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@ARTICLE{Louis:138234,
      author       = {Louis, Marcell and Hofmann, Kay and Broemer, Meike},
      title        = {{E}volutionary {L}oss of {A}ctivity in
                      {D}e-{U}biquitylating {E}nzymes of the {OTU} {F}amily.},
      journal      = {PLOS ONE},
      volume       = {10},
      number       = {11},
      issn         = {1932-6203},
      address      = {San Francisco, California, US},
      publisher    = {PLOS},
      reportid     = {DZNE-2020-04556},
      pages        = {e0143227},
      year         = {2015},
      abstract     = {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.},
      keywords     = {Amino Acid Sequence / Amino Acid Substitution / Animals /
                      Apoptosis: genetics / Binding Sites / Catalytic Domain /
                      Conserved Sequence / Cysteine: metabolism / Drosophila
                      Proteins: genetics / Drosophila Proteins: metabolism /
                      Drosophila melanogaster: genetics / Drosophila melanogaster:
                      metabolism / Evolution, Molecular / Gene Expression
                      Regulation / Humans / Inhibitor of Apoptosis Proteins:
                      antagonists $\&$ inhibitors / Inhibitor of Apoptosis
                      Proteins: genetics / Inhibitor of Apoptosis Proteins:
                      metabolism / Molecular Sequence Data / Protein Binding /
                      RNA, Small Interfering: genetics / RNA, Small Interfering:
                      metabolism / Sequence Alignment / Sequence Homology, Amino
                      Acid / Serine: metabolism / Ubiquitin: genetics / Ubiquitin:
                      metabolism / Ubiquitin-Specific Proteases: genetics /
                      Ubiquitin-Specific Proteases: metabolism / Ubiquitination /
                      Drosophila Proteins (NLM Chemicals) / Inhibitor of Apoptosis
                      Proteins (NLM Chemicals) / RNA, Small Interfering (NLM
                      Chemicals) / Ubiquitin (NLM Chemicals) / otu protein,
                      Drosophila (NLM Chemicals) / Serine (NLM Chemicals) / OTUD4
                      protein, human (NLM Chemicals) / Ubiquitin-Specific
                      Proteases (NLM Chemicals) / Cysteine (NLM Chemicals)},
      cin          = {AG Brömer 2 / AG Brömer 1},
      ddc          = {610},
      cid          = {I:(DE-2719)1013021 / I:(DE-2719)5000021},
      pnm          = {341 - Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26588485},
      pmc          = {pmc:PMC4654579},
      doi          = {10.1371/journal.pone.0143227},
      url          = {https://pub.dzne.de/record/138234},
}