Copper-zinc superoxide dismutase is activated through a sulfenic acid intermediate at a copper ion entry site

Morgan M. Fetherolf, Stefanie D. Boyd, Alexander B. Taylor, Hee Jong Kim, James A. Wohlschlegel, Ninian J. Blackburn, P. John Hart, Dennis R. Winge, Duane D. Winkler

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12025-12040
Number of pages16
JournalJournal of Biological Chemistry
Volume292
Issue number29
DOIs
StatePublished - Jul 21 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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