Copper-Zinc Superoxide Dismutase Is Activated through a Sulfenic Acid Intermediate at a Copper Ion Entry Site


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.



Molecular chaperones, Cytology, Enzymes, Metal ions, Metals, Oxygen, Sulfur compounds, Zinc, Oxidoreductases, Superoxide dismutase, Copper, Copper ions, Cysteine, Oxidoreductases, Sulfenic acids, Superoxide dismutase, Apoenzymes, Ccs1 protein, s cerevisiae, Cystine, Ligands, Lys7 protein, S cerevisiae, Recombinant Proteins, Saccharomyces cerevisiae, Cytoplasm, Enzyme activation, Ion Transport, Protein protein interactions, Spectrum analysis, Structure-activity relationships (Biochemistry), Amino Acid Substitution, Binding Sites, Chemistry, Enzyme Stability, Genetics, Humans, Metabolism, Models, Molecular, Mutation, Oxidation -Reduction, Protein Conformation, Protein Domains, Mutagenesis, Site-Directed, Crystallography, X-Ray

This work was supported in part by National Institutes of Health Grants R01 GM110755, R01 GM054803, R01 NS39112, R01 GM112763, and R01 GM120252; United States Department of Veterans Affairs Merit Review Award I01 BX002580; National Institutes of Health Grant P41 GM103403 and United States Department of Energy Grant DE-AC02-06CH11357; San Antonio Cancer Institute Grant P30 CA054174; United States Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-76SF00515;


© 2017, American Society for Biochemistry and Molecular Biology Inc. All rights reserved.