Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site.
Publication Type:Journal Article
Source:J Biol Chem, Volume 292, Issue 29, p.12025-12040 (2017)
Keywords:Amino Acid Substitution, Apoenzymes, Binding Sites, Copper, Crystallography, X-Ray, Cysteine, Cystine, Enzyme Activation, Enzyme Stability, Humans, Ligands, Models, Molecular, Molecular Chaperones, Mutagenesis, Site-Directed, Mutation, Oxidation-Reduction, Protein Conformation, Protein Interaction Domains and Motifs, Protein Processing, Post-Translational, Recombinant Proteins, Saccharomyces cerevisiae Proteins, Superoxide Dismutase
<p>Metallochaperones are a diverse family of trafficking molecules that provide metal ions to protein targets for use as cofactors. The copper chaperone for superoxide dismutase (Ccs1) activates immature copper-zinc superoxide dismutase (Sod1) by delivering copper and facilitating the oxidation of the Sod1 intramolecular disulfide bond. Here, we present structural, spectroscopic, and cell-based data supporting a novel copper-induced mechanism for Sod1 activation. Ccs1 binding exposes an electropositive cavity and proposed "entry site" for copper ion delivery on immature Sod1. Copper-mediated sulfenylation leads to a sulfenic acid intermediate that eventually resolves to form the Sod1 disulfide bond with concomitant release of copper into the Sod1 active site. Sod1 is the predominant disulfide bond-requiring enzyme in the cytoplasm, and this copper-induced mechanism of disulfide bond formation obviates the need for a thiol/disulfide oxidoreductase in that compartment.</p>