COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase

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-coilhelix 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.Fil: Soma, Shivatheja. Texas A&M University. Department of Biochemistry and Biophysics; United States.Fil: Morgada, Marcos N. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Morgada, Marcos N. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Biológica. Área Biofísica; Argentina.Fil: Naik, Mandar T. Texas A&M University. Department of Biochemistry and Biophysics; United States.Fil: Naik, Mandar T. Brown University. Department of Molecular Pharmacology, Physiology, and Biotechnology; United States.Fil: Boulet, Aren. University of Saskatchewan. Department of Biochemistry, Microbiology and Immunology; Canada.Fil: Roesler, Anna A. University of Saskatchewan. Department of Biochemistry, Microbiology and Immunology; Canada.Fil: Dziuba, Nathaniel. Texas A&M University. Department of Biochemistry and Biophysics; United States.Fil: Ghosh, Alok. Texas A&M University. Department of Biochemistry and Biophysics; United States.Fil: Ghosh, Alok. University of Calcutta. Department of Biochemistry; India.Fil: Yu, Qinhong. University of California. Department of Chemistry; United States.Fil: Lindahl, Paul A. Texas A&M University. Department of Biochemistry and Biophysics; United States.Fil: Lindahl, Paul A. Texas A&M University. Department of Chemistry; United States.Fil: Ames, James B. University of California. Department of Chemistry; United States.Fil: Leary, Scot C. University of Saskatchewan. Department of Biochemistry, Microbiology and Immunology; Canada.Fil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Biológica. Área Biofísica; Argentina.Fil: Gohil, Vishal M. Texas A&M University. Department of Biochemistry and Biophysics; United States