A molecular chaperone activity of CCS restores the maturation of SOD1 fALS mutants

Sci Rep. 2017 Dec 12;7(1):17433. doi: 10.1038/s41598-017-17815-y.

Abstract

Superoxide dismutase 1 (SOD1) is an important metalloprotein for cellular oxidative stress defence, that is mutated in familiar variants of Amyotrophic Lateral Sclerosis (fALS). Some mutations destabilize the apo protein, leading to the formation of misfolded, toxic species. The Copper Chaperone for SOD1 (CCS) transiently interacts with SOD1 and promotes its correct maturation by transferring copper and catalyzing disulfide bond formation. By in vitro and in-cell NMR, we investigated the role of the SOD-like domain of CCS (CCS-D2). We showed that CCS-D2 forms a stable complex with zinc-bound SOD1 in human cells, that has a twofold stabilizing effect: it both prevents the accumulation of unstructured mutant SOD1 and promotes zinc binding. We further showed that CCS-D2 interacts with apo-SOD1 in vitro, suggesting that in cells CCS stabilizes mutant apo-SOD1 prior to zinc binding. Such molecular chaperone function of CCS-D2 is novel and its implications in SOD-linked fALS deserve further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Escherichia coli
  • HEK293 Cells
  • Humans
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / metabolism*
  • Mutation*
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Domains
  • Protein Multimerization
  • Protein Stability
  • Proton Magnetic Resonance Spectroscopy
  • Superoxide Dismutase-1 / genetics*
  • Superoxide Dismutase-1 / metabolism*
  • Transfection
  • Zinc / metabolism

Substances

  • CCS protein, human
  • Molecular Chaperones
  • SOD1 protein, human
  • Superoxide Dismutase-1
  • Zinc