| Structural highlights
Disease
[COA6_HUMAN] Fatal infantile cytochrome C oxidase deficiency. The disease is caused by mutations affecting the gene represented in this entry.
Function
[COA6_HUMAN] Involved in the maturation of the mitochondrial respiratory chain complex IV subunit MT-CO2/COX2. Thereby, may regulate early steps of complex IV assembly. Mitochondrial respiratory chain complex IV or cytochrome c oxidase is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. May also be required for efficient formation of respiratory supercomplexes comprised of complexes III and IV.[1] [2] [3]
Publication Abstract from PubMed
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.
COA6 Is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase in Copper Delivery to Mitochondrial Cytochrome c Oxidase.,Soma S, Morgada MN, Naik MT, Boulet A, Roesler AA, Dziuba N, Ghosh A, Yu Q, Lindahl PA, Ames JB, Leary SC, Vila AJ, Gohil VM Cell Rep. 2019 Dec 17;29(12):4114-4126.e5. doi: 10.1016/j.celrep.2019.11.054. PMID:31851937[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ghosh A, Trivedi PP, Timbalia SA, Griffin AT, Rahn JJ, Chan SS, Gohil VM. Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency. Hum Mol Genet. 2014 Jul 1;23(13):3596-606. doi: 10.1093/hmg/ddu069. Epub 2014 Feb, 18. PMID:24549041 doi:http://dx.doi.org/10.1093/hmg/ddu069
- ↑ Pacheu-Grau D, Bareth B, Dudek J, Juris L, Vogtle FN, Wissel M, Leary SC, Dennerlein S, Rehling P, Deckers M. Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies. Cell Metab. 2015 Jun 2;21(6):823-33. doi: 10.1016/j.cmet.2015.04.012. Epub 2015, May 7. PMID:25959673 doi:http://dx.doi.org/10.1016/j.cmet.2015.04.012
- ↑ Stroud DA, Maher MJ, Lindau C, Vogtle FN, Frazier AE, Surgenor E, Mountford H, Singh AP, Bonas M, Oeljeklaus S, Warscheid B, Meisinger C, Thorburn DR, Ryan MT. COA6 is a mitochondrial complex IV assembly factor critical for biogenesis of mtDNA-encoded COX2. Hum Mol Genet. 2015 Oct 1;24(19):5404-15. doi: 10.1093/hmg/ddv265. Epub 2015 Jul , 9. PMID:26160915 doi:http://dx.doi.org/10.1093/hmg/ddv265
- ↑ Soma S, Morgada MN, Naik MT, Boulet A, Roesler AA, Dziuba N, Ghosh A, Yu Q, Lindahl PA, Ames JB, Leary SC, Vila AJ, Gohil VM. 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. PMID:31851937 doi:http://dx.doi.org/10.1016/j.celrep.2019.11.054
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