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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenylpyridinium / toxicity
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Amino Acid Substitution
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Cell Line, Tumor
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Cysteine / analogs & derivatives*
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Cysteine / chemistry
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Cysteine / genetics
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Cysteine / metabolism*
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Humans
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Intracellular Membranes / metabolism
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Intracellular Signaling Peptides and Proteins
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Mitochondria / metabolism*
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Models, Molecular
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Neuroprotective Agents / metabolism*
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Neurotransmitter Agents
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Oncogene Proteins / chemistry
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Oxidation-Reduction
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Oxidative Stress
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Protein Deglycase DJ-1
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Protein Isoforms
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Static Electricity
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Transfection
Substances
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Intracellular Signaling Peptides and Proteins
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Neuroprotective Agents
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Neurotransmitter Agents
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Oncogene Proteins
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Protein Isoforms
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Recombinant Proteins
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PARK7 protein, human
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Protein Deglycase DJ-1
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Cysteine
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1-Methyl-4-phenylpyridinium
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cysteine sulfinic acid