Molecular basis of the redox regulation of SUMO proteases: a protective mechanism of intermolecular disulfide linkage against irreversible sulfhydryl oxidation.
Sumoylation has emerged as an indispensable post-translational modification that modulates the functions of a broad spectrum of proteins. Recent studies have demonstrated that reactive oxygen species influence the equilibrium of sumoylation-desumoylation. We show herein that H2O2 induces formation of an intermolecular disulfide linkage of human SUMO protease SENP1 via the active-site Cys 603 and a unique residue Cys 613. Such reversible modification confers a higher recovery of enzyme activity, which is also observed in yeast Ulp1, but not in human SENP2, suggesting its protective role against irreversible sulfhydryl oxidation. In vivo formation of a disulfide-linked dimer of SENP1 is also detected in cultured cells in response to oxidative stress. The modifications are further elucidated by the crystal structures of Ulp1 with the catalytic cysteine oxidized to sulfenic, sulfinic, and sulfonic acids. Our findings suggest that, in addition to SUMO conjugating enzymes, SUMO proteases may act as redox sensors and effectors modulating the desumoylation pathway and specific cellular responses to oxidative stress.
Xu
Zheng
Z
Centre of Protein Science and Crystallography, Department of Biochemistry, Faculty of Science, The Chinese University of Hong Kong, Hong Kong.
Lam
Levina Suk Mi
LS
Lam
Lok Hei
LH
Chau
So Fun
SF
Ng
Tzi Bun
TB
Au
Shannon Wing Ngor
SW
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D019281:Dimerization; D004220:Disulfides / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D047468:Immunoprecipitation; D010084:Oxidation-Reduction; D011480:Protease Inhibitors / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D004220:Disulfides; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases