COA6

Cytochrome c oxidase assembly factor 6 is a protein that in humans is encoded by the COA6 gene.[3] 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.[4][5] The COA6 gene encodes an assembly factor for mitochondrial complex IV and is a member of the cytochrome c oxidase subunit 6B family.[3][6] 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.[7] Mutations in this gene result in fatal infantile cardioencephalomyopathy.[6]

COA6
Identifiers
AliasesCOA6, C1orf31, CEMCOX4, cytochrome c oxidase assembly factor 6, MC4DN13
External IDsOMIM: 614772 GeneCards: COA6
Orthologs
SpeciesHumanMouse
Entrez

388753

n/a

Ensembl

ENSG00000168275

n/a

UniProt

Q5JTJ3

n/a

RefSeq (mRNA)

NM_001301733
NM_001012985
NM_001206641

n/a

RefSeq (protein)

NP_001013003
NP_001193570
NP_001288662

n/a

Location (UCSC)Chr 1: 234.37 – 234.39 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Structure

The COA6 gene is located on the q arm of chromosome 1 in position 42.2 and spans 10,612 base pairs.[3] The gene produces a 14.1 kDa protein composed of 125 amino acids.[8][9] The COA6 protein is found a complex with TMEM177, COX20, MT-CO2/COX2, COX18, SCO1 and SCO2.[4][5] 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.[10][11]

Function

The COA6 encodes a protein which is an assembly factor for Complex IV.[3] 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.[10]

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.[4][5] Inheritance of this mutation is autosomal recessive and results in a phenotype of fatal infantile cardioencephalomyopathy due to Complex IV deficiency.[6] Symptoms include hypertrophic cardiomyopathy, left ventricular non-compaction, lactic acidosis, and metabolic hypotonia.[4][5]

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.[7] Additionally, this protein interacts with COA1, SCO1, COX16, TTC19, DTX2, NADSYN1, GABARAP, AIFM1, COX4I1, CD81, COX14, SFXN1, and PLGRKT.[4][5][12]

References
  1. GRCh38: Ensembl release 89: ENSG00000168275 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Entrez Gene: Cytochrome c oxidase assembly factor 6". Retrieved 2018-08-08.
  4. "COA6 - Cytochrome c oxidase assembly factor 6 homolog - Homo sapiens (Human) - COA6 gene & protein". www.uniprot.org. Retrieved 2018-08-07. This article incorporates text available under the CC BY 4.0 license.
  5. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  6. Online Mendelian Inheritance in Man (OMIM): 614772
  7. Pacheu-Grau D, Bareth B, Dudek J, Juris L, Vögtle FN, Wissel M, et al. (June 2015). "Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies". Cell Metabolism. 21 (6): 823–33. doi:10.1016/j.cmet.2015.04.012. PMID 25959673.
  8. 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 (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  9. "COA6 - Cytochrome c oxidase assembly factor 6 homolog". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2018-08-09. Retrieved 2018-08-09.
  10. 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. (2019). "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. doi:10.1016/j.celrep.2019.11.054. PMC 6946597. PMID 31851937.
  11. Maghool, S.; Cooray NDG; Stroud, D. A.; Aragão, D.; Ryan, M. T.; Maher, M. J. (2019). "Structural and functional characterization of the mitochondrial complex IV assembly factor Coa6". Life Science Alliance. 2 (5): e201900458. doi:10.26508/lsa.201900458. PMC 6743065. PMID 31515291.
  12. IntAct. "COA6 interactions". www.ebi.ac.uk. Retrieved 2018-08-08.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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