title: Regulation of A20 and other OTU deubiquitinases by reversible oxidation.
abstract: Protein ubiquitination is a highly versatile post-translational modification that regulates as diverse processes as protein degradation and kinase activation. Deubiquitinases hydrolyse ubiquitin modifications from proteins and are hence key regulators of the ubiquitin system. Ovarian tumour deubiquitinases comprise a family of fourteen human enzymes, many of which regulate cellular signalling pathways. Ovarian tumour deubiquitinases are cysteine proteases that cleave polyubiquitin chains in vitro and in cells, but little is currently known about their regulation. Here we show that ovarian tumour deubiquitinases are susceptible to reversible oxidation of the catalytic cysteine residue. High-resolution crystal structures of the catalytic domain of A20 in four different oxidation states reveal that the reversible form of A20 oxidation is a cysteine sulphenic acid intermediate, which is stabilised by the architecture of the catalytic centre. Using chemical tools to detect sulphenic acid intermediates, we show that many ovarian tumour deubiquitinases undergo reversible oxidation upon treatment with H2O2, revealing a new mechanism to regulate deubiquitinase activity.
authors: Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
authors: Yogesh
authors: Y
authors: Kulathu
authors: Francisco J
authors: FJ
authors: Garcia
authors: Tycho E T
authors: TE
authors: Mevissen
authors: Martin
authors: M
authors: Busch
authors: Nadia
authors: N
authors: Arnaudo
authors: Kate S
authors: KS
authors: Carroll
authors: David
authors: D
authors: Barford
authors: David
authors: D
authors: Komander
mesh_terms: D000595:Amino Acid Sequence; D055162:Biocatalysis / Q000187:drug effects; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology*; D010084:Oxidation-Reduction / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019163:Reducing Agents / Q000494:pharmacology; D013434:Sulfenic Acids / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D019163:Reducing Agents; D013434:Sulfenic Acids; D010450:Endopeptidases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003545:Cysteine