COA6 Is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase in Copper Delivery to Mitochondrial Cytochrome c Oxidase
Shivatheja Soma,
Marcos N. Morgada,
Mandar T. Naik,
Aren Boulet,
Anna A. Roesler,
Nathaniel Dziuba,
Alok Ghosh,
Qinhong Yu,
Paul A. Lindahl,
James B. Ames,
Scot C. Leary,
Alejandro J. Vila,
Vishal M. Gohil
Affiliations
Shivatheja Soma
Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
Marcos N. Morgada
Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Área Biofísica, Departamento de Química Biológica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario (2000), Argentina
Mandar T. Naik
Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
Aren Boulet
Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Anna A. Roesler
Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Nathaniel Dziuba
Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
Alok Ghosh
Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA
Qinhong Yu
Department of Chemistry, University of California, Davis, Davis, CA 95616, USA
Paul A. Lindahl
Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA; Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
James B. Ames
Department of Chemistry, University of California, Davis, Davis, CA 95616, USA
Scot C. Leary
Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Alejandro J. Vila
Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET), Área Biofísica, Departamento de Química Biológica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario (2000), Argentina
Vishal M. Gohil
Department of Biochemistry and Biophysics, MS 3474, Texas A&M University, College Station, TX 77843, USA; Corresponding author
Summary: 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. : Soma et al. reports the solution structure of cytochrome c oxidase assembly factor COA6 and establishes that it functions as a thiol-disulfide oxidoreductase in a relay system that delivers copper to COX2, a copper-containing subunit of the mitochondrial cytochrome c oxidase. Keywords: Mitochondria, cytochrome c oxidase, copper, COA6, SCO1, SCO2, COX2, metallochaperone, thiol-disulfide oxidoredcutase
