COA6

Summary: Inherited protein-disulfide reductase activity is supported by direct human COA6 experiments.

Reason: Current PAINT support includes the target itself with experimental reductase evidence. Recombinant human isoform 3 reduces oxidized SCO proteins and COX2; cellular substrate effects depend on the tested system. Target self inclusion is valid descendant evidence, and the historical IBD placement was not reconstructed.

Summary: Refine the broad assembly process to mitochondrial complex-IV assembly.

Reason: The positive phylogenetic assignment agrees with human COA6 depletion and rescue experiments. COA6 performs redox work on copper-site assembly clients in mitochondria, making the mitochondrial child more precise. This is target-grounded specificity, not a claim that the historical PAINT placement failed.

Proposed replacements: mitochondrial respiratory chain complex IV assembly

Summary: Refine inherited mitochondrial localization to the intermembrane space.

Reason: The current source includes experimentally localized human COA6. Human mitochondrial fractionation and protease accessibility identify a soluble intermembrane-space protein, supporting the more specific location. The uninspected historical tree is not inferred from donor count.

Proposed replacements: mitochondrial intermembrane space

Summary: Refine the broad InterPro location to the experimentally supported intermembrane space.

Reason: The family-derived mitochondrial prediction is positive. Independent human carbonate extraction and protease protection resolve COA6 to the soluble intermembrane space; the refinement uses this target evidence rather than claiming that InterPro itself provides subcompartment resolution.

Proposed replacements: mitochondrial intermembrane space

Summary: The UniProt location mapping correctly places COA6 in the intermembrane space.

Reason: The UniProt location mapping is corroborated by human mitochondrial subfractionation, protease-accessibility and soluble-fraction evidence. Retain intermembrane-space localization at the source qualifier and product scope.

Summary: Refine the electronic assembly annotation to mitochondrial complex-IV assembly.

Reason: The InterPro-derived process assignment is consistent with target experiments. Human COA6 depletion reduces COX2 and complex-IV biogenesis, while the demonstrated reductase activity contributes to mitochondrial CuA maturation. Preserve the original electronic source and use the mitochondrial process as the precise target interpretation.

Proposed replacements: mitochondrial respiratory chain complex IV assembly

Summary: Retire the historical unscoped aggregate from the active annotation set.

Reason: This preserved historical HuRI aggregate is retired because the current partner-scoped assertions for TTC19, DTX2 and CABP2 represent its evidence. Its original fields and historical non-core action remain unchanged for provenance; it is not an additional active annotation or independent replication. The partner-scoped assertions carry the current decisions.

Summary: The HPA immunofluorescence annotation supports mitochondrial localization.

Reason: The authenticated HPA target record assigns mitochondrial localization in A-431, U-251 MG and U2OS cells, with an additional nucleoplasm label in U2OS. These observations support the broad mitochondrial term without resolving the intermembrane space.

Summary: Purified human COA6 reduces protein disulfides.

Reason: The source uses recombinant human isoform 3 for structural and reduction assays. Reduced COA6 generates free thiols in oxidized SCO1, SCO2 and COX2 in vitro; patient fibroblasts show a SCO1 redox shift but unchanged SCO2 distribution. A later HEK293T knockout/rescue study detects effects on both SCO proteins. These distinct models support reductase activity without proving all substrates were reduced in living cells.

Summary: Genetic and biochemical evidence supports mitochondrial complex-IV assembly.

Reason: The current IGI record names yeast COA6 Q3E846; this is not SCO2 and the historical source field is preserved. The paper uses yeast genetic interaction and human–yeast chimeric complementation alongside human-cell rescue and purified human redox assays. These experiments jointly support the conserved assembly role while retaining their species and construct boundaries.

Summary: COA6 depletion impairs the mitochondrial complex-IV pathway.

Reason: The genuine full Results show human MCH58 shRNA depletion with selective COX2 reduction, yeast assembly defects and zebrafish phenotypes. Copper supplementation rescues yeast respiration and Cox2 levels; this paper does not demonstrate that same supplementation rescue in human cells. The preserved IMP reflects the experimentally supported assembly requirement.

Summary: COA6 supports nascent COX2 maturation during complex-IV assembly.

Reason: The recovered source demonstrates rapid nascent Cox2 turnover in yeast coa6-deleted cells. Separately, human HEK293T knockdown reduces complex-IV content/activity, and human COA6 isolation recovers SCO2 and newly synthesized COX2 in an assembly intermediate. These complementary experiments support the conserved assembly role without attributing the yeast turnover assay to human cells or asserting autonomous copper transfer.

Summary: Human COA6 knockout impairs complex-IV assembly through COX2 biogenesis.

Reason: The authenticated original abstract explicitly reports a human HEK293T knockout, defective COX2 biogenesis and accumulation of assembly intermediates. Full text remains unavailable for this paper, so detailed assay claims are not added. Later accessible human knockout/rescue and biochemical studies corroborate the positive assembly function.

Summary: MitoCoP contains a positive COA6 mitochondrial-proteome record.

Reason: The original Table S1 identifies Q5JTJ3-3 in protein group 6735 as a Class1 mitochondrial detection and includes canonical COA6 in the consensus gene table. This supports the preserved gene-level mitochondrial location, without turning the proteomics result into intermembrane-space resolution or equal testing of all three products.

Summary: Human COA6 is a soluble mitochondrial intermembrane-space protein.

Reason: The recovered original article uses carbonate extraction and proteinase K accessibility of human HEK293T mitochondria/mitoplasts, with compartment controls, to locate COA6 in the soluble intermembrane space. This is direct target localization rather than a family prediction.

Summary: Retain the positive association with the COX2 assembly factor COX16.

Reason: Human COX16 co-isolation recovers COA6 in a nascent-COX2-dependent assembly context. The original study shows COX16 facilitating SCO1 recruitment and merger of COX2- and COX1-containing assembly modules; it does not establish that COX16 binds nascent or unfolded chains to ensure their folding or transport, as required for GO:0051087. Preserve the positive complex association as non-core without assigning the COX20 chaperone class to every assembly factor.

Summary: Refine the positive COX20 association to protein-folding chaperone binding.

Reason: Human COX20-FLAG co-isolates COA6 within the COX2 maturation module. COX20 binds and stabilizes nascent COX2 before later maturation steps, matching the nascent-polypeptide folding-or-transport scope of GO:0051087. This partner-class refinement retains complex-mediated assay scope; the experiment does not establish an isolated COA6–COX20 interface.

Proposed replacements: protein-folding chaperone binding

Summary: Refine COX20 co-isolation to protein-folding chaperone binding.

Reason: Human COX20 affinity isolation recovers COA6, supported by quantitative enrichment and follow-up co-isolation. COX20 is the nascent-COX2 stabilization chaperone, fitting GO:0051087; COX16 recruitment/module-merger activity does not establish that same class. The refinement describes association with a defined partner class, not an independent direct interface between every co-isolated pair.

Proposed replacements: protein-folding chaperone binding

Summary: Retain demonstrated copper-binding capacity while leaving its physiological delivery role unresolved.

Reason: The original positive abstract reports copper binding. The later human isoform-3 experiments measure 1:1 Cu(I) binding after deliberate CuSO4 loading with reduced glutathione and test competition under reducing conditions, with cysteine-mutant controls. PMID:31851937 finds no endogenous copper in purified E. coli-expressed COA6 and no COA6-associated copper peak in yeast mitochondria, but observes binding after CuSO4/glutathione reconstitution and questions its physiological relevance. Retain measured capacity as non-core, not an established autonomous copper-delivery role. The cellular C58S/C90S rescue defect is additionally confounded by cytosolic mislocalization.

Summary: Refine direct assembly evidence to mitochondrial complex-IV assembly.

Reason: The recovered human experiments place COA6 in nascent COX2 maturation and identify a native COA6/SCO2/COX2-containing intermediate. The source supports the mitochondrial child of the preserved broad assembly term; it does not show autonomous oxidase catalysis by COA6.

Proposed replacements: mitochondrial respiratory chain complex IV assembly

Summary: Refine the positive human assembly annotation to its mitochondrial process.

Reason: The original abstract explicitly reports human COA6-dependent COX2 biogenesis and complex-IV assembly intermediates. The mitochondrial child supplies the specific setting while preserving the original IDA source and the abstract-only access boundary.

Proposed replacements: mitochondrial respiratory chain complex IV assembly

Summary: The original localization supplement supports the intermembrane space.

Reason: The official publisher page exposes the original Supplement Figure S1 legend: human HEK293 fractionation and protease accessibility compare intact mitochondria, mitoplasts and detergent treatment using compartment controls. COA6 is assigned to the soluble intermembrane space. The actual legend was inspected; the inaccessible supplement PDF and full article were not claimed as read.

Summary: Refine the conserved complex-IV assembly phenotype to mitochondrial assembly.

Reason: The human shRNA series reduces COX2, and the same study separately measures yeast assembly defects and copper rescue. These positive experiments support the mitochondrial process child. Zebrafish cardiac phenotypes are contextual consequences, not a new molecular activity or an additional proposed developmental process.

Proposed replacements: mitochondrial respiratory chain complex IV assembly

Summary: Retain the experimentally reported SCO1 association.

Reason: The original authenticated abstract positively reports COA6 association with SCO1 and newly synthesized COX2. Later accessible human purified-protein studies corroborate SCO1 interaction and reductase-client specificity. The copper-chaperone designation alone does not establish a protein-folding chaperone class, so this positive source-specific association remains non-core.

Summary: Retire the historical unscoped aggregate from the active annotation set.

Reason: This preserved historical human assembly aggregate is retired because the current partner-scoped assertions for SCO2 and MT-CO2 represent its evidence. Its original fields and historical non-core action remain unchanged for provenance; it is not an additional active annotation or independent replication. The partner-scoped assertions carry the current decisions.

Summary: Retain the measured RNA-contact result as a non-core capability.

Reason: The authentic supplementary row places C1orf31/COA6 in the mRNA-interactome set: detected in crosslinked and control samples, p.adj.DESeq=1 and p.adj.IC=0.00267341282992018. These are adjusted P values; the authors use either analysis at a 0.01 false-discovery threshold after UV crosslinking and stringent LiCl/LiDS oligo-dT purification. The nonsignificant DESeq arm therefore does not negate the qualifying ion-count arm. A mature soluble IMS protein has no established route to cytosolic poly(A) RNA in this experiment; the contacted RNA, cellular pool and tested product remain unresolved. That topology question does not by itself demonstrate nonspecific capture. Retain the HDA contact observation as non-core without an independently validated native RNA-processing function. The source-evidence index provides public original PDF/XLS URLs, hashes, the exact table row and assay/statistical locators.

Summary: Retain curator-mediated mitochondrial localization transfer from mouse Coa6.

Reason: Official Q8BGD8 resolves to mouse Coa6 and current same-term records include experimental mitochondrial-proteome grounding. Human mitochondrial and intermembrane-space experiments independently corroborate localization. This source check does not reconstruct the original transfer decision or claim that the mouse proteomics assay resolves the human subcompartment.

Summary: Retain the current scoped SCO2 interaction imported from GOA.

Reason: This exact machine-derived source object supplies the SCO2-specific scope previously represented only by a historical aggregate. The original human native-complex and immunoisolation experiments support association with COA6; the later human HEK293T study adds cysteine-dependent interaction and redox rescue. Retain the positive pair without assigning a separate folding-chaperone binding activity.

Summary: Retain the current scoped MT-CO2 interaction imported from GOA.

Reason: The original human source recovers newly synthesized COX2 with COA6 and SCO2 in a native assembly intermediate. This exact imported row retains the client-specific association separately from the historical aggregate. COX2 is a catalytic subunit within cytochrome c oxidase; its identity alone does not demonstrate binding to an independently active enzyme.

Summary: Retain the positive HuRI TTC19 interaction at the tested-fragment scope.

Reason: Three positive HuRI records retain the TTC19 pair, including a 108–380 sufficient-binding region. The official partner record supports complex-III maintenance through handling of UQCRFS1-derived fragments, but does not establish a more specific binding-partner class for this construct. Retain the measured association as non-core; no native cross-complex coordination is inferred.

Summary: Refine the positive DTX2 pair to ubiquitin protein ligase binding.

Reason: Three positive HuRI records map DTX2 to the canonical 622-residue product, with no reported truncation. Its official E3 ubiquitin-ligase identity matches GO:0031625. This verified partner class supports greater specificity than the TTC19 and CABP2 pairs, irrespective of their equal record counts. The assay does not establish a native COA6 ubiquitination pathway. The yeast assay does not reproduce mitochondrial IMS versus cytosolic/nuclear topology; that limits a native-contact interpretation but does not invalidate the reported positive pair or the independently established E3 partner class.

Proposed replacements: ubiquitin protein ligase binding

Summary: Retain the positive HuRI CABP2 interaction.

Reason: Three positive HuRI records support the mapped 220-residue CABP2 pair. CABP2 is a calcium-channel regulator, not calmodulin; no more specific applicable binding class is established here. Preserve the association as non-core without assigning COA6 a calcium-signaling process.