Gene Ontology annotation through association of InterPro records with GO terms
Use of the ND evidence code for Gene Ontology (GO) terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Combined Automated Annotation using Multiple IEA Methods
Global analysis of protein localization in budding yeast.
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Genome-wide C-terminal GFP fusion localization library. Source of both the nucleus and the cytoplasm HDA rows for Coa4. Only the nucleus call is contested: it conflicts with every targeted localization source for this protein and has no described import route. The cytoplasm call is retained as correct, since Mia40 substrates genuinely occupy the cytosol while awaiting import.
Systematic analysis of the twin cx(9)c protein family.
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Systematic survey of the 14 yeast twin Cx9C proteins. Coa4 was identified here as Cmc3, its import shown to depend on the Mia40-Erv1 disulfide relay, and most family deletions found to impair respiratory chain assembly or stability.
"which we demonstrated to be dependent for import"
Analysis of Leigh syndrome mutations in the yeast SURF1 homolog reveals a new member of the cytochrome oxidase assembly factor family.
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Coa4 is a twin CX9C intermembrane space protein associated with the inner membrane; cells lacking it have depressed cytochrome c oxidase activity but normal Cox1 maturation and a normal Shy1-stabilized Cox1 assembly intermediate, placing Coa4 downstream of Cox1 synthesis and hemylation.
"Cells lacking Coa4 are depressed in CcO activity but show no impairment in Cox1 maturation or formation of the Shy1-stabilized Cox1 assembly intermediate"
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coa4-null cells have reduced mitochondrial copper content, prompting the proposal that Coa4 participates in copper routing.
"Cells lacking Coa4 resemble shy1 Δ cells in exhibiting a reduced mitochondrial copper content"
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High-copy CYC1 restores respiratory function to coa4-null cells; COA4 was itself isolated as an allele-specific suppressor of the Shy1 G137E mutant. Source of the SHY1 and CYC1 genetic interactions.
"Respiratory function of coa4 Δ cells was restored by the overexpression of"
Intermembrane space proteome of yeast mitochondria.
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Bax-release profiling of isotope-labelled yeast mitochondria recovered 29 of the 31 known soluble intermembrane space proteins and identified 20 further IMS proteins, one of which is Coa4. Source of the EXP localization row.
"From the known 31 soluble IMS proteins, 29 proteins"
Inaccurately assembled cytochrome c oxidase can lead to oxidative stress-induced growth arrest.
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Deletion of COA4 (like CMC1) causes cytochrome c oxidase assembly defects, with loss of Cox1 and rapid degradation of Cox2 and Cox3. Source of the CMC1 genetic interaction.
"Deletion of CMC1 or COA4 leads to assembly defects of cytochrome c"
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Reductants restore respiratory growth of coa4-null cells without restoring cytochrome c oxidase assembly - the growth defect is driven by hydrogen peroxide from partially assembled complex IV intermediates. A necessary caveat when reading any respiratory-growth rescue as evidence of restored assembly.
"the presence of the reductants does not suppress these assembly defects and the levels of cytochrome c oxidase remain reduced"
MIA40:ERV1 oxidizes cysteine residues to cystine disulfide bonds
A yeast suppressor screen links Coa4 to the mitochondrial copper delivery pathway for cytochrome c oxidase.
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COX11 overexpression restores Cox1 abundance, cytochrome c oxidase assembly and respiration in coa4-null cells, and the rescue requires the copper-coordinating cysteines of Cox11 - establishing restored copper delivery rather than suppression of reactive oxygen species.
"cysteine mutants of Cox11 that are incapable of binding copper, failed to rescue the respiratory defect"
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The rescue is unidirectional, placing Coa4 upstream of Cox11 in the copper delivery pathway to the CuB site of Cox1.
"suggests that Coa4 acts upstream of Cox11 in the copper delivery pathway"
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Coa4 is not a copper metallochaperone: it lacks the copper-coordinating cysteine motif of Cox17 and its deletion phenotype is far milder than that of the bona fide chaperones. This is the direct justification for retaining the ND molecular_function annotation.
"Importantly, Coa4 lacks the copper-binding cysteine motif that is found in Cox17, further negating its metallochaperone role"
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Human COA4 complements the yeast coa4-null mutant, establishing that the function is evolutionarily conserved and licensing transfer of this yeast mechanism to the human ortholog.
"we demonstrate that human COA4 can replace the function of yeast Coa4 indicating its evolutionarily conserved role"
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The authors explicitly could not detect a physical Coa4-Cox11 interaction by co-immunoprecipitation/mass spectrometry, leaving the genetic interaction unexplained biochemically until the 2026 crosslinking study.
"Our initial attempts to detect protein:protein interaction between Cox11 and Coa4 via coimmunoprecipitation/mass spectrometry experiments were not successful"
The predicted interactome of the human mitochondrial proteome.
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Co-immunoprecipitation of yeast Coa4-V5 from DSSO-crosslinked mitochondria recovered Cox11, supplying the direct physical interaction that the 2022 study could not detect - plausibly because crosslinking captures a transient contact.
"immunoprecipitation (Co-IP) of yeast Coa4-V5 from chemically"
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The same co-IP enriched the IMS-localized phosphatase Ptc5, suggesting that reversible phosphorylation of Coa4 may regulate copper delivery to cytochrome c oxidase. This is suggestive only - no functional follow-up was performed - and is recorded as a hypothesis, not as annotation evidence.
"the IMS-localized Ptc5 phosphatase, which suggests a role for this"