Cox19 is a 98-residue twin CX9C protein distributed between the cytosol and the mitochondrial intermembrane space, and is required for cytochrome c oxidase assembly. It acts as a chaperone for the copper metallochaperone Cox11, binding a cysteine-containing sequence in Cox11 through a hydrophobic surface on its helical hairpin defined by two conserved tyrosine-leucine dipeptides. The interaction appears to be redox regulated - oxidative modification of the target Cox11 cysteine stimulates Cox19 binding - and is required for stable accumulation of Cox19 in mitochondria. Cox19 resembles Cox17 in fold and in the ability to coordinate Cu(I) in vitro, but its established role is as a Cox11 chaperone supporting Cox11 copper coordination rather than as a copper donor in its own right. Cox19 is one of two intermembrane space twin CX9C proteins now known to converge on Cox11, the other being Coa4.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of protein folding chaperone activity across the COX19 family. Reason: Directly supported on the target by IDA: Cox19 binds and chaperones Cox11, and that binding is required for Cox11 copper coordination. The chaperone framing is the best available molecular function for this protein. Supporting Evidence: PMID:25926683 dynamic manner with Cox11, a copper transfer protein that facilitates metalation |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of the complex IV assembly role. Reason: Directly supported on the target by IDA evidence in two independent studies. Core biological process. Supporting Evidence: PMID:12171940 probably functions post-translationally during assembly of the enzyme |
| GO:0005758 mitochondrial intermembrane space | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of intermembrane space localization. Reason: Corroborated on the target by two EXP rows, IDA and TAS. Cox19 is functional when tethered to the inner membrane, which independently argues that its site of action is the IMS. Supporting Evidence: PMID:12171940 present in the cytoplasm and mitochondria, where it exists as a soluble |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt-derived intermembrane space localization. Reason: Consistent with the EXP and IDA evidence on the target. Supporting Evidence: PMID:12171940 present in the cytoplasm and mitochondria, where it exists as a soluble |
| GO:0005829 cytosol | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt-derived cytosolic localization. Cox19 genuinely partitions between cytosol and intermembrane space. Reason: A real dual distribution, reported directly and recorded in UniProt, not an artifact. Kept non-core because the functionally relevant pool is the intermembrane space one: Cox19 remains functional when tethered to the inner membrane. Supporting Evidence: PMID:12171940 present in the cytoplasm and mitochondria, where it exists as a soluble |
| GO:0006457 protein folding | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Protein folding, propagated automatically from the protein folding chaperone molecular function. Reason: A mechanical MF-to-BP inference. Not wrong, but Cox19's biologically meaningful process annotation is complex IV assembly; generic protein folding adds little and risks implying a general chaperone role the protein does not have. Supporting Evidence: PMID:25926683 dynamic manner with Cox11, a copper transfer protein that facilitates metalation |
| GO:0005758 mitochondrial intermembrane space | EXP PMID:22984289 Intermembrane space proteome of yeast mitochondria. | ACCEPT | Summary: Direct experimental placement in the intermembrane space by Bax-release proteomics. Reason: Targeted IMS proteomics with high coverage of the known soluble IMS proteome. Supporting Evidence: PMID:22984289 From the known 31 soluble IMS proteins, 29 proteins...were reproducibly identified, corresponding to a coverage of >90% |
| GO:0005758 mitochondrial intermembrane space | EXP PMID:25926683 Redox-regulated dynamic interplay between Cox19 and the copp... | ACCEPT | Summary: Direct experimental intermembrane space localization from the Cox11 interaction study. Reason: Independent confirmation by a second group and method. Supporting Evidence: PMID:25926683 Of interest, both proteins form a nonpersistent redox-dependent complex in the IMS. |
| GO:0008535 respiratory chain complex IV assembly | IDA PMID:25926683 Redox-regulated dynamic interplay between Cox19 and the copp... | KEEP AS NON CORE | Summary: Respiratory chain complex IV assembly - the taxon-neutral parent of the mitochondrial term also annotated to this gene. Reason: Correct but less specific than GO:0033617, which is annotated separately from the same body of evidence. Retained as a correct parent rather than modified, since both terms are already present. Supporting Evidence: PMID:25926683 critical for copper transfer in the IMS and thus for biogenesis of cytochrome c |
| GO:0044183 protein folding chaperone | IDA PMID:25926683 Redox-regulated dynamic interplay between Cox19 and the copp... | ACCEPT | Summary: Direct assay evidence that Cox19 acts as a chaperone for Cox11, binding a cysteine-containing sequence in Cox11 via conserved tyrosine-leucine dipeptides that are essential for Cox19 function. Reason: The best available statement of Cox19's molecular function, with a defined binding surface, defined target sequence, and mutational support. Core molecular function. Supporting Evidence: PMID:25926683 dynamic manner with Cox11, a copper transfer protein that facilitates metalation |
| GO:0051604 protein maturation | IDA PMID:25926683 Redox-regulated dynamic interplay between Cox19 and the copp... | KEEP AS NON CORE | Summary: Protein maturation, from the same study. Reason: A reasonable but generic framing of what chaperoning Cox11 achieves. The specific content is captured by the chaperone MF and the complex IV assembly BP. Supporting Evidence: PMID:25926683 dynamic manner with Cox11, a copper transfer protein that facilitates metalation |
| GO:0005758 mitochondrial intermembrane space | TAS Reactome:R-SCE-1252260 | ACCEPT | Summary: Reactome traceable author statement placing Cox19 in the intermembrane space. Reason: Consistent with the direct evidence; adds nothing independent. Supporting Evidence: PMID:12171940 present in the cytoplasm and mitochondria, where it exists as a soluble |
| GO:0005507 copper ion binding | IDA PMID:17237235 characterization of the cytochrome c oxidase assembly factor... | KEEP AS NON CORE | Summary: Copper ion binding demonstrated in vitro for recombinant Cox19, which resembles Cox17 in coordinating Cu(I). Reason: The binding is real in vitro, but the authors frame it as a resemblance to Cox17 rather than as an established physiological role, and the subsequent mechanistic work identifies Cox19 as a Cox11 chaperone supporting Cox11 copper coordination rather than as a copper donor itself. Retained as a genuine biochemical property, but it should not be read as evidence that Cox19 is a metallochaperone. Supporting Evidence: PMID:17237235 Cox17 in its ability to coordinate Cu(I). Recombinant Cox19 binds 1 mol eq of...Cu(I) per monomer |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:12171940 Characterization of COX19, a widely distributed gene require... | ACCEPT | Summary: Direct assay intermembrane space localization from the original characterization of the gene. Reason: Primary experimental localization, later confirmed by IMS proteomics and by the Cox11 interaction study. Supporting Evidence: PMID:12171940 present in the cytoplasm and mitochondria, where it exists as a soluble |
| GO:0005829 cytosol | IDA PMID:12171940 Characterization of COX19, a widely distributed gene require... | KEEP AS NON CORE | Summary: Cytosolic localization from the original characterization. Reason: Same as the IEA cytosol row: a real dual distribution, but the IMS pool is the functional one. Supporting Evidence: PMID:12171940 present in the cytoplasm and mitochondria, where it exists as a soluble |
| GO:0030001 metal ion transport | IDA PMID:12171940 Characterization of COX19, a widely distributed gene require... | MARK AS OVER ANNOTATED | Summary: Metal ion transport, inferred in the original characterization from Cox19's resemblance to Cox17 rather than from any demonstrated transport activity. Reason: No metal transport by Cox19 has ever been demonstrated. The in vitro Cu(I) coordination reported later is a binding property, not transport, and the mechanistic study that followed assigns Cox19 the role of chaperoning Cox11 so that Cox11 can coordinate copper - a distinct claim. GO:0030001 is also strikingly non-specific for a protein with a defined binding partner and binding surface. The term overstates what is known; the chaperone MF and complex IV assembly BP carry the real content. Supporting Evidence: PMID:25926683 dynamic manner with Cox11, a copper transfer protein that facilitates metalation |
| GO:0033617 mitochondrial respiratory chain complex IV assembly | IDA PMID:12171940 Characterization of COX19, a widely distributed gene require... | ACCEPT | Summary: Direct assay evidence for a role in cytochrome c oxidase assembly: cox19 mutants synthesize both mitochondrial and nuclear subunits but fail to assemble the enzyme. Reason: Places Cox19 at a post-translational assembly step, consistent with its later-defined role as a Cox11 chaperone. Core biological process. Supporting Evidence: PMID:12171940 probably functions post-translationally during assembly of the enzyme |
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Download this section (compressed HTML)Q: Should GO:0030001 metal ion transport be retired for Cox19? It was inferred from resemblance to Cox17 rather than from demonstrated transport, and the mechanistic follow-up recasts Cox19 as a Cox11 chaperone rather than a copper carrier.
Suggested experts: SGD curators, GO transport curation group
Q: Cox19 and Coa4 are both intermembrane space twin CX9C proteins that act on Cox11. Do they bind Cox11 at the same site, compete, or act sequentially? Neither study examined the other protein.
Suggested experts: Herrmann lab, Gohil lab, Winge lab
Q: Is the in vitro Cu(I) coordination by Cox19 physiologically meaningful, or an incidental property of the twin CX9C fold shared with Cox17?
Suggested experts: Winge lab
Experiment: Test whether Coa4 and Cox19 co-occupy Cox11 by sequential immunoprecipitation, map each binding site by crosslinking, and assay complex IV assembly and Cox11 copper occupancy in single and double null strains.
Hypothesis: Cox19 and Coa4 act on Cox11 at distinct sites and at distinct steps of CuB-site metallation.
Type: biochemical
Experiment: Substitute the Cu(I)-coordinating residues of Cox19 while preserving the tyrosine-leucine Cox11-binding surface, and test respiratory growth, complex IV assembly and Cox11 binding.
Hypothesis: Cu(I) binding by Cox19 is dispensable for its function.
Type: genetic
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