title: Conservation of oxidative protein stabilization in an insect homologue of parkinsonism-associated protein DJ-1.
abstract: DJ-1 is a conserved, disease-associated protein that protects against oxidative stress and mitochondrial damage in multiple organisms. Human DJ-1 contains a functionally essential cysteine residue (Cys106) whose oxidation is important for regulating protein function by an unknown mechanism. This residue is well-conserved in other DJ-1 homologues, including two (DJ-1α and DJ-1β) in Drosophila melanogaster. Because D. melanogaster is a powerful model system for studying DJ-1 function, we have determined the crystal structure and impact of cysteine oxidation on Drosophila DJ-1β. The structure of D. melanogaster DJ-1β is similar to that of human DJ-1, although two important residues in the human protein, Met26 and His126, are not conserved in DJ-1β. His126 in human DJ-1 is substituted with a tyrosine in DJ-1β, and this residue is not able to compose a putative catalytic dyad with Cys106 that was proposed to be important in the human protein. The reactive cysteine in DJ-1 is oxidized readily to the cysteine-sulfinic acid in both flies and humans, and this may regulate the cytoprotective function of the protein. We show that the oxidation of this conserved cysteine residue to its sulfinate form (Cys-SO(2)(-)) results in considerable thermal stabilization of both Drosophila DJ-1β and human DJ-1. Therefore, protein stabilization is one potential mechanism by which cysteine oxidation may regulate DJ-1 function in vivo. More generally, most close DJ-1 homologues are likely stabilized by cysteine-sulfinic acid formation but destabilized by further oxidation, suggesting that they are biphasically regulated by oxidative modification.
authors.affiliation: Department of Biochemistry and Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA.
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Lin
authors.forename: Janani
authors.initials: J
authors.lastname: Prahlad
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D029721:Drosophila Proteins / Q000737:chemistry*; D004331:Drosophila melanogaster; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D015513:Oncogene Proteins / Q000737:chemistry*; D010084:Oxidation-Reduction; D000071617:Protein Deglycase DJ-1; D055550:Protein Stability
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; C506879:DJ-1beta protein, Drosophila; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D003545:Cysteine; C013461:cysteine sulfinic acid