COA6 explained

Cytochrome c oxidase assembly factor 6 is a protein that in humans is encoded by the COA6 gene.^[1] 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.^{[2] [3]} The COA6 gene encodes an assembly factor for mitochondrial complex IV and is a member of the cytochrome c oxidase subunit 6B family. This protein is located in the intermembrane space, associating with SCO2 and COX2. It stabilizes newly formed COX2 and is part of the mitochondrial copper relay system.^[4] Mutations in this gene result in fatal infantile cardioencephalomyopathy.

Structure

The COA6 gene is located on the q arm of chromosome 1 in position 42.2 and spans 10,612 base pairs. The gene produces a 14.1 kDa protein composed of 125 amino acids.^{[5] [6]} The COA6 protein is found a complex with TMEM177, COX20, MT-/COX2, COX18, SCO1 and SCO2. The protein has a CX9CXnCX10C motif and a CHCH domain, which hints that the protein is most likely a redox protein rather than a copper metallochaperone.^{[7] [8]}

Function

The COA6 encodes a protein which is an assembly factor for Complex IV. This protein is specifically required for COX2 biogenesis and stability; the absence of this protein will cause fast turnover of newly synthesized COX2.The presence of a CHCH domain facilitates its function as a thiol-disulfide reductant as it facilitates the transfer of copper from SCO1 to COX2.

Clinical Significance

Two mutations have been identified in this protein: W66R and W59C. The latter mutation results in the protein being mistargeted to the mitochondrial matrix, resulting in the loss of interaction with SCO2 and COX2. Inheritance of this mutation is autosomal recessive and results in a phenotype of fatal infantile cardioencephalomyopathy due to Complex IV deficiency. Symptoms include hypertrophic cardiomyopathy, left ventricular non-compaction, lactic acidosis, and metabolic hypotonia.

Interactions

This protein interacts transiently with the copper-containing catalytic domain of newly synthesized COX2 via its C-terminal tail exposed to the intermembrane space. It also interacts selectively with the copper metallochaperone SCO2 in a COX2-dependent manner and with COX20 in a COX2- and COX18-dependent manner. Additionally, this protein interacts with COA1, SCO1, COX16, TTC19, DTX2, NADSYN1, GABARAP, AIFM1, COX4I1, CD81, COX14, SFXN1, and PLGRKT.^[9]

Further reading

• Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA, Goedert JJ, Kirk GD, Gomperts ED, Buchbinder SP, Troyer JL, O'Brien SJ . Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression . PLOS ONE . 5 . 9 . e12862 . September 2010 . 20877624 . 2943476 . 10.1371/journal.pone.0012862 . 2010PLoSO...512862H . free .
• Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, Dimauro S, Thorburn DR, Mootha VK . Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing . Science Translational Medicine . 4 . 118 . 118ra10 . January 2012 . 22277967 . 3523805 . 10.1126/scitranslmed.3003310 .
• Szklarczyk R, Wanschers BF, Cuypers TD, Esseling JJ, Riemersma M, van den Brand MA, Gloerich J, Lasonder E, van den Heuvel LP, Nijtmans LG, Huynen MA . Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase . Genome Biology . 13 . 2 . R12 . February 2012 . 22356826 . 3334569 . 10.1186/gb-2012-13-2-r12 . free .
• Szklarczyk R, Wanschers BF, Cuypers TD, Esseling JJ, Riemersma M, van den Brand MA, Gloerich J, Lasonder E, van den Heuvel LP, Nijtmans LG, Huynen MA . Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase . Genome Biology . 13 . 2 . R12 . February 2012 . 22356826 . 3334569 . 10.1186/gb-2012-13-2-r12 . free .
• 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 . COA6 Is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase in Copper Delivery to Mitochondrial Cytochrome C Oxidase. Cell Reports . 29 . 12 . 4114–26 . December 2019 . 31851937 . 6946597 . 10.1016/j.celrep.2019.11.054.
• Shadi Maghool . N Dinesha G Cooray . David A Stroud . David Aragão . Michael T Ryan . Megan J Maher. Structural and Functional Characterization of the Mitochondrial Complex IV Assembly Factor Coa6. Life Sci Alliance. 2 . 5. September 2019 . e201900458 . 10.26508/lsa.201900458. 31515291 . 6743065 .
• Pacheu-Grau D, Bareth B, Dudek J, Juris L, Vögtle 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 Metabolism . 21 . 6 . 823–33 . June 2015 . 25959673 . 10.1016/j.cmet.2015.04.012 . free .

Notes and References

1. Web site: Entrez Gene: Cytochrome c oxidase assembly factor 6. 2018-08-08.
2. Web site: COA6 - Cytochrome c oxidase assembly factor 6 homolog - Homo sapiens (Human) - COA6 gene & protein. www.uniprot.org. en. 2018-08-07.
3. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
4. Pacheu-Grau D, Bareth B, Dudek J, Juris L, Vögtle FN, Wissel M, Leary SC, Dennerlein S, Rehling P, Deckers M . 6 . Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies . Cell Metabolism . 21 . 6 . 823–33 . June 2015 . 25959673 . 10.1016/j.cmet.2015.04.012 . free .
5. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
6. Web site: COA6 - Cytochrome c oxidase assembly factor 6 homolog. Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 2018-08-09. https://web.archive.org/web/20180809025439/https://amino.heartproteome.org/web/protein/Q5JTJ3. 2018-08-09. dead.
7. 31851937 . 2019 . Soma . S. . Morgada . M. N. . Naik . M. T. . Boulet . A. . Roesler . A. A. . Dziuba . N. . Ghosh . A. . Yu . Q. . Lindahl . P. A. . Ames . J. B. . Leary . S. C. . Vila . A. J. . Gohil . V. M. . COA6 is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase in Copper Delivery to Mitochondrial Cytochrome c Oxidase . Cell Reports . 29 . 12 . 4114–4126.e5 . 10.1016/j.celrep.2019.11.054 . 6946597 .
8. 31515291 . 2019 . Maghool . S. . Cooray NDG . Stroud . D. A. . Aragão . D. . Ryan . M. T. . Maher . M. J. . Structural and functional characterization of the mitochondrial complex IV assembly factor Coa6 . Life Science Alliance . 2 . 5 . e201900458 . 10.26508/lsa.201900458 . 6743065 .
9. Web site: COA6 interactions. IntAct. www.ebi.ac.uk. en. 2018-08-08.