Oxygen-induced maturation of SOD1: A key role for disulfide formation by the copper chaperone CCS

Yoshiaki Furukawa, Andrew S. Torres, Thomas V. O'Halloran

Research output: Contribution to journalArticle

246 Citations (Scopus)

Abstract

The antioxidant enzyme Cu,Zn-superoxide dismutase (SOD1) has the distinction of being one of the most abundant disulfide-containing protein known in the eukaryotic cytosol; however, neither catalytic nor physiological roles for the conserved disulfide are known. Here we show that the disulfide status of Saccharomyces cerevisiae SOD1 significantly affects the monomer-dimer equilibrium, the interaction with the copper chaperone CCS, and the activity of the enzyme itself. Disulfide formation in SOD1 by O2 is slow but is greatly accelerated by the Cubound form of CCS (Cu-CCS) in vivo and in vitro even in the presence of excess reductants; once formed, this disulfide is kinetically stable. Biochemical assays reveal that Cu-CCS facilitates Cys oxidation and disulfide isomerization in the stepwise conversion of the immature form of the enzyme to the active state. The immature form of SOD1 is most susceptible to oxidative insult and to aggregation reminiscent of that observed in amyotrophic lateral sclerosis. Thus Cu-CCS mediation of correct disulfide formation in SOD1 is important for regulation of enzyme activity and for prevention of misfolding or aggregation.

Original languageEnglish
Pages (from-to)2872-2881
Number of pages10
JournalEMBO Journal
Volume23
Issue number14
DOIs
Publication statusPublished - 2004 Jul 21
Externally publishedYes

Fingerprint

Disulfides
Copper
Oxygen
Enzymes
Agglomeration
Reducing Agents
Amyotrophic Lateral Sclerosis
Enzyme activity
Isomerization
Dimers
Cytosol
Yeast
Saccharomyces cerevisiae
Assays
Antioxidants
Monomers
Oxidation
Proteins

Keywords

  • Copper chaperone
  • Disulfide bond
  • fALS
  • Oxidative stress
  • Superoxide dismutase

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Oxygen-induced maturation of SOD1 : A key role for disulfide formation by the copper chaperone CCS. / Furukawa, Yoshiaki; Torres, Andrew S.; O'Halloran, Thomas V.

In: EMBO Journal, Vol. 23, No. 14, 21.07.2004, p. 2872-2881.

Research output: Contribution to journalArticle

Furukawa, Yoshiaki ; Torres, Andrew S. ; O'Halloran, Thomas V. / Oxygen-induced maturation of SOD1 : A key role for disulfide formation by the copper chaperone CCS. In: EMBO Journal. 2004 ; Vol. 23, No. 14. pp. 2872-2881.
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