138234 20240321220409.0 10.1371/journal.pone.0143227 doi pmid:26588485 pmid pmc:PMC4654579 pmc altmetric:4791045 altmetric DZNE-2020-04556 English 610 Louis, Marcell P:(DE-2719)2810402 0 First author Evolutionary Loss of Activity in De-Ubiquitylating Enzymes of the OTU Family. San Francisco, California, US 2015 PLOS online Crossref Public Library of Science (PLoS) 2015-11-20 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1602156681_5666 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Understanding function and specificity of de-ubiquitylating enzymes (DUBs) is a major goal of current research, since DUBs are key regulators of ubiquitylation events and have been shown to be mutated in human diseases. Most DUBs are cysteine proteases, relying on a catalytic triad of cysteine, histidine and aspartate to cleave the isopeptide bond between two ubiquitin units in a poly-ubiquitin chain. We have discovered that the two Drosophila melanogaster homologues of human OTUD4, CG3251 and Otu, contain a serine instead of a cysteine in the catalytic OTU (ovarian tumor) domain. DUBs that are serine proteases instead of cysteine- or metallo-proteases have not been described. In line with this, neither CG3251 nor Otu protein were active to cleave ubiquitin chains. Re-introduction of a cysteine in the catalytic center did not render the enzymes active, indicating that further critical features for ubiquitin binding or cleavage have been lost in these proteins. Sequence analysis of OTUD4 homologues from various other species showed that within this OTU subfamily, loss of the catalytic cysteine has occurred frequently in presumably independent events, as well as gene duplications or triplications, suggesting DUB-independent functions of OTUD4 proteins. Using an in vivo RNAi approach, we show that CG3251 might function in the regulation of Inhibitor of Apoptosis (IAP)-antagonist-induced apoptosis, presumably in a DUB-independent manner. 341 - Molecular Signaling (POF3-341) G:(DE-HGF)POF3-341 POF3-341 POF III 0 2015-11-20 Crossref http://creativecommons.org/licenses/by/4.0/ Dataset connected to CrossRef, PubMed, Drosophila Proteins NLM Chemicals Inhibitor of Apoptosis Proteins NLM Chemicals RNA, Small Interfering NLM Chemicals Ubiquitin NLM Chemicals otu protein, Drosophila NLM Chemicals Serine 452VLY9402 NLM Chemicals OTUD4 protein, human EC 3.4.19.12 NLM Chemicals Ubiquitin-Specific Proteases EC 3.4.19.12 NLM Chemicals Cysteine K848JZ4886 NLM Chemicals Amino Acid Sequence MeSH Amino Acid Substitution MeSH Animals MeSH Apoptosis: genetics MeSH Binding Sites MeSH Catalytic Domain MeSH Conserved Sequence MeSH Cysteine: metabolism MeSH Drosophila Proteins: genetics MeSH Drosophila Proteins: metabolism MeSH Drosophila melanogaster: genetics MeSH Drosophila melanogaster: metabolism MeSH Evolution, Molecular MeSH Gene Expression Regulation MeSH Humans MeSH Inhibitor of Apoptosis Proteins: antagonists & inhibitors MeSH Inhibitor of Apoptosis Proteins: genetics MeSH Inhibitor of Apoptosis Proteins: metabolism MeSH Molecular Sequence Data MeSH Protein Binding MeSH RNA, Small Interfering: genetics MeSH RNA, Small Interfering: metabolism MeSH Sequence Alignment MeSH Sequence Homology, Amino Acid MeSH Serine: metabolism MeSH Ubiquitin: genetics MeSH Ubiquitin: metabolism MeSH Ubiquitin-Specific Proteases: genetics MeSH Ubiquitin-Specific Proteases: metabolism MeSH Ubiquitination MeSH Hofmann, Kay P:(DE-HGF)0 1 Broemer, Meike P:(DE-2719)2810307 2 Last author 10.1371/journal.pone.0143227 : Public Library of Science (PLoS), 2015-11-20 11 e0143227 journal-article Crossref PLOS ONE 10 2015 1932-6203 10.1371/journal.pone.0143227 Vol. 10, no. 11, p. e0143227 - PERI:(DE-600)2267670-3 11 10:11<e0143227 - e0143227 PLOS ONE 10 2015 1932-6203 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143227 Pubmed Central http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654579 http://pub.dzne.de/record/138234/files/547.PDF OpenAccess http://pub.dzne.de/record/138234/files/547.gif?subformat=icon icon OpenAccess http://pub.dzne.de/record/138234/files/547.jpg?subformat=icon-1440 icon-1440 OpenAccess http://pub.dzne.de/record/138234/files/547.jpg?subformat=icon-180 icon-180 OpenAccess http://pub.dzne.de/record/138234/files/547.jpg?subformat=icon-640 icon-640 OpenAccess oai:pub.dzne.de:138234 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2810402 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)2810307 DE-HGF Forschungsbereich Gesundheit Erkrankungen des Nervensystems G:(DE-HGF)POF3-340 G:(DE-HGF)POF3-341 G:(DE-HGF)POF3-300 Molecular Signaling 0 2015 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS Creative Commons Attribution CC BY (No Version) LIC:(DE-HGF)CCBYNV V:(DE-HGF) DOAJ DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search DBCoverage StatID:(DE-HGF)1040 StatID Zoological Record JCR StatID:(DE-HGF)0100 StatID PLOS ONE : 2017 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal DBCoverage StatID:(DE-HGF)0500 StatID DOAJ WoS StatID:(DE-HGF)0111 StatID Science Citation Index Expanded DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection IF < 5 StatID:(DE-HGF)9900 StatID OpenAccess StatID:(DE-HGF)0510 StatID Peer Review StatID:(DE-HGF)0030 StatID ASC DBCoverage StatID:(DE-HGF)0310 StatID NCBI Molecular Biology Database DBCoverage StatID:(DE-HGF)0300 StatID Medline DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List I:(DE-2719)1013021 AG Brömer 2 AG Brömer 0 I:(DE-2719)5000021 AG Brömer 1 Ubiquitin-mediated Processes in Neurodegenerative Diseases 1 journal VDB UNRESTRICTED I:(DE-2719)1013021 I:(DE-2719)5000021 FullTexts -- missing cx lookup -- 10.1146/annurev-biochem-060310-170328 Crossref 10.1146/annurev-biochem-060310-170328 -- missing cx lookup -- 10.1152/physrev.00002.2013 Crossref 10.1152/physrev.00002.2013 -- missing cx lookup -- 10.1042/BJ20071399 Crossref 10.1042/BJ20071399 -- missing cx lookup -- 10.1016/S0968-0004(99)01530-3 Crossref 10.1016/S0968-0004(99)01530-3 -- missing cx lookup -- 10.1038/sj.embor.7400201 Crossref 10.1038/sj.embor.7400201 -- missing cx lookup -- 10.1016/j.cell.2013.05.046 Crossref 10.1016/j.cell.2013.05.046 -- missing cx lookup -- 10.1371/journal.pgen.1004117 Crossref 10.1371/journal.pgen.1004117 -- missing cx lookup -- 10.1002/bies.950080106 Crossref 10.1002/bies.950080106 -- missing cx lookup -- 10.1128/MCB.9.12.5726 Crossref 10.1128/MCB.9.12.5726 -- missing cx lookup -- 10.1101/gad.463208 Crossref 10.1101/gad.463208 -- missing cx lookup -- 10.1038/nrg1111 Crossref 10.1038/nrg1111 -- missing cx lookup -- 10.1038/scientificamerican0774-74 Crossref 10.1038/scientificamerican0774-74 -- missing cx lookup -- 10.1016/S0968-0004(96)30049-2 Crossref 10.1016/S0968-0004(96)30049-2 -- missing cx lookup -- 10.1016/j.tibs.2013.08.002 Crossref 10.1016/j.tibs.2013.08.002 -- missing cx lookup -- 10.1038/msb.2011.75 Crossref 10.1038/msb.2011.75 -- missing cx lookup -- 10.15252/embj.201490497 Crossref 10.15252/embj.201490497 -- missing cx lookup -- 10.1093/nar/gkf436 Crossref 10.1093/nar/gkf436 1987 Crossref N Saitou 1987 -- missing cx lookup -- 10.1186/1756-0500-5-670 Crossref 10.1186/1756-0500-5-670 -- missing cx lookup -- 10.1101/gad.9.14.1694 Crossref 10.1101/gad.9.14.1694 -- missing cx lookup -- 10.1016/0092-8674(95)90150-7 Crossref 10.1016/0092-8674(95)90150-7 -- missing cx lookup -- 10.1126/science.271.5250.805 Crossref 10.1126/science.271.5250.805 -- missing cx lookup -- 10.1038/nrm2731 Crossref 10.1038/nrm2731 -- missing cx lookup -- 10.1016/j.bbrc.2003.12.050 Crossref 10.1016/j.bbrc.2003.12.050 -- missing cx lookup -- 10.1371/journal.pone.0000679 Crossref 10.1371/journal.pone.0000679 -- missing cx lookup -- 10.1016/j.chom.2007.09.014 Crossref 10.1016/j.chom.2007.09.014 -- missing cx lookup -- 10.1038/embor.2011.17 Crossref 10.1038/embor.2011.17 -- missing cx lookup -- 10.1038/nrm3478 Crossref 10.1038/nrm3478 -- missing cx lookup -- 10.1038/sj.emboj.7600628 Crossref 10.1038/sj.emboj.7600628 -- missing cx lookup -- 10.1002/dvg.1020070102 Crossref 10.1002/dvg.1020070102 1995 Crossref C Rodesch 1995 1993 Crossref GL Sass 1993 -- missing cx lookup -- 10.1016/S0925-4773(01)00314-8 Crossref 10.1016/S0925-4773(01)00314-8 1972 Crossref I Schneider 1972 -- missing cx lookup -- 10.1016/j.devcel.2008.01.003 Crossref 10.1016/j.devcel.2008.01.003 -- missing cx lookup -- 10.1038/sj.cdd.4401868 Crossref 10.1038/sj.cdd.4401868