Cytochrome c oxidase assembly factor 6 is a protein that in humans is encoded by the COA6 gene.^[5] 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.^[6][7] The COA6 gene encodes an assembly factor for mitochondrial complex IV and is a member of the cytochrome c oxidase subunit 6B family.^[5][8] 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.^[9] Mutations in this gene result in fatal infantile cardioencephalomyopathy.^[8]

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COA6
Identifiers
Aliases	COA6, C1orf31, CEMCOX4, cytochrome c oxidase assembly factor 6, MC4DN13
External IDs	OMIM: 614772; MGI: 1915142; GeneCards: COA6; OMA:COA6 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q42.2 Start 234,373,456 bp[1] End 234,385,080 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 E2 Start 127,149,254 bp[2] End 127,152,172 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle putamen deltoid muscle caudate nucleus quadriceps femoris muscle vastus lateralis muscle nucleus accumbens Brodmann area 9 cingulate gyrus prefrontal cortex Top expressed in atrioventricular valve endocardial cushion proximal tubule medullary collecting duct kidney intercostal muscle left lobe of liver fossa renal corpuscle facial motor nucleus More reference expression data BioGPS n/a
Gene ontology Molecular function copper ion binding protein binding RNA binding Cellular component mitochondrial intermembrane space mitochondrion plasma membrane Biological process plasma membrane ATP synthesis coupled electron transport respiratory chain complex IV assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 388753 67892 Ensembl ENSG00000168275 ENSMUSG00000051671 UniProt Q5JTJ3 Q8BGD8 RefSeq (mRNA) NM_001301733 NM_001012985 NM_001206641 NM_174987 RefSeq (protein) NP_001013003 NP_001193570 NP_001288662 NP_778152 Location (UCSC) Chr 1: 234.37 – 234.39 Mb Chr 8: 127.15 – 127.15 Mb PubMed search [3] [4]
Wikidata
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The COA6 gene is located on the q arm of chromosome 1 in position 42.2 and spans 10,612 base pairs.^[5] The gene produces a 14.1 kDa protein composed of 125 amino acids.^[10][11] The COA6 protein is found a complex with TMEM177, COX20, MT-CO₂/COX2, COX18, SCO1 and SCO2.^[6][7] 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.^[12][13]

The COA6 encodes a protein which is an assembly factor for Complex IV.^[5] 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.^[12]

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.^[6][7] Inheritance of this mutation is autosomal recessive and results in a phenotype of fatal infantile cardioencephalomyopathy due to Complex IV deficiency.^[8] Symptoms include hypertrophic cardiomyopathy, left ventricular non-compaction, lactic acidosis, and metabolic hypotonia.^[6][7]

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.^[9] Additionally, this protein interacts with COA1, SCO1, COX16, TTC19, DTX2, NADSYN1, GABARAP, AIFM1, COX4I1, CD81, COX14, SFXN1, and PLGRKT.^[6][7][14]