title: The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.
abstract: Loss-of-function DJ-1 mutations can cause early-onset Parkinson's disease. The function of DJ-1 is unknown, but an acidic isoform accumulates after oxidative stress, leading to the suggestion that DJ-1 is protective under these conditions. We addressed whether this represents a posttranslational modification at cysteine residues by systematically mutating cysteine residues in human DJ-1. WT or C53A DJ-1 was readily oxidized in cultured cells, generating a pI 5.8 isoform, but an artificial C106A mutant was not. We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46. Oxidation of DJ-1 was promoted by the crystallization procedure. In addition, oxidation-induced mitochondrial relocalization of DJ-1 and protection against cell death were abrogated in C106A but not C53A or C46A. We suggest that DJ-1 protects against neuronal death, and that this is signaled by acidification of the key cysteine residue, C106.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, 9000 Rockville Pike, Bethesda, MD 20892-1589, USA.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Canet-Avilés
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.forename: David W
authors.initials: DW
authors.lastname: Miller
authors.forename: Rili
authors.initials: R
authors.lastname: Ahmad
authors.forename: Chris
authors.initials: C
authors.lastname: McLendon
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Baptista
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000378:metabolism*; D018377:Neurotransmitter Agents; D015513:Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D000071617:Protein Deglycase DJ-1; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D015513:Oncogene Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D003545:Cysteine; D015655:1-Methyl-4-phenylpyridinium; C013461:cysteine sulfinic acid