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Review
. 2011 Jul 1;15(1):111-22.
doi: 10.1089/ars.2010.3481. Epub 2011 Jan 14.

The role of cysteine oxidation in DJ-1 function and dysfunction

Mark A Wilson  1
Affiliations
Review

The role of cysteine oxidation in DJ-1 function and dysfunction

Mark A Wilson. Antioxid Redox Signal. .

Abstract

DJ-1 is a member of the large and functionally diverse DJ-1/PfpI superfamily and has homologs in nearly all organisms. Because of its connection to parkinsonism and cancer, human DJ-1 has been intensely studied for over a decade. The current view is that DJ-1 is a multifunctional oxidative stress response protein that defends cells against reactive oxygen species and mitochondrial damage, although the details of its biochemical function remain unclear. A conserved cysteine residue in DJ-1 (Cys106) is both functionally essential and subject to oxidation to the cysteine-sulfinate and cysteine-sulfonate. Consequently, the oxidative modification of Cys106 has been proposed to allow DJ-1 to act as a sensor of cellular redox homeostasis and to participate in cytoprotective signaling pathways in the cell. This review explores the current evidence for the role of cysteine oxidation in DJ-1 function, with emphasis on emerging models for how oxidative modification may regulate DJ-1's protective function and also contribute to dysfunction and disease.

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Figures

FIG. 1.
FIG. 1.
A divergent-eye stereo view of the DJ-1 dimer. A ribbon diagram of dimeric DJ-1 is shown with the molecular twofold axis perpendicular to the plane of the page. One monomer is shown in gold and the other in blue. The three cysteine residues in DJ-1 are shown in stick representation, although Cys46 is partially obscured in this view. Cys106 resides at the bottom of a prominent surface grove and is situated at the sharp turn between a strand and helix that is called the “nucleophile elbow.” Cys106 is the only functionally essential cysteine residue in DJ-1. C, carboxy terminus; N, amino terminus.
FIG. 2.
FIG. 2.
Two views of the stable Cys106-sulfinate oxidized form of DJ-1. In (A), the region around Cys106 from the crystal structure of Cys106-sulfinate DJ-1 (opaque; PDB accession code 1SOA) is superimposed over the structure of reduced DJ-1 (semitransparent; PDB accession code 1P5F). Stabilizing hydrogen bonds between the Cys106-SO2− and surrounding residues are shown in dashed lines, with the key interaction between Glu18 and Cys106-SO2− labeled. Oxidation of Cys106 occurs very readily and alters the function of the protein, but does not result in any notable structural change. In (B), the lengths of the key hydrogen bonds are shown, emphasizing the unusually short and strong hydrogen bond between Cys106-SO2− and the protonated carboxylate of Glu18. This interaction plays an important role in stabilizing the oxidized form of the protein.
FIG. 3.
FIG. 3.
Aspartate is not a good structural mimic for cysteine-sulfinate. In both panels, all atoms are labeled. (A) A stick representation of cysteine-sulfinate, illustrating that the lone pair of electrons on the Sγ atom results in a bent geometry for the oxygen atoms (Oδ1 and Oδ2) in relation to the sulfur atom. (B) The different electronic configuration of the Cγ atom in aspartate results in sp2 hybridization and a planar arrangement of the oxygen atoms with Cγ atom. This geometric difference prevents aspartate from satisfying the same set of hydrogen bonds that are made by Cys106-SO2− (Fig. 2), which may help explain why the C106D DJ-1 mutant is not functional.
FIG. 4.
FIG. 4.
His126 may sterically impede oxidation of Cys106 to the sulfonate. A hypothetical model of the Cys106-sulfonate was built using the crystal structure of DJ-1 Cys106-sulfinate (PDB accession code 1SOA) as the starting model. Stabilizing hydrogen bonds between the Cys106-SO3− and surrounding residues are shown in dashed black lines, with lengths given in angstroms (Å). The 2.4 Å clash between His126 and an oxygen atom of Cys106-SO3− is shown with a red dashed line. This steric clash may disfavor formation of the Cys106-sulfonate and cause conformational changes in Cys106-SO3− DJ-1.
FIG. 5.
FIG. 5.
A schema of the current evidence for various roles of the major oxidized forms of DJ-1. A question mark is used to indicate unresolved aspects of the current set of proposals for DJ-1 function.
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