The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.
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.
Canet-Avilés
Rosa M
RM
Laboratory of Neurogenetics, National Institute on Aging, 9000 Rockville Pike, Bethesda, MD 20892-1589, USA.
Wilson
Mark A
MA
Miller
David W
DW
Ahmad
Rili
R
McLendon
Chris
C
Bandyopadhyay
Sourav
S
Baptista
Melisa J
MJ
Ringe
Dagmar
D
Petsko
Gregory A
GA
Cookson
Mark R
MR
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
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