COA7 (cytochrome c oxidase assembly factor 7; also RESA1/RESpiratory chain Assembly 1, C1orf163, SELRC1) is a metazoan-specific, soluble protein of the mitochondrial intermembrane space that acts as an assembly factor for respiratory chain complex IV (cytochrome c oxidase). It is a ~25 kDa Sel1-like repeat protein (five helix-turn-helix repeats, hcp beta-lactamase family) whose disulfide-rich fold is imported and oxidatively folded in the intermembrane space via the MIA pathway (CHCHD4/MIA40). COA7 is a heme-binding protein with protein-disulfide reductase activity: it reduces the disulfide bonds that form the copper-binding sites of the copper metallochaperones SCO1 and SCO2, regenerating the copper relay that delivers copper to the CuA site of MT-CO2/COX2, and thereby promotes an early step of complex IV assembly following formation of the COX1 module. Loss of COA7 also reduces complex I levels. Recessive loss-of-function variants cause spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), a mitochondrial complex-IV-deficiency disorder with peripheral neuropathy and leukoencephalopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008535 respiratory chain complex IV assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred role in cytochrome c oxidase (complex IV) assembly. This is the core biological process of COA7 and is directly supported by human experimental data (IMP/knockdown). GO:0008535 is the broader parent of the mitochondria-specific GO:0033617 that also carries an IMP; both are correct. Reason: COA7/RESA1 is a well-characterized complex IV assembly factor; the IBA correctly captures the conserved function at a slightly more general level. Supporting Evidence: PMID:24333015 we observe the strongest defects in the assembly of complex IV |
| GO:0015035 protein-disulfide reductase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred protein-disulfide reductase activity, matching the experimentally demonstrated activity of human COA7 (heme-COA7 reduces disulfide bonds in SCO1/SCO2). This is a core molecular function. Reason: Independently supported by direct assay (IDA, PMID:35210360). The reductase acts on the copper-site disulfides of SCO1/SCO2 to regenerate the copper relay for complex IV assembly. Supporting Evidence: PMID:35210360 The heme bound to COA7 has a reduction potential of −353 mV and can reduce the disulfide bonds that compose the copper binding sites in the assembly factors SCO1 and SCO2, enabling regeneration of the copper relay system. |
| GO:0005758 mitochondrial intermembrane space | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred localization/activity in the mitochondrial intermembrane space, consistent with direct experimental evidence that COA7 is a soluble IMS protein imported via the MIA pathway. This is the correct core location. Reason: Directly corroborated by IDA localization data (PMID:24333015, PMID:30885959). Supporting Evidence: PMID:24333015 C1orf163 is a mitochondrial soluble intermembrane space protein |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation from the UniProt Subcellular Location vocabulary (SL-0169, Mitochondrion intermembrane space). Correct and consistent with experimental IDA evidence. Reason: The SubCell mapping matches the curated UniProt location and direct experimental data. Supporting Evidence: file:human/COA7/COA7-uniprot.txt Mitochondrion intermembrane space |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a large-scale binary interactome (HuRI) map. The GO term is uninformative and the reported partners in this screen include many proteins with no plausible intermembrane-space/complex-IV connection (e.g. FGFR3, RAN, GSN, CASP6), likely reflecting high-throughput noise rather than physiological interactions. Reason: "Protein binding" (GO:0005515) conveys no specific function and these are high-throughput Y2H interactions without demonstrated biological relevance to COA7. Retained (not removed) per curation policy for IPI evidence; flagged as over-annotation. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a neurodegeneration-focused interactome screen. Uninformative GO term; the partners reported for COA7 in this dataset are largely unrelated to its IMS complex IV assembly function. Reason: Non-specific GO:0005515 from a high-throughput screen without evidence of physiological relevance to COA7. Retained per policy; flagged as over-annotation. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from the BioPlex affinity-purification/MS interactome. Uninformative GO term; does not add specific functional information beyond a list of co-purifying proteins. Reason: Non-specific GO:0005515 from a high-throughput AP-MS network without demonstrated biological relevance. Retained per policy; flagged as over-annotation. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" derived from multimodal cell-map/proximity data. Uninformative GO term with no specific functional content for COA7. Reason: Non-specific GO:0005515 from a high-throughput cell-mapping study. Retained per policy; flagged as over-annotation. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:24333015 C1orf163/RESA1 is a novel mitochondrial intermembrane space ... | ACCEPT | Summary: Direct mutant-phenotype evidence: knockdown of COA7/C1orf163 reduces OXPHOS complex levels with the strongest defect in complex IV assembly, establishing COA7 as a complex IV assembly factor. This is the core biological process, at the correct mitochondria-specific level. Reason: Well-supported experimental annotation and the central function of the gene. Later work shows COA7 acts early in complex IV assembly (after COX1 module formation) via reduction of SCO1/SCO2 copper-site disulfides. Supporting Evidence: PMID:24333015 The activity of complexes I and IV is reduced in C1orf163-depleted PMID:35210360 acts in the early stages of complex IV assembly |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:35210360 Mitochondrial COA7 is a heme-binding protein with disulfide ... | ACCEPT | Summary: Direct biochemical demonstration that heme-bound COA7 is a protein-disulfide reductase: it reduces the disulfide bonds forming the copper-binding sites of SCO1 and SCO2, regenerating the copper relay to the CuA site of COX2. This is the core molecular function of COA7. Reason: Definitive in vitro reductase assay with a physiologically relevant substrate (SCO1/SCO2), linking the activity directly to complex IV assembly. Supporting Evidence: PMID:35210360 The heme bound to COA7 has a reduction potential of −353 mV and can reduce the disulfide bonds that compose the copper binding sites in the assembly factors SCO1 and SCO2, enabling regeneration of the copper relay system. |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:24333015 C1orf163/RESA1 is a novel mitochondrial intermembrane space ... | ACCEPT | Summary: Direct experimental localization of COA7 as a soluble protein of the mitochondrial intermembrane space. Core cellular component. Reason: Primary experimental evidence establishing the IMS location where COA7 performs its reductase/assembly function. Supporting Evidence: PMID:24333015 C1orf163 is a mitochondrial soluble intermembrane space protein |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput detection of COA7 in a high-confidence human mitochondrial proteome. Correct but less specific than the intermembrane-space localization established by direct experiments. Reason: Accurate but subsumed by the more informative GO:0005758 (mitochondrial intermembrane space) IDA annotations; kept as supporting, non-core localization evidence. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics |
| GO:0005515 protein binding | IPI PMID:30885959 Inhibition of proteasome rescues a pathogenic variant of res... | MARK AS OVER ANNOTATED | Summary: "Protein binding" capturing the interaction between COA7 and CHCHD4/MIA40 (UniProtKB Q8N4Q1). Unlike the other IPI rows, this interaction is physiologically meaningful: MIA40 imports and oxidatively folds COA7 in the IMS via transient intermolecular disulfide bonds. However, the GO term GO:0005515 itself is uninformative and does not convey this oxidoreductase-substrate relationship. Reason: The underlying interaction is real and biologically important (MIA40-mediated import), but "protein binding" is too generic to represent it. Retained (not removed) per curation policy; flagged as over-annotation. A more specific relation (MIA pathway substrate) would be preferable if a suitable term existed. Supporting Evidence: PMID:30885959 COA7 interacts with MIA40 through disulfide bonds PMID:30885959 COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:30885959 Inhibition of proteasome rescues a pathogenic variant of res... | ACCEPT | Summary: Direct experimental localization of COA7 to the mitochondrial intermembrane space, where it accumulates via the MIA/CHCHD4 import pathway. Core cellular component. Reason: Independent IDA confirming the IMS location established by PMID:24333015. Supporting Evidence: PMID:30885959 COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS |
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Download this section (compressed HTML)Q: Is COA7's protein-disulfide reductase activity toward SCO1/SCO2 the sole mechanism by which it promotes complex IV assembly, or does it have additional roles (e.g. in complex I, as suggested by reduced complex I levels on COA7 loss)?
Q: How is COA7 re-reduced after donating electrons to SCO1/SCO2, and does the bound heme cycle redox states in vivo?
Experiment: Structure/function analysis of the COA7 SCAN3 disease variants (e.g. Y137C) to test whether they impair reductase activity, heme binding, or MIA-dependent import, and correlate with residual complex IV activity in patient cells.
Hypothesis: SCAN3 disease variants of COA7 act by impairing reductase activity, heme binding, or MIA-dependent import, reducing residual complex IV activity.
Experiment: Time-resolved complex IV assembly assays in COA7-null cells reconstituted with catalytically dead (reductase-inactive) COA7 to confirm that reductase activity drives the copper-relay step.
Hypothesis: Catalytic (reductase) activity of COA7, not merely its presence, is required for progression of complex IV assembly beyond the COX1 module.
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