Increased affinity for copper mediated by cysteine 111 in forms of mutant superoxide dismutase 1 linked to amyotrophic lateral sclerosis

Shohei Watanabe, Seiichi Nagano, James Duce, Mahmoud Kiaei, Qiao Xin Li, Stephanie M. Tucker, Ashutosh Tiwari, Robert H. Brown, M. Flint Beal, Lawrence J. Hayward, Valeria C. Culotta, Satoshi Yoshihara, Saburo Sakoda, Ashley I. Bush

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in Cu,Zn-superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (ALS). It has been proposed that neuronal cell death might occur due to inappropriately increased Cu interaction with mutant SOD1. Using Cu immobilized metal-affinity chromatography (IMAC), we showed that mutant SOD1 (A4V, G85R, and G93A) expressed in transfected COS7 cells, transgenic mouse spinal cord tissue, and transformed yeast possessed higher affinity for Cu than wild-type SOD1. Serine substitution for cysteine at the Cys111 residue in mutant SOD1 abolished the Cu interaction on IMAC. C111S substitution reversed the accelerated degradation of mutant SOD1 in transfected cells, suggesting that the Cys111 residue is critical for the stability of mutant SOD1. Aberrant Cu binding at the Cys111 residue may be a significant factor in altering mutant SOD1 behavior and may explain the benefit of controlling Cu access to mutant SOD1 in models of familial ALS.

Original languageEnglish (US)
Pages (from-to)1534-1542
Number of pages9
JournalFree Radical Biology and Medicine
Volume42
Issue number10
DOIs
StatePublished - May 15 2007

Keywords

  • Amyotrophic lateral sclerosis
  • Copper
  • Cu chaperone for SOD1
  • Cu,Zn-superoxide dismutase
  • Cysteine
  • Free radicals
  • Immobilized metal affinity chromatography
  • Oxidative stress
  • Protein stability

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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