P:proteasome assembly; IMP:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR InterPro; IPR003323; OTU_dom.
DR InterPro; IPR038765; Papain-like_cys_pep_sf.
DR Pfam; PF02338; OTU; 1.
DR SUPFAM; SSF54001; SSF54001; 1.
DR PROSITE; PS50802; OTU; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Disease variant; Epilepsy; Hydrolase;
KW Intellectual disability; Protease; Reference proteome; Thiol protease;
KW Ubl conjugation pathway.
FT CHAIN 1..293
FT /note="Deubiquitinase OTUD6B"
FT /id="PRO_0000076279"
FT DOMAIN 147..284
FT /note="OTU"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00139"
FT REGION 152..158
FT /note="Cys-loop"
FT /evidence="ECO:0000250"
FT REGION 219..229
FT /note="Variable-loop"
FT /evidence="ECO:0000250"
FT REGION 267..277
FT /note="His-loop"
FT /evidence="ECO:0000250"
FT ACT_SITE 155
FT /evidence="ECO:0000250"
FT ACT_SITE 158
FT /note="Nucleophile"
FT /evidence="ECO:0000305|PubMed:21267069"
FT ACT_SITE 277
FT /evidence="ECO:0000250"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378"
FT VAR_SEQ 1..105
FT /note="MEAVLTEELDEEEQLLRRHRKEKKELQAKIQGMKNAVPKNDKKRRKQLTEDV
FT AKLEKEMEQKHREELEQLKLTTKENKIDSVAVNISNLVLENQPPRISKAQKRR -> MI
FT SK (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055378"
FT VARIANT 145..293
FT /note="Missing (in IDDFSDA; dbSNP:rs368313959)"
FT /evidence="ECO:0000269|PubMed:28343629"
FT /id="VAR_080403"
FT VARIANT 186
FT /note="Y -> C (in IDDFSDA; unknown pathological
FT significance; dbSNP:rs1064797103)"
FT /evidence="ECO:0000269|PubMed:28343629"
FT /id="VAR_080404"
FT VARIANT 283
FT /note="R -> Q (in dbSNP:rs3210518)"
FT /evidence="ECO:0000269|PubMed:17974005"
FT /id="VAR_034144"
FT MUTAGEN 158
FT /note="C->S: Abolishes the deubiquitinating enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:21267069"
FT CONFLICT 285..293
FT /note="VNIVTENCS -> GKHSY (in Ref. 1; AAD34073)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 293 AA; 33813 MW; 468DB88E2637D869 CRC64;
MEAVLTEELD EEEQLLRRHR KEKKELQAKI QGMKNAVPKN DKKRRKQLTE DVAKLEKEME
QKHREELEQL KLTTKENKID SVAVNISNLV LENQPPRISK AQKRREKKAA LEKEREERIA
EAEIENLTGA RHMESEKLAQ ILAARQLEIK QIPSDGHCMY KAIEDQLKEK DCALTVVALR
SQTAEYMQSH VEDFLPFLTN PNTGDMYTPE EFQKYCEDIV NTAAWGGQLE LRALSHILQT
PIEIIQADSP PIIVGEEYSK KPLILVYMRH AYGLGEHYNS VTRLVNIVTE NCS
