1. Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site
- Author
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Fetherolf, Morgan M, Boyd, Stefanie D, Taylor, Alexander B, Kim, Hee Jong, Wohlschlegel, James A, Blackburn, Ninian J, Hart, P John, Winge, Dennis R, and Winkler, Duane D
- Subjects
Biochemistry and Cell Biology ,Chemical Sciences ,Biological Sciences ,2.1 Biological and endogenous factors ,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 ,X-ray crystallography ,chaperone ,copper ,enzyme activation ,metalloenzyme ,superoxide dismutase ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
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.
- Published
- 2017