Conservation of Oxidative
Protein Stabilization in
an Insect Homologue of Parkinsonism-Associated Protein DJ-1
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Abstract
DJ-1 is a conserved, disease-associated protein that
protects against
oxidative stress and mitochondrial damage in multiple organisms. Human
DJ-1 contains a functionally essential cysteine residue (Cys106) whose
oxidation is important for regulating protein function by an unknown
mechanism. This residue is well-conserved in other DJ-1 homologues,
including two (DJ-1α and DJ-1β) in <i>Drosophila
melanogaster</i>. Because <i>D. melanogaste</i>r is
a powerful model system for studying DJ-1 function, we have determined
the crystal structure and impact of cysteine oxidation on <i>Drosophila</i> DJ-1β. The structure of <i>D. melanogaster</i> DJ-1β is similar to that of human DJ-1, although two important
residues in the human protein, Met26 and His126, are not conserved
in DJ-1β. His126 in human DJ-1 is substituted with a tyrosine
in DJ-1β, and this residue is not able to compose a putative
catalytic dyad with Cys106 that was proposed to be important in the
human protein. The reactive cysteine in DJ-1 is oxidized readily to
the cysteine-sulfinic acid in both flies and humans, and this may
regulate the cytoprotective function of the protein. We show that
the oxidation of this conserved cysteine residue to its sulfinate
form (Cys-SO<sub>2</sub><sup>–</sup>) results in considerable
thermal stabilization of both <i>Drosophila</i> DJ-1β
and human DJ-1. Therefore, protein stabilization is one potential
mechanism by which cysteine oxidation may regulate DJ-1 function in
vivo. More generally, most close DJ-1 homologues are likely stabilized
by cysteine-sulfinic acid formation but destabilized by further oxidation,
suggesting that they are biphasically regulated by oxidative modification