COX5A

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045277 respiratory chain complex IV	IBA GO_REF:0000033	ACCEPT	Summary: COX5A is a bona fide structural subunit of respiratory chain complex IV (cytochrome c oxidase). This is the correct, current cellular-component term for the complex COX5A is part of, and is well supported phylogenetically and by human structural data. Reason: COX5A is one of the 11 nuclear-encoded supernumerary subunits of the 14-subunit human cytochrome c oxidase (complex IV); the IBA membership call is consistent with UniProt and cryo-EM structure. GO:0045277 is the current term (the older "mitochondrial respiratory chain complex IV" GO:0005751 is obsolete). Supporting Evidence: PMID:30030519 assigned the NDUFA4 subunit into complex-IV file:human/COX5A/COX5A-uniprot.txt a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen	IBA GO_REF:0000033	ACCEPT	Summary: As a structural subunit of complex IV, COX5A participates in the terminal step of the mitochondrial electron transport chain, in which electrons are transferred from reduced cytochrome c to molecular oxygen. This is the core biological process of the complex and is appropriate for COX5A as a complex member. Reason: Correct complex-level process for a complex IV subunit; well supported by UniProt function annotation and the phylogenetic inference across orthologs. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Component of the cytochrome c oxidase, the last enzyme in the
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: COX5A localises to the mitochondrial inner membrane, where complex IV resides. This electronic annotation agrees with the experimental UniProt subcellular location and with the curated experimental annotations below. Reason: Correct localisation, consistent with UniProt (mitochondrion inner membrane, peripheral membrane protein, matrix side) and with EXP/IDA annotations for the same term. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Peripheral membrane protein
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic annotation to the terminal electron-transport process of complex IV. Consistent with the IBA and NAS annotations to the same term; correct for a complex IV subunit. Reason: Redundant with, and consistent with, the IBA/NAS annotations to GO:0006123; the InterPro cytochrome c oxidase subunit 5A/6 signature legitimately maps to this process. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Component of the cytochrome c oxidase, the last enzyme in the
GO:0045277 respiratory chain complex IV	IEA GO_REF:0000120	ACCEPT	Summary: Electronic complex-membership annotation to respiratory chain complex IV, redundant with and consistent with the IBA, IPI, IMP and IDA annotations to the same current term. Reason: Correct complex membership; agrees with all experimental and phylogenetic evidence for COX5A as a complex IV subunit. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Component of the cytochrome c oxidase (complex IV, CIV), a
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: Complex IV pumps protons across the inner membrane coupled to electron transfer, contributing to the proton-motive force. This term is inferred logically from the cytochrome-c oxidase activity mapping. It reflects a complex-level activity rather than an intrinsic activity of the non-catalytic COX5A subunit. Reason: Proton pumping is a genuine activity of the holo-complex that COX5A is part of, so the annotation is not wrong; however it is a complex-level process driven by the mtDNA-encoded catalytic core, not a core/intrinsic function of the structural COX5A subunit, so it is kept as non-core. Supporting Evidence: PMID:30030519 It accepts electrons from cytochrome c to reduce the oxygen to water and meanwhile pumps two protons from the matrix side to the intermembrane space (IMS)
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a proteome-scale binary interactome screen (partners include KRT31, KRT40, EXOSC8). This term is uninformative about COX5A's molecular function and the partners are high-throughput hits without an established biological role for COX5A. Reason: GO:0005515 conveys no specific molecular function; the interactions derive from a large-scale interactome map rather than a characterised COX5A activity. Per curation policy this experimental IPI is not removed but flagged as an over-annotation; COX5A's informative molecular role is structural (see core_functions). Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a reference binary interactome map (partners SPDEF, MESD). Uninformative and derived from a high-throughput screen rather than a specific characterised interaction. Reason: GO:0005515 is uninformative and the partners are high-throughput binary interactome hits with no established COX5A biology; retained as an experimental IPI but flagged as over-annotation rather than removed. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a neurodegeneration-focused interactome screen (partners APP, PIK3R1). Uninformative term from a high-throughput dataset. Reason: GO:0005515 does not describe a specific molecular function; the interactions are high-throughput and not shown to reflect a characterised COX5A activity. Kept as an experimental IPI but flagged as over-annotation. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
GO:0006119 oxidative phosphorylation	IEA GO_REF:0000041	ACCEPT	Summary: COX5A, as a complex IV subunit, participates in oxidative phosphorylation. This UniPathway-derived electronic annotation is correct but broader than the more specific GO:0006123 (electron transport, cytochrome c to oxygen). Reason: Correct high-level process; complex IV is the terminal oxidase driving oxidative phosphorylation. More general than GO:0006123 but not wrong; retained. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt mitochondrial electron transport chain which drives oxidative
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen	NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: ComplexPortal (NAS) annotation of the complex IV subunit to the terminal electron-transport process. Consistent with the IBA and IEA annotations to the same term and with the structural characterisation of human complex IV. Reason: Correct core complex-level process; agrees with all other evidence for GO:0006123. Supporting Evidence: PMID:30030519 CIV is the terminal oxidase of the electron transport chain in mitochondria
GO:0031966 mitochondrial membrane	IDA PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: COX5A is a component of complex IV, which resides in the mitochondrial (inner) membrane. This ComplexPortal IDA to the broader "mitochondrial membrane" term is correct but less specific than the mitochondrial inner membrane annotations. Reason: Correct localisation; complex IV is embedded in the mitochondrial inner membrane. GO:0031966 is a valid parent of GO:0005743 and is not wrong, though the inner-membrane term is more informative. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0045277 respiratory chain complex IV	IPI PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: Structural/ComplexPortal evidence that COX5A is a subunit of respiratory chain complex IV, directly resolved in the intact 14-subunit human cytochrome c oxidase structure. Reason: Direct structural evidence for complex membership; the strongest support for the core cellular-component assignment. Supporting Evidence: PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidase.
GO:0045333 cellular respiration	NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: As a complex IV subunit, COX5A participates in cellular respiration. This is a correct but high-level (broad parent) process annotation. Reason: Correct high-level process; complex IV is a central respiratory chain complex. Broader than GO:0006123 but not wrong; retained as non-core-level breadth. Supporting Evidence: PMID:30030519 CIV is the terminal oxidase of the electron transport chain in mitochondria
GO:0005743 mitochondrial inner membrane	EXP PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: Experimental localisation of COX5A to the mitochondrial inner membrane, the site of complex IV. This is the most specific and best-supported cellular-component term and matches the UniProt experimental subcellular location. Reason: Experimentally supported, specific, and consistent with UniProt (mitochondrion inner membrane; peripheral membrane protein, matrix side). Core localisation. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Matrix side
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial proteome study confirms COX5A as a mitochondrial protein. Correct but broad (organelle-level) localisation, subsumed by the more specific mitochondrial inner membrane annotations. Reason: Correct organelle assignment from a high-confidence mitochondrial proteome dataset; consistent with all other localisation evidence, though less specific than GO:0005743. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics
GO:0045277 respiratory chain complex IV	IMP PMID:19393246 Knockdown of human COX17 affects assembly and supramolecular...	ACCEPT	Summary: In HeLa cells, COX17 knockdown perturbs assembly and supramolecular organisation of cytochrome c oxidase; in this context COX5A is treated as a subunit of complex IV whose incorporation/assembly is assayed. Supports COX5A complex membership. Reason: COX5A is a genuine complex IV subunit; the assembly study is consistent with this membership. Per curation policy, this experimental annotation is accepted (full text not in cache, but the complex-membership call is well corroborated by structure and phylogeny). Supporting Evidence: PMID:19393246 Knockdown of human COX17 affects assembly and supramolecular organization of
GO:0045277 respiratory chain complex IV	IDA PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro...	ACCEPT	Summary: Mitochondrial interactome study that maps COX5A within complex IV / the respirasome. Direct evidence supporting COX5A as a complex IV subunit. Reason: Consistent with structural and phylogenetic evidence for COX5A complex IV membership; a legitimate experimental complex-membership annotation. Supporting Evidence: PMID:31536960 Regulators of the Respirasome and Neurogenesis
GO:0005758 mitochondrial intermembrane space	TAS Reactome:R-HSA-9865412	MARK AS OVER ANNOTATED	Summary: This Reactome (TAS) annotation places COX5A in the mitochondrial intermembrane space, but COX5A is experimentally a peripheral inner-membrane protein on the matrix side (UniProt). The IMS term reflects the reaction context (electrons originate from cytochrome c in the IMS) rather than the topology of COX5A itself, so it mislocalises the subunit. Reason: UniProt experimental evidence places COX5A on the matrix side of the inner membrane, not in the intermembrane space. The IMS assignment overstates/mislocates COX5A; the inner-membrane annotations (GO:0005743) are the correct localisation. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Matrix side
GO:0005515 protein binding	IPI PMID:31536960 Rewiring of the Human Mitochondrial Interactome during Neuro...	MARK AS OVER ANNOTATED	Summary: Curated IPI (partner RAB5IF/Q9BUV8) from the mitochondrial interactome study. RAB5IF is a respirasome/complex IV assembly factor and its interaction with COX5A is recorded in UniProt; however the GO term used (bare "protein binding") is uninformative about COX5A's molecular function. Reason: The specific COX5A-RAB5IF interaction is biologically meaningful (assembly-factor contact), but GO:0005515 captures none of that specificity. Retained as an experimental IPI and flagged as over-annotation; the informative function is structural (assembly into complex IV), captured in core_functions. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Interacts with AFG1L (PubMed:26759378). Interacts with RAB5IF
GO:0005515 protein binding	IPI PMID:26759378 The mammalian homologue of yeast Afg1 ATPase (lactation elev...	MARK AS OVER ANNOTATED	Summary: Curated IPI (partner AFG1L/LACE1, Q8WV93). LACE1 physically interacts with COX5A and mediates degradation of nuclear-encoded complex IV subunits including COX5A; biologically meaningful, but the GO term "protein binding" is uninformative. Reason: The COX5A-LACE1/AFG1L interaction (turnover of complex IV subunits) is a real characterised contact, but GO:0005515 conveys no specific molecular function. Kept as an experimental IPI, flagged as over-annotation rather than removed. Supporting Evidence: PMID:26759378 the protein interacts physically with COX4 and COX5A subunits of complex IV
GO:0005743 mitochondrial inner membrane	IDA PMID:19393246 Knockdown of human COX17 affects assembly and supramolecular...	ACCEPT	Summary: Experimental (IDA) localisation of COX5A to the mitochondrial inner membrane, consistent with its role as an inner-membrane complex IV subunit and with the UniProt subcellular location. Reason: Correct, specific localisation supported experimentally and by UniProt. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-163214	ACCEPT	Summary: Reactome (TAS) annotation localising COX5A to the mitochondrial inner membrane in the context of the electron-transfer reaction. Correct and consistent with the experimental inner-membrane annotations. Reason: Correct inner-membrane localisation for a complex IV subunit; agrees with EXP/IDA/IEA evidence for GO:0005743. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9709406	ACCEPT	Summary: Reactome (TAS) inner-membrane localisation from a complex IV reaction context. Correct localisation for a complex IV subunit; redundant with the other GO:0005743 annotations. Reason: Correct inner-membrane localisation; consistent with experimental evidence. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9838627	ACCEPT	Summary: Reactome (TAS) inner-membrane localisation in the context of AFG3L2-mediated inner-membrane protein handling. Correct localisation for a complex IV subunit; redundant with the other GO:0005743 annotations. Reason: Correct inner-membrane localisation; consistent with experimental evidence. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9839113	ACCEPT	Summary: Reactome (TAS) inner-membrane localisation in the context of AFG3L2-mediated degradation of inner-membrane proteins. Correct localisation for a complex IV subunit; redundant with the other GO:0005743 annotations. Reason: Correct inner-membrane localisation; consistent with experimental evidence. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865412	ACCEPT	Summary: Reactome (TAS) inner-membrane localisation in the context of complex IV assembly (TIMM21 delivering COX4/COX5A/COX6C to the MT-CO1:MITRAC intermediate). Correct localisation for a complex IV subunit; redundant with the other GO:0005743 annotations. Reason: Correct inner-membrane localisation; consistent with experimental evidence and with COX5A's role in complex IV assembly. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865449	ACCEPT	Summary: Reactome (TAS) inner-membrane localisation in a complex IV assembly reaction (copper insertion into MT-CO1). Correct localisation for a complex IV subunit; redundant with the other GO:0005743 annotations. Reason: Correct inner-membrane localisation; consistent with experimental evidence. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865579	ACCEPT	Summary: Reactome (TAS) inner-membrane localisation in a complex IV assembly reaction (MT-CO1/MT-CO2 association and heme installation). Correct localisation for a complex IV subunit; redundant with the other GO:0005743 annotations. Reason: Correct inner-membrane localisation; consistent with experimental evidence. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865663	ACCEPT	Summary: Reactome (TAS) inner-membrane localisation in a complex IV assembly reaction (MT-CO3, COX6A/B/7A and NDUFA4 binding the holo-MT-CO1,2 complex). Correct localisation for a complex IV subunit; redundant with the other GO:0005743 annotations. Reason: Correct inner-membrane localisation; consistent with experimental evidence. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt Mitochondrion inner membrane
GO:0009055 electron transfer activity	TAS PMID:2853101 Subunit Va of human and bovine cytochrome c oxidase is highl...	MARK AS OVER ANNOTATED	Summary: This MF is annotated with "enables", implying COX5A itself carries electron-transfer activity. However, the redox centres that transfer electrons (heme a, heme a3, Cu_A, Cu_B) reside in the mtDNA-encoded catalytic core subunits MT-CO1 and MT-CO2, not in the non-catalytic nuclear-encoded COX5A. The originating reference (PMID:2853101) is a 1988 cDNA-cloning/conservation paper establishing COX5A as a COX subunit; it does not demonstrate intrinsic electron-transfer activity for COX5A. Reason: Electron transfer is a catalytic activity of the holo-complex located in the mtDNA-encoded core, not an intrinsic molecular function of the structural COX5A subunit. Annotating COX5A as "enables" this activity over-attributes catalysis; COX5A's role is structural (see core_functions, where cytochrome-c oxidase activity is captured as contributes_to at the complex level). Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in
GO:0004129 cytochrome-c oxidase activity	TAS PMID:2853101 Subunit Va of human and bovine cytochrome c oxidase is highl...	MARK AS OVER ANNOTATED	Summary: Cytochrome-c oxidase activity (reduction of O2 to water using electrons from cytochrome c) is the catalytic activity of the assembled complex IV, carried out at the binuclear centre in MT-CO1. COX5A is a non-catalytic structural subunit and does not itself enable this activity; the "enables" annotation over-attributes catalysis to COX5A. Reason: The catalytic cytochrome-c oxidase activity resides in the mtDNA-encoded core (binuclear centre of MT-CO1), not in the structural COX5A subunit. Rather than removing this old TAS annotation, it is flagged as an over-annotation; the appropriate representation is contributes_to GO:0004129 at the complex level (captured in core_functions), with COX5A's own MF being structural molecule activity. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt The BNC reduces molecular oxygen to 2
GO:0005198 structural molecule activity	IBA GO_REF:0000033	NEW	Summary: Proposed molecular-function annotation capturing COX5A's actual role as a non-catalytic structural subunit that provides structural integrity to complex IV, rather than the catalytic cytochrome-c oxidase / electron transfer activities that belong to the mtDNA-encoded core. This is the informative MF for COX5A and is used as its core molecular function. Reason: COX5A is a supernumerary structural subunit; structural molecule activity is the appropriate molecular function, in place of the over-attributed catalytic MF terms (GO:0004129, GO:0009055) which reflect the holo-complex, not this subunit. Supporting Evidence: file:human/COX5A/COX5A-uniprot.txt a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Notes

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