COA3 (also known as CCDC56 and MITRAC12) is a small (106 aa) single-pass mitochondrial inner-membrane protein that acts as a non-catalytic assembly factor for respiratory chain complex IV (cytochrome c oxidase). Together with COX14 it is a core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) complex, which couples translation of the mitochondrially encoded catalytic subunit MT-CO1 (COX1) to complex IV assembly. COA3 associates with newly synthesised MT-CO1 within an early COX1-COA3-COX14 assembly intermediate, stabilises it, and coordinates the incorporation of nuclear-encoded subunits. It has no catalytic activity of its own. Biallelic loss-of-function variants cause mitochondrial complex IV deficiency (nuclear type 14, MC4DN14), presenting with neuropathy, encephalopathy, exercise intolerance, obesity, and short stature.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to complex IV assembly, the central and best-supported biological role of COA3 as a MITRAC assembly factor. Reason: This is the core evolved function of COA3, supported by experimental evidence in human cells (MITRAC characterisation and the early COX1-COA3-COX14 assembly intermediate) and consistent across the COA3 family. Supporting Evidence: PMID:28082314 CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 file:human/COA3/COA3-uniprot.txt Required for efficient translation of MT-CO1 and mitochondrial |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing COA3 at the mitochondrial inner membrane, where it functions as a single-pass membrane assembly factor. Reason: Directly matches the experimentally determined subcellular localisation and membrane topology of COA3; is_active_in correctly conveys that COA3 carries out its assembly-factor role at this location. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation to mitochondrial inner membrane derived from the UniProt Subcellular Location vocabulary mapping. Reason: Consistent with the experimentally curated inner-membrane localisation; this IEA mapping is correct and appropriately specific. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0006457 protein folding | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Electronic inter-ontology inference of the biological process 'protein folding' from the 'protein folding chaperone' molecular function annotation. Reason: COA3 is best described as a complex IV assembly factor that stabilises newly synthesised MT-CO1 rather than a bona fide protein-folding catalyst; the generic 'protein folding' BP over-states this and is redundant with the more informative complex IV assembly process. The chaperone-type activity is captured by the GO:0044183 molecular-function annotation. Supporting Evidence: PMID:28082314 CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation mapping the Coa3 domain (IPR041752) to complex IV assembly. Reason: The InterPro-to-GO mapping is correct and corresponds to the experimentally supported core function of COA3. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Required for efficient translation of MT-CO1 and mitochondrial |
| GO:0005515 protein binding | IPI PMID:23260140 MITRAC links mitochondrial protein translocation to respirat... | MARK AS OVER ANNOTATED | Summary: IntAct binary interaction annotations (MT-CO1/P00395 and SURF1/Q15526) recorded as the uninformative 'protein binding' molecular function. Reason: The underlying interactions with MT-CO1 and SURF1 are real and biologically meaningful (they underpin COA3's role in the MITRAC assembly intermediate), but the bare 'protein binding' term is uninformative about molecular function. Not removed per curation policy for experimental IPI annotations; the interaction partners are better represented in the assembly-factor core function. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Along with COX14, core component of the MITRAC (mitochondrial |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence-based direct assay localising COA3 to the mitochondrion. Reason: Correct but less specific than the inner-membrane localisation; retained as a valid direct-assay observation of mitochondrial localisation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:28082314 A CMC1-knockout reveals translation-independent control of h... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence that COA3 participates in complex IV assembly, from the CMC1-knockout study defining the early COX1-COA3-COX14 intermediate. Reason: Direct experimental support that COA3 acts in complex IV biogenesis as part of an early COX1-containing assembly intermediate; this is the core function. Supporting Evidence: PMID:28082314 factors, the cardiomyopathy proteins COA3 and COX14. PMID:28082314 CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 |
| GO:0044183 protein folding chaperone | IDA PMID:28082314 A CMC1-knockout reveals translation-independent control of h... | KEEP AS NON CORE | Summary: Direct-assay molecular-function annotation describing COA3 as a chaperone that stabilises newly synthesised MT-CO1. Reason: COA3 does bind and stabilise nascent MT-CO1 within the COX1-COA3-COX14 intermediate, consistent with a chaperone-type binding activity. However, the protein has no catalytic activity and its defining evolved role is as a complex IV assembly factor rather than a general protein-folding chaperone; retained as a non-core molecular function. Supporting Evidence: PMID:28082314 CMC1 stabilizes a COX1-COA3-COX14 complex before the incorporation of COX4 |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomics (MitoCoP high-confidence mitochondrial proteome) assignment of COA3 to the mitochondrion. Reason: Supports mitochondrial localisation with high-confidence proteomic evidence; less specific than the inner-membrane annotation but correct. Supporting Evidence: PMID:34800366 high-confidence proteome (MitoCoP) of 1,134 protein-coding genes |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865350 | ACCEPT | Summary: Reactome traceable-author-statement placing COA3 at the mitochondrial inner membrane within the complex IV assembly pathway. Reason: Consistent with the experimentally determined inner-membrane localisation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865412 | ACCEPT | Summary: Reactome traceable-author-statement placing COA3 at the mitochondrial inner membrane within the complex IV assembly pathway. Reason: Consistent with the experimentally determined inner-membrane localisation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865449 | ACCEPT | Summary: Reactome traceable-author-statement placing COA3 at the mitochondrial inner membrane within the complex IV assembly pathway. Reason: Consistent with the experimentally determined inner-membrane localisation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865579 | ACCEPT | Summary: Reactome traceable-author-statement placing COA3 at the mitochondrial inner membrane within the complex IV assembly pathway. Reason: Consistent with the experimentally determined inner-membrane localisation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865630 | ACCEPT | Summary: Reactome traceable-author-statement placing COA3 at the mitochondrial inner membrane within the complex IV assembly pathway. Reason: Consistent with the experimentally determined inner-membrane localisation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9865663 | ACCEPT | Summary: Reactome traceable-author-statement placing COA3 at the mitochondrial inner membrane within the complex IV assembly pathway. Reason: Consistent with the experimentally determined inner-membrane localisation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:26321642 MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Chec... | MARK AS OVER ANNOTATED | Summary: IPI interaction annotations recording COA3 binding partners (MT-CO1, SURF1, TIMM21, SMIM20/MITRAC7) as the uninformative 'protein binding' term. Reason: The interactions are experimentally supported and biologically relevant to MITRAC/complex IV assembly, but the bare 'protein binding' molecular function is uninformative. Not removed per curation policy for experimental IPI; the functional context is captured by the assembly-factor core function. Supporting Evidence: PMID:26321642 The MITRAC complex represents |
| GO:0005743 mitochondrial inner membrane | IDA PMID:23260140 MITRAC links mitochondrial protein translocation to respirat... | ACCEPT | Summary: Direct-assay localisation of COA3 to the mitochondrial inner membrane from the MITRAC characterisation study. Reason: Primary experimental evidence for the inner-membrane localisation and single-pass membrane topology of COA3; this is the most authoritative CC annotation. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Mitochondrion inner membrane |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IMP PMID:23260140 MITRAC links mitochondrial protein translocation to respirat... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence from the MITRAC study that COA3 is required for complex IV assembly. Reason: Core experimentally supported function; COA3 as a core MITRAC component is required for efficient MT-CO1 translation and complex IV assembly. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Required for efficient translation of MT-CO1 and mitochondrial |
| GO:0070131 positive regulation of mitochondrial translation | IMP PMID:23260140 MITRAC links mitochondrial protein translocation to respirat... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence that COA3 positively regulates mitochondrial translation, specifically of MT-CO1, coupling translation to complex IV assembly. Reason: Supported by the MITRAC study (COA3 required for efficient MT-CO1 translation); this is a genuine secondary function reflecting MITRAC-mediated translational coupling. Later work (PMID:28082314) frames the translation-regulation role as proposed rather than fully established, but the primary IMP evidence justifies retaining it. Supporting Evidence: file:human/COA3/COA3-uniprot.txt Required for efficient translation of MT-CO1 and mitochondrial PMID:26321642 regulates mitochondrial translation of COX1 mRNA |
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Download this section (compressed HTML)Q: Is COA3's positive effect on MT-CO1 translation a direct regulatory activity or a secondary consequence of stabilising nascent MT-CO1 within the MITRAC intermediate?
Q: What is the precise structural role of the single transmembrane helix and C-terminal coiled coil of COA3 in organising the COX1-COA3-COX14 assembly intermediate?
Experiment: Structural determination (cryo-EM) of the human COX1-COA3-COX14 (MITRAC) assembly intermediate to define COA3's contacts with MT-CO1 and COX14.
Experiment: Pulse-chase labelling of mitochondrial translation products in COA3-null versus rescued cells to distinguish effects on MT-CO1 synthesis rate from effects on nascent MT-CO1 stability.
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