The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.

TitleThe Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization.
Publication TypeJournal Article
Year of Publication2004
AuthorsCanet-Avilés RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR
JournalProc Natl Acad Sci U S A
Volume101
Issue24
Pagination9103-8
Date Published2004 Jun 15
ISSN0027-8424
Keywords1-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
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.

DOI10.1073/pnas.0402959101
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/15181200?dopt=Abstract
PMCPMC428480
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID15181200