COX6A2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen	IBA GO_REF:0000033	ACCEPT	Summary: COX6A2 is a structural subunit of cytochrome c oxidase (Complex IV), the terminal enzyme that transfers electrons from reduced cytochrome c to molecular oxygen. This IBA annotation to the core biological process for a Complex IV subunit is correct and represents a core function of the gene. Reason: Consistent with the phylogenetic assignment across the cytochrome c oxidase subunit 6A family and with the UniProt FUNCTION statement placing COX6A2 as a component of the enzyme that transfers electrons from cytochrome c to oxygen during oxidative phosphorylation. Supporting Evidence: file:human/COX6A2/COX6A2-uniprot.txt Component of the cytochrome c oxidase, the last enzyme in the file:human/COX6A2/COX6A2-uniprot.txt reduction of oxygen to water.
GO:0045277 respiratory chain complex IV	IBA GO_REF:0000033	ACCEPT	Summary: COX6A2 is one of the nuclear-encoded supernumerary subunits of Complex IV (cytochrome c oxidase). This is the current, correct cellular-component term for Complex IV membership and represents a core aspect of the gene. Reason: UniProt SUBUNIT describes COX6A2 as a component of the 14-subunit cytochrome c oxidase complex; membership in respiratory chain complex IV is well established. (The obsolete term GO:0005751 is superseded by GO:0045277.) Supporting Evidence: file:human/COX6A2/COX6A2-uniprot.txt multisubunit enzyme composed of 14 subunits. file:human/COX6A2/COX6A2-uniprot.txt 11 supernumerary subunits COX4I1 (or
GO:0030234 enzyme regulator activity	IBA GO_REF:0000033	MODIFY	Summary: This IBA molecular-function annotation frames COX6A2 as a regulator of the cytochrome c oxidase enzyme. COX6A2 is, however, a non-catalytic structural (supernumerary) subunit whose characterized role is in assembly and stabilization of the complex rather than as a classical enzyme regulator. A structural molecule activity term more accurately captures its molecular function. Reason: UniProt describes COX6A2 as playing a role in assembly and stabilization of Complex IV, consistent with a scaffolding/structural role rather than enzyme regulation. Structural molecule activity (GO:0005198) better reflects the molecular contribution of this non-catalytic supernumerary subunit; it may additionally contribute to the overall cytochrome-c oxidase activity of the assembled complex. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000161400 · Cytochrome c oxidase subunit 6A family (PANTHER) SUPPORTS SOURCE BUT NOT TARGET The family-level 'enzyme regulator activity' call reflects reports that COX6A subunits modulate holoenzyme activity, but for the human subunit the well-supported molecular role is structural/assembly rather than enzyme regulation. Proposed replacements: structural molecule activity Supporting Evidence: file:human/COX6A2/COX6A2-uniprot.txt Plays a role in the assembly and
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: COX6A2 is a single-pass mitochondrial inner-membrane protein, as expected for a Complex IV subunit. This is the correct and specific anatomical location of the gene product. Reason: UniProt SUBCELLULAR LOCATION and the transmembrane topology features support inner-membrane localization; multiple independent lines of evidence (IEA, ISS, Reactome TAS) agree. Supporting Evidence: file:human/COX6A2/COX6A2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0045277 respiratory chain complex IV	IEA GO_REF:0000107	ACCEPT	Summary: Electronically transferred (Ensembl Compara) annotation placing COX6A2 in respiratory chain complex IV. This duplicates and is consistent with the IBA Complex IV membership annotation and is correct. Reason: Complex IV membership is well supported by UniProt SUBUNIT; this is the current, correct cellular-component term. Supporting Evidence: file:human/COX6A2/COX6A2-uniprot.txt multisubunit enzyme composed of 14 subunits.
GO:0006119 oxidative phosphorylation	IEA GO_REF:0000041	ACCEPT	Summary: As a subunit of the terminal oxidase of the electron transport chain, COX6A2 participates in oxidative phosphorylation. This is a correct, if broad, biological-process annotation. Reason: UniProt PATHWAY assigns COX6A2 to energy metabolism / oxidative phosphorylation; the more specific process (GO:0006123) is also annotated. Supporting Evidence: file:human/COX6A2/COX6A2-uniprot.txt PATHWAY: Energy metabolism; oxidative phosphorylation.
GO:0005743 mitochondrial inner membrane	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity-based inner-membrane localization, transferred from the bovine ortholog (P07471). Correct and consistent with the direct topology evidence. Reason: Inner-membrane localization is established for the cytochrome c oxidase subunit 6A family and supported by UniProt SUBCELLULAR LOCATION. Supporting Evidence: file:human/COX6A2/COX6A2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteomics detected COX6A2 as a mitochondrial protein. This is correct, though less specific than the inner-membrane localization also annotated. Reason: Supported by a quantitative high-confidence human mitochondrial proteome study; consistent with COX6A2 being a mitochondrial inner-membrane Complex IV subunit. Broad but not incorrect. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-163214	ACCEPT	Summary: Reactome (electron transfer from reduced cytochrome c to molecular oxygen) places COX6A2 in the mitochondrial inner membrane as part of Complex IV. Correct. Reason: Consistent with the established inner-membrane localization of Complex IV subunits; a curated Reactome traceable assertion. Supporting Evidence: Reactome:R-HSA-163214 Complex IV (COX, cytochrome c oxidase) contains the hemeprotein cytochrome a and a3.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9709406	ACCEPT	Summary: Reactome (CO binds to cytochrome c oxidase) localizes COX6A2 to the mitochondrial inner membrane as a Complex IV subunit. Correct location. Reason: Consistent with inner-membrane localization of Complex IV; curated Reactome traceable assertion. Supporting Evidence: Reactome:R-HSA-9709406 CO binds to cytochrome c oxidase, the terminal enzyme in the electron transfer chain
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865663	ACCEPT	Summary: Reactome models the final Complex IV assembly step in which COX6A (with other subunits) binds the holo-MT-CO1,2 complex in the inner membrane. This both localizes COX6A2 to the inner membrane and supports its role in Complex IV assembly. Reason: Curated Reactome traceable assertion placing COX6A among the final assembly subunits of Complex IV in the inner membrane; consistent with the structural/assembly role of COX6A2. Supporting Evidence: Reactome:R-HSA-9865663 The final assembly of Complex IV consists of binding of the MT-CO3, COX6A, COX6B, COX7A, and NDUFA4 subunits to the holo-MT-CO1, MT-CO2 complex
GO:0006091 generation of precursor metabolites and energy	TAS PMID:9284905 Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1...	MARK AS OVER ANNOTATED	Summary: This broad energy-metabolism biological-process term is essentially correct for a Complex IV subunit (Complex IV drives energy generation), but it is a high-level parent of the more specific and more informative GO:0006123 that is already annotated. In addition, the cited reference PMID:9284905 is a mapping/pseudogene-assignment paper about the paralog COX6A1 (and the COX6A1P pseudogene), not COX6A2, and does not specifically support this gene's function. Reason: The term is a very general ancestor of the specific process already captured by GO:0006123 (mitochondrial electron transport, cytochrome c to oxygen), and the supporting ProtInc reference concerns the COX6A1 paralog rather than COX6A2, so it adds no specific, well-supported information for this gene. Supporting Evidence: PMID:9284905 Assignment of COX6A1 to 6p21 and a pseudogene (COX6A1P) to 1p31.1 by in situ hybridization and somatic cell hybrids.