The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.
|Title||The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.|
|Publication Type||Journal Article|
|Year of Publication||2004|
|Authors||Canet-Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR|
|Journal||Proc Natl Acad Sci U S A|
|Date Published||2004 Jun 15|
|Keywords||1-Methyl-4-phenylpyridinium, Amino Acid Substitution, Cell Line, Tumor, Cysteine, Humans, Intracellular Membranes, Intracellular Signaling Peptides and Proteins, Mitochondria, Models, Molecular, Neuroprotective Agents, Neurotransmitter Agents, Oncogene Proteins, Oxidation-Reduction, Oxidative Stress, Protein Isoforms, Recombinant Proteins, Static Electricity, Transfection|
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.
|Alternate Title||Proc. Natl. Acad. Sci. U.S.A.|