Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage.
Mutations in DJ-1 cause recessively transmitted early-onset Parkinson disease (PD), and oxidative damage to DJ-1 has been associated with the pathogenesis of late-onset sporadic PD. The precise biochemical function of DJ-1 remains elusive. Here, we report that DJ-1 is synthesized as a latent protease zymogen with low-intrinsic proteolytic activity. DJ-1 ... protease zymogen is activated by the removal of a 15-amino acid peptide at its C terminus. The activated DJ-1 functions as a cysteine protease with Cys-106 and His-126 as the catalytic diad. We show that endogenous DJ-1 in dopaminergic cells undergoes C-terminal cleavage in response to mild oxidative stress, suggesting that DJ-1 protease activation occurs in a redox-dependent manner. Moreover, we find that the C-terminally cleaved form of DJ-1 with activated protease function exhibits enhanced cytoprotective action against oxidative stress-induced apoptosis. The cytoprotective action of DJ-1 is abolished by the C106A and H126A mutations. Our findings support a role for DJ-1 protease in cellular defense against oxidative stress and have important implications for understanding and treating PD.
Mesh Terms:
Animals, Cell Line, Enzyme Precursors, Humans, Mice, Mice, Knockout, Mutation, Oncogene Proteins, Oxidative Stress, Parkinson Disease, Peptide Hydrolases, Protein Structure, Tertiary
Animals, Cell Line, Enzyme Precursors, Humans, Mice, Mice, Knockout, Mutation, Oncogene Proteins, Oxidative Stress, Parkinson Disease, Peptide Hydrolases, Protein Structure, Tertiary
Hum. Mol. Genet.
Date: Jun. 15, 2010
PubMed ID: 20304780
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