STRUCTURAL AND FUNCTIONAL STUDIES OF DJ-1

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DJ-1 is a ubiquitously expressed human protein whose absence or inactivation causes early-onset Parkinsonism and whose overabundance has been implicated in certain types of cancer. The biochemical function of DJ-1 is obscure, however it is known to protect cells from oxidative stress, possess a redox-regulated chaperone activity against a-synuclein, is involved in the Akt/PTEN pathway, is involved in transcriptional regulation of many stress-response proteins, and has an indirect role in glutathione metabolism. Some of these protective functions of DJ-1 are regulated by the oxidation of a key conserved cysteine residue (C106) to a cysteine-sulfinic acid, however the mechanism by which oxidation enhances the protective functions of DJ-1 is unknown. We have investigated the redox regulation of DJ-1 function by employing structural and biophysical methods to test the hypothesis that DJ-1 is stabilized by oxidation of C106 to C106-sulfinc acid, but destabilized by further oxidation of C106. Because DJ-1 is subject to regulatory cysteine oxidation and is implicated in multiple human diseases, it is of direct relevance for understanding the role of cellular redox status on cell survival and human health.