COA6 Is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase in Copper Delivery to Mitochondrial Cytochrome c Oxidase

Cell Rep. 2019 Dec 17;29(12):4114-4126.e5. doi: 10.1016/j.celrep.2019.11.054.


In eukaryotes, cellular respiration is driven by mitochondrial cytochrome c oxidase (CcO), an enzyme complex that requires copper cofactors for its catalytic activity. Insertion of copper into its catalytically active subunits, including COX2, is a complex process that requires metallochaperones and redox proteins including SCO1, SCO2, and COA6, a recently discovered protein whose molecular function is unknown. To uncover the molecular mechanism by which COA6 and SCO proteins mediate copper delivery to COX2, we have solved the solution structure of COA6, which reveals a coiled-coil-helix-coiled-coil-helix domain typical of redox-active proteins found in the mitochondrial inter-membrane space. Accordingly, we demonstrate that COA6 can reduce the copper-coordinating disulfides of its client proteins, SCO1 and COX2, allowing for copper binding. Finally, our determination of the interaction surfaces and reduction potentials of COA6 and its client proteins provides a mechanism of how metallochaperone and disulfide reductase activities are coordinated to deliver copper to CcO.

Keywords: COA6; COX2; Mitochondria; SCO1; SCO2; copper; cytochrome c oxidase; metallochaperone; thiol-disulfide oxidoredcutase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Molecular Chaperones / metabolism
  • Mutation / genetics
  • Protein Binding
  • Protein Disulfide Reductase (Glutathione) / genetics
  • Protein Disulfide Reductase (Glutathione) / metabolism*


  • COA6 protein, human
  • Carrier Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • SCO1 protein, human
  • SCO2 protein, human
  • Protein Disulfide Reductase (Glutathione)
  • Electron Transport Complex IV