COA6

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0015035 protein-disulfide reductase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) propagation of thiol-disulfide oxidoreductase activity. This is directly supported by experimental structural/biochemical work showing COA6 acts as a thiol-disulfide oxidoreductase on SCO1 and COX2 to enable copper binding. Reason: The IBA is corroborated by direct experimental evidence (PMID:31851937) that COA6 exhibits thiol-disulfide oxidoreductase activity toward its client proteins SCO1 and COX2 in the copper-delivery pathway to complex IV. This is the core molecular function of COA6. Supporting Evidence: PMID:31851937 COA6 adopts a coiled-coil-helix-coiled-coil-helix (CHCH) domain, preferentially interacts with SCO1, and exhibits thiol-disulfide oxidoreductase activity both in vitro and in vivo, with SCO1 and COX2 being its client proteins.
GO:0008535 respiratory chain complex IV assembly	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assignment of a role in complex IV assembly, well supported by experimental data across yeast, zebrafish and human cells. Reason: Complex IV assembly is a well-established, experimentally supported role for COA6. This is a valid (if less specific than GO:0033617) BP term; retained as a correct annotation. The more specific mitochondrial term GO:0033617 is the core BP. Supporting Evidence: PMID:24549041 shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) mitochondrial localization. Correct but broad; the informative localization is the intermembrane space (GO:0005758). Reason: COA6 is an evolutionarily conserved mitochondrial protein; mitochondrial localization is well established. Broad but not incorrect. Supporting Evidence: PMID:24549041 we have identified a conserved mitochondrial protein, C1orf31/COA6
GO:0005739 mitochondrion	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic mapping to mitochondrion. Correct but broad. Reason: Consistent with experimental localization data; broad but correct. Supporting Evidence: PMID:24549041 we have identified a conserved mitochondrial protein, C1orf31/COA6
GO:0005758 mitochondrial intermembrane space	IEA GO_REF:0000044	ACCEPT	Summary: UniProt SubCell mapping to mitochondrial intermembrane space, matching the curated experimental subcellular location. Reason: This is the informative, specific localization. COA6 is a twin-CX9C IMS protein imported by the MIA pathway; UniProt records IMS localization from experimental data (PubMed:25339201, 25959673). Supporting Evidence: file:human/COA6/COA6-uniprot.txt Mitochondrion intermembrane space
GO:0008535 respiratory chain complex IV assembly	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic mapping to complex IV assembly, consistent with experimental evidence. Reason: Correct BP; duplicates the experimentally supported assembly role. Core BP is the more specific GO:0033617. Supporting Evidence: PMID:24549041 shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare protein-binding IPI from a high-throughput binary (HuRI) interactome screen, with partners (TTC19, DTX2, CABP2) that are not part of the COX2 copper-delivery module. Reason: Uninformative 'protein binding' term. The interactors reported here (UniProtKB:Q6DKK2 TTC19, Q86UW9 DTX2, Q9NPB3 CABP2) are high-throughput yeast two-hybrid hits with no established role in COA6/complex IV biology and likely represent indirect or non-physiological interactions. Per curation guidelines, bare protein binding is not retained as an informative function. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence localization to mitochondrion. Correct but broad. Reason: Direct immunofluorescence evidence for mitochondrial localization; broad but correct. The specific compartment is the intermembrane space. Supporting Evidence: PMID:24549041 we have identified a conserved mitochondrial protein, C1orf31/COA6
GO:0015035 protein-disulfide reductase activity	IDA PMID:31851937 COA6 Is Structurally Tuned to Function as a Thiol-Disulfide ...	ACCEPT	Summary: Direct experimental demonstration that COA6 has thiol-disulfide oxidoreductase activity toward client proteins SCO1 and COX2, enabling copper binding at the CuA site. This is the core molecular function of COA6. Reason: Structural (NMR) and biochemical evidence show COA6 adopts a CHCH redox fold and reduces the copper-coordinating disulfides of SCO1 and COX2, both in vitro and in vivo. This directly grounds the disulfide-reductase MF and is the mechanistically informative activity of COA6. Supporting Evidence: PMID:31851937 COA6 adopts a coiled-coil-helix-coiled-coil-helix (CHCH) domain, preferentially interacts with SCO1, and exhibits thiol-disulfide oxidoreductase activity both in vitro and in vivo, with SCO1 and COX2 being its client proteins. PMID:31851937 COA6 can reduce the copper-coordinating
GO:0033617 mitochondrial respiratory chain complex IV assembly	IGI PMID:31851937 COA6 Is Structurally Tuned to Function as a Thiol-Disulfide ...	ACCEPT	Summary: Genetic-interaction evidence for a role in mitochondrial complex IV assembly, consistent with COA6's function in the copper-delivery pathway to COX2. Reason: Core biological process. COA6's oxidoreductase/copper-relay activity is required for CuA-site maturation of COX2 during complex IV assembly. Supporting Evidence: PMID:31851937 COA6 and SCO2 act as disulfide reductases during the stepwise transfer of Cu from Cox17 to the CuA site
GO:0033617 mitochondrial respiratory chain complex IV assembly	IMP PMID:24549041 Copper supplementation restores cytochrome c oxidase assembl...	ACCEPT	Summary: Loss-of-function (yeast/zebrafish/human) evidence that COA6 is required for complex IV biogenesis. Core biological process. Reason: COA6 knockdown/knockout impairs respiratory complex IV assembly across species, and copper supplementation rescues the yeast defect, placing COA6 in the copper-delivery pathway for CcO assembly. Supporting Evidence: PMID:24549041 shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells
GO:0033617 mitochondrial respiratory chain complex IV assembly	IMP PMID:25959673 Cooperation between COA6 and SCO2 in COX2 maturation during ...	ACCEPT	Summary: Loss-of-COA6 experiments show it is specifically required for COX2 biogenesis during cytochrome c oxidase assembly. Core biological process. Reason: COA6 is specifically required for COX2 maturation; its absence causes rapid turnover of newly synthesized COX2 and reduced CcO levels, defining COA6 as a constituent of the mitochondrial copper relay system. Supporting Evidence: PMID:25959673 COA6 is specifically required for COX2 biogenesis PMID:25959673 define COA6 as a constituent of the mitochondrial copper relay system, linking defects in COX2 metallation to cardiac cytochrome c oxidase deficiency
GO:0033617 mitochondrial respiratory chain complex IV assembly	IMP PMID:26160915 COA6 is a mitochondrial complex IV assembly factor critical ...	ACCEPT	Summary: COA6 knockout in HEK293T causes complex IV deficiency via impaired COX2 biogenesis and accumulation of assembly intermediates. Core biological process. Reason: Complete loss of COA6 profoundly impairs complex IV biogenesis through defective maturation of the copper-bound COX2 subunit, directly supporting the assembly-factor role. Supporting Evidence: PMID:26160915 caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteome localization to mitochondrion. Correct but broad. Reason: Consistent with all other localization evidence; broad but correct. Supporting Evidence: PMID:34800366 human mitochondrial proteome
GO:0005758 mitochondrial intermembrane space	EXP PMID:25959673 Cooperation between COA6 and SCO2 in COX2 maturation during ...	ACCEPT	Summary: Experimental evidence for intermembrane-space localization. This is the informative, specific subcellular location of COA6. Reason: COA6 is a twin-CX9C IMS protein imported via the MIA pathway; IMS localization is the mechanistically relevant compartment where it engages the COX2 copper-delivery machinery. UniProt curates IMS from this reference. Supporting Evidence: file:human/COA6/COA6-uniprot.txt Mitochondrion intermembrane space
GO:0005515 protein binding	IPI PMID:29381136 COX16 promotes COX2 metallation and assembly during respirat...	MARK AS OVER ANNOTATED	Summary: IPI with COX16 (UniProtKB:Q9P0S2), a COX2 metallation/assembly factor. The interaction is biologically meaningful but the bare 'protein binding' term is uninformative. Reason: The COA6-COX16 interaction is part of the COX2 copper-delivery module, but per curation guidelines the generic 'protein binding' term conveys no functional information; the underlying biology is captured by the complex IV assembly BP and the disulfide-reductase MF. Supporting Evidence: PMID:29381136 Patient mimicking amino acid exchanges in SCO1 and COA6 impact COX16 association with these metallochaperones.
GO:0005515 protein binding	IPI PMID:28330871 Human mitochondrial cytochrome c oxidase assembly factor COX...	MARK AS OVER ANNOTATED	Summary: IPI with COX20 (UniProtKB:Q5RI15), the COX2-specific chaperone. Meaningful module partner but bare 'protein binding' is uninformative. Reason: COA6 interacts with COX20 within the COX2 maturation module; however generic 'protein binding' is not retained as an informative function. The biology is captured by the assembly-factor BP/MF. Supporting Evidence: PMID:28330871 COA6
GO:0005515 protein binding	IPI PMID:29154948 The mitochondrial TMEM177 associates with COX20 during COX2 ...	MARK AS OVER ANNOTATED	Summary: IPI with COX20 (UniProtKB:Q5RI15); COA6 co-isolates with COX20 within the COX2 biogenesis complex. Bare 'protein binding' is uninformative. Reason: COA6 was efficiently co-isolated with COX20 as part of the COX2 maturation module, but generic 'protein binding' is not an informative MF; the assembly role is captured elsewhere. Supporting Evidence: PMID:29154948 as well as COA6 and TMEM177, were efficiently co-isolated with COX20
GO:0005507 copper ion binding	IDA PMID:26160915 COA6 is a mitochondrial complex IV assembly factor critical ...	MARK AS OVER ANNOTATED	Summary: In vitro evidence that COA6 has the capacity to bind copper. Later structural/biochemical work shows COA6 is not a physiological copper-binding protein and instead acts as a disulfide reductase in the copper relay. Reason: PMID:26160915 reported that COA6 "has the capacity to bind copper" in vitro. However, the definitive structural study (PMID:31851937) demonstrated that COA6 is not a Cu-binding protein under physiological conditions and that its activity is independent of metalation state, functioning instead as a thiol-disulfide oxidoreductase. Copper ion binding therefore over-states the physiological function; retained (not removed) as it reflects a real experimental observation, but flagged as over-annotation. Supporting Evidence: PMID:26160915 COA6 has the capacity to bind copper and can associate with newly translated PMID:31851937 We further demonstrate that COA6 is not a Cu-binding protein under physiological conditions and that its enzymatic activity is independent of metalation state.
GO:0008535 respiratory chain complex IV assembly	IDA PMID:25959673 Cooperation between COA6 and SCO2 in COX2 maturation during ...	ACCEPT	Summary: Direct evidence for a role in complex IV (cytochrome c oxidase) assembly via COX2 biogenesis. Core biological process. Reason: COA6 is specifically required for COX2 biogenesis during cytochrome c oxidase assembly; the more specific mitochondrial term GO:0033617 is the core BP. Supporting Evidence: PMID:25959673 COA6 is specifically required for COX2 biogenesis
GO:0008535 respiratory chain complex IV assembly	IDA PMID:26160915 COA6 is a mitochondrial complex IV assembly factor critical ...	ACCEPT	Summary: Direct evidence that COA6 is a complex IV assembly factor critical for COX2 biogenesis. Core biological process. Reason: COA6 loss impairs biogenesis of the copper-bound COX2 subunit and causes accumulation of complex IV assembly intermediates; the more specific term GO:0033617 is the core BP. Supporting Evidence: PMID:26160915 caused by impaired biogenesis of the copper-bound mitochondrial DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly intermediates
GO:0005758 mitochondrial intermembrane space	IDA PMID:25339201 Mutations in COA6 cause cytochrome c oxidase deficiency and ...	ACCEPT	Summary: Direct experimental localization of COA6 to the mitochondrial intermembrane space. Informative, specific subcellular location. Reason: IMS localization is the mechanistically relevant compartment; UniProt curates this location from PubMed:25339201 (full text). This is the specific CC that should be retained as core localization. Supporting Evidence: file:human/COA6/COA6-uniprot.txt Mitochondrion intermembrane space
GO:0008535 respiratory chain complex IV assembly	IMP PMID:24549041 Copper supplementation restores cytochrome c oxidase assembl...	ACCEPT	Summary: Loss-of-function evidence (yeast/zebrafish/human) for a required role in complex IV biogenesis. Core biological process. Reason: COA6 is required for respiratory complex IV biogenesis across species, with copper supplementation rescuing the defect; the more specific mitochondrial term GO:0033617 is the core BP. Supporting Evidence: PMID:24549041 shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells
GO:0005515 protein binding	IPI PMID:26160915 COA6 is a mitochondrial complex IV assembly factor critical ...	MARK AS OVER ANNOTATED	Summary: IPI with SCO1 (UniProtKB:O75880), a copper chaperone and client of COA6's disulfide-reductase activity. Meaningful module partner but bare 'protein binding' is uninformative. Reason: COA6 associates with the copper chaperone SCO1, one of its oxidoreductase clients; however the generic 'protein binding' term is uninformative and the biology is captured by the disulfide-reductase MF and complex IV assembly BP. Supporting Evidence: PMID:26160915 COA6 has the capacity to bind copper and can associate with newly translated COX2 and the mitochondrial copper chaperone SCO1
GO:0005515 protein binding	IPI PMID:25959673 Cooperation between COA6 and SCO2 in COX2 maturation during ...	MARK AS OVER ANNOTATED	Summary: IPI with SCO2 (UniProtKB:O43819) and MT-CO2/COX2 (UniProtKB:P00403), the copper-relay partner and client of COA6. Bare 'protein binding' is uninformative. Reason: COA6 interacts with SCO2 and transiently with the copper-containing catalytic domain of newly synthesized COX2, within the copper relay system; the generic 'protein binding' term is uninformative and the biology is captured by the assembly-factor MF/BP. Supporting Evidence: PMID:25959673 COA6 interacts transiently with the copper-containing catalytic domain of newly synthesized COX2
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	MARK AS OVER ANNOTATED	Summary: RNA binding assigned from a global mRNA-interactome capture screen. No dedicated evidence that COA6 is a bona fide RNA-binding protein or that RNA binding relates to its function. Reason: This annotation derives from a high-throughput mRNA-bound proteome atlas (PMID:22658674). COA6 is a mitochondrial IMS copper-relay/disulfide-reductase complex IV assembly factor with no established RNA-binding role; the term is an over-annotation likely reflecting nonspecific capture. Supporting Evidence: PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
GO:0005739 mitochondrion	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity transfer of mitochondrial localization from mouse ortholog. Correct but broad. Reason: Consistent with experimental localization; broad but correct. Supporting Evidence: PMID:24549041 we have identified a conserved mitochondrial protein, C1orf31/COA6

Gene Description

Existing Annotations Review

Core Functions

Thiol-disulfide oxidoreductase that reduces the copper-coordinating disulfides of its client proteins (the copper chaperone SCO1 and the cytochrome c oxidase subunit MT-CO2/COX2), enabling copper loading during CuA-site metallation.

Acts as a copper-relay/assembly factor in the mitochondrial intermembrane space that mediates copper delivery to and maturation of the mtDNA-encoded subunit MT-CO2/COX2, together with SCO1, SCO2 and COX20, and is thereby required for biogenesis of respiratory chain complex IV (cytochrome c oxidase).

References

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