COA6

COA6
Identifiers
Aliases	COA6 , C1orf31, CEMCOX4, cytochrome c oxidase assembly factor 6, MC4DN13
External IDs	OMIM: 614772 GeneCards: COA6
Gene location (Human)
Chr.	Chromosome 1 (human)
End	234,385,080 bp
RNA expression pattern
	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;
	n/a
	More reference expression data
	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
	388753
	n/a
	ENSG00000168275
	n/a
	Q5JTJ3
	n/a
	NM_001301733 ; NM_001012985 ; NM_001206641
	n/a
	NP_001013003 ; NP_001193570 ; NP_001288662
	n/a
	Wikidata
View/Edit Human

Last updated July 26, 2023

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]

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]

Related Research Articles

The enzyme cytochrome c oxidase or Complex IV, is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.

Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that is encoded by the MT-CO1 gene in eukaryotes. The gene is also called COX1, CO1, or COI. Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. In humans, mutations in MT-CO1 have been associated with Leber's hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia, Complex IV deficiency, colorectal cancer, sensorineural deafness, and recurrent myoglobinuria.

Cytochrome c oxidase II is a protein in eukaryotes that is encoded by the MT-CO2 gene. Cytochrome c oxidase subunit II, abbreviated COXII, COX2, COII, or MT-CO2, is the second subunit of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits of respiratory complex IV.

Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene. The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex, which is involved in the regulation of cytochrome c oxidase assembly. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).

SCO2 cytochrome c oxidase assembly is a protein that in humans is encoded by the SCO2 gene. The encoded protein is one of the cytochrome c oxidase (COX)(Complex IV) assembly factors. Human COX is a multimeric protein complex that requires several assembly factors. Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6.

Protein SCO1 homolog, mitochondrial, also known as SCO1, cytochrome c oxidase assembly protein, is a protein that in humans is encoded by the SCO1 gene. SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable, as well as to tissues with high levels of oxidative phosphorylation. The expression of SCO2 is also much higher than that of SCO1 in muscle tissue, while SCO1 is expressed at higher levels in liver tissue than SCO2. Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific cytochrome c oxidase deficiency.

Cytochrome c oxidase copper chaperone is a protein that in humans is encoded by the COX17 gene.

Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) is an enzyme that in humans is encoded by the COX4I1 gene. COX4I1 is a nuclear-encoded isoform of cytochrome c oxidase (COX) subunit 4. Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Antibodies against COX4 can be used to identify the inner membrane of mitochondria in immunofluorescence studies. Mutations in COX4I1 have been associated with COX deficiency and Fanconi anemia.

Cytochrome c oxidase subunit 4 isoform 2, mitochondrial is an enzyme that in humans is encoded by the COX4I2 gene. COX4I2 is a nuclear-encoded isoform of cytochrome c oxidase (COX) subunit 4. Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Mutations in COX4I2 have been associated with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (EPIDACH).

Cytochrome c oxidase subunit 6B1 is an enzyme that in humans is encoded by the COX6B1 gene. Cytochrome c oxidase 6B1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. Mutations of the COX6B1 gene are associated with severe infantile encephalomyopathy and mitochondrial complex IV deficiency (MT-C4D).

Protoheme IX farnesyltransferase, mitochondrial is an enzyme that in humans is encoded by the COX10 gene. Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene, COX10, encodes heme A: farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A duplication and with HNPP deletion.

Cytochrome c oxidase subunit 7B, mitochondrial (COX7B) is an enzyme that in humans is encoded by the COX7B gene. COX7B is a nuclear-encoded subunit of cytochrome c oxidase (COX). Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Work with Oryzias latices has linked disruptions in COX7B with microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Clinically, mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies.

Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the COX15 gene. This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis. COX15 is also part of a three-component mono-oxygenase that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule. Mutations in this gene has been reported in patients with hypertrophic cardiomyopathy as well as Leigh syndrome, and characterized by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs.

Cytochrome c oxidase subunit 5a is a protein that in humans is encoded by the COX5A gene. Cytochrome c oxidase 5A is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

Cytochrome c oxidase assembly factor 3, also known as Coiled-coil domain-containing protein 56, or Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 12 kDa is a protein that in humans is encoded by the COA3 gene. This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function.

Cytochrome c oxidase assembly factor 5 is a protein that in humans is encoded by the COA5 gene. This gene encodes an ortholog of yeast Pet191, which in yeast is a subunit of a large oligomeric complex associated with the mitochondrial inner membrane, and required for the assembly of the cytochrome c oxidase complex. Mutations in this gene are associated with mitochondrial complex IV deficiency.

Cytochrome c oxidase assembly factor COX14 is a protein that in humans is encoded by the COX14 gene. This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants.

Cytochrome c oxidase assembly factor 7 (putative) (COA7), also known as Beta-lactamase hap-like protein, Respiratory chain assembly factor 1 (RESA1), Sel1 repeat-containing protein 1 (SELRC1), or C1orf163 is a protein that in humans is encoded by the COA7 gene. The protein encoded by COA7 is an assembly factor important for the mitochondrial respiratory chain. Mutations in COA7 have been associated with cytochrome c oxidase deficiency resulting in spinocerebellar ataxia with axonal neuropathy type 3 and mitochondrial myopathy.

Cytochrome c oxidase assembly factor COX20 is a protein that in humans is encoded by the COX20 gene. This gene encodes a protein that plays a role in the assembly of cytochrome c oxidase, an important component of the respiratory pathway. Mutations in this gene can cause mitochondrial complex IV deficiency. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants.

PET100 homolog is a protein that in humans is encoded by the PET100 gene. Mitochondrial complex IV, or cytochrome c oxidase, is a large transmembrane protein complex that is part of the respiratory electron transport chain of mitochondria. The small protein encoded by the PET100 gene plays a role in the biogenesis of mitochondrial complex IV. This protein localizes to the inner mitochondrial membrane and is exposed to the intermembrane space. Mutations in this gene are associated with mitochondrial complex IV deficiency. This gene has a pseudogene on chromosome 3. Alternative splicing results in multiple transcript variants.

References

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1 2 3 Online Mendelian Inheritance in Man (OMIM): 614772
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