id: P20674
gene_symbol: COX5A
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: COX5A (cytochrome c oxidase subunit 5A, mitochondrial) is a nuclear-encoded,
  non-catalytic structural (supernumerary) subunit of mitochondrial respiratory Complex
  IV (cytochrome c oxidase, COX), the terminal enzyme of the electron transport chain.
  Complex IV transfers electrons from reduced cytochrome c to molecular oxygen, reducing
  it to water, and pumps protons across the mitochondrial inner membrane to help generate
  the proton-motive force that drives oxidative phosphorylation. The catalytic redox
  centres (heme a, heme a3, Cu_A, Cu_B) reside in the three mtDNA-encoded core subunits
  MT-CO1, MT-CO2 and MT-CO3; COX5A is one of the eleven nuclear-encoded supernumerary
  subunits that surround and stabilise this catalytic core. The mature protein is a
  peripheral inner-membrane protein on the matrix side, produced from a precursor with
  a cleaved N-terminal mitochondrial transit peptide. Biallelic loss-of-function variants
  cause mitochondrial complex IV deficiency (nuclear type 20), presenting with pulmonary
  arterial hypertension, lactic acidemia and failure to thrive.
existing_annotations:
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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      "mitochondrial respiratory chain complex IV" GO:0005751 is obsolete).
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: assigned the NDUFA4 subunit into complex-IV
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: 'a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded
        in'
- term:
    id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Correct complex-level process for a complex IV subunit; well supported by
      UniProt function annotation and the phylogenetic inference across orthologs.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Component of the cytochrome c oxidase, the last enzyme in the
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct localisation, consistent with UniProt (mitochondrion inner membrane,
      peripheral membrane protein, matrix side) and with EXP/IDA annotations for the
      same term.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Peripheral membrane protein
- term:
    id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Component of the cytochrome c oxidase, the last enzyme in the
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    reason: Correct complex membership; agrees with all experimental and phylogenetic
      evidence for COX5A as a complex IV subunit.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Component of the cytochrome c oxidase (complex IV, CIV), a
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: 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)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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).
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare "protein binding" from a neurodegeneration-focused interactome screen
      (partners APP, PIK3R1). Uninformative term from a high-throughput dataset.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease
        Proteins
- term:
    id: GO:0006119
    label: oxidative phosphorylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    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).
    action: ACCEPT
    reason: Correct high-level process; complex IV is the terminal oxidase driving oxidative
      phosphorylation. More general than GO:0006123 but not wrong; retained.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: mitochondrial electron transport chain which drives oxidative
- term:
    id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  evidence_type: NAS
  original_reference_id: PMID:30030519
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Correct core complex-level process; agrees with all other evidence for GO:0006123.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: CIV is the terminal oxidase of the electron transport chain in
        mitochondria
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:30030519
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IPI
  original_reference_id: PMID:30030519
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    reason: Direct structural evidence for complex membership; the strongest support for
      the core cellular-component assignment.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: Structure of the intact 14-subunit human cytochrome c oxidase.
- term:
    id: GO:0045333
    label: cellular respiration
  evidence_type: NAS
  original_reference_id: PMID:30030519
  qualifier: involved_in
  review:
    summary: As a complex IV subunit, COX5A participates in cellular respiration. This
      is a correct but high-level (broad parent) process annotation.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: CIV is the terminal oxidase of the electron transport chain in
        mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:30030519
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Experimentally supported, specific, and consistent with UniProt (mitochondrion
      inner membrane; peripheral membrane protein, matrix side). Core localisation.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Matrix side
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct organelle assignment from a high-confidence mitochondrial proteome
      dataset; consistent with all other localisation evidence, though less specific than
      GO:0005743.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and its
        dynamics
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IMP
  original_reference_id: PMID:19393246
  qualifier: part_of
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:19393246
      supporting_text: Knockdown of human COX17 affects assembly and supramolecular
        organization of
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IDA
  original_reference_id: PMID:31536960
  qualifier: part_of
  review:
    summary: Mitochondrial interactome study that maps COX5A within complex IV / the
      respirasome. Direct evidence supporting COX5A as a complex IV subunit.
    action: ACCEPT
    reason: Consistent with structural and phylogenetic evidence for COX5A complex IV
      membership; a legitimate experimental complex-membership annotation.
    supported_by:
    - reference_id: PMID:31536960
      supporting_text: Regulators of the Respirasome and Neurogenesis
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865412
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Matrix side
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31536960
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Interacts with AFG1L (PubMed:26759378). Interacts with RAB5IF
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26759378
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:26759378
      supporting_text: the protein interacts physically with COX4 and COX5A subunits of
        complex IV
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:19393246
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct, specific localisation supported experimentally and by UniProt.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163214
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation for a complex IV subunit; agrees with
      EXP/IDA/IEA evidence for GO:0005743.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709406
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9838627
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9839113
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865412
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation; consistent with experimental evidence
      and with COX5A's role in complex IV assembly.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865449
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865579
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865663
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Correct inner-membrane localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0009055
    label: electron transfer activity
  evidence_type: TAS
  original_reference_id: PMID:2853101
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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).
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: 'a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded
        in'
- term:
    id: GO:0004129
    label: cytochrome-c oxidase activity
  evidence_type: TAS
  original_reference_id: PMID:2853101
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: The BNC reduces molecular oxygen to 2
- term:
    id: GO:0005198
    label: structural molecule activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: NEW
    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.
    supported_by:
    - reference_id: file:human/COX5A/COX5A-uniprot.txt
      supporting_text: 'a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded
        in'
core_functions:
- description: Structural (supernumerary) subunit that assembles into and stabilises
    mitochondrial respiratory chain complex IV (cytochrome c oxidase), surrounding the
    mtDNA-encoded catalytic core; COX5A is non-catalytic and contributes to the complex's
    cytochrome-c oxidase activity through structural integrity rather than enabling catalysis
    itself.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  contributes_to_molecular_function:
    id: GO:0004129
    label: cytochrome-c oxidase activity
  directly_involved_in:
  - id: GO:0006123
    label: mitochondrial electron transport, cytochrome c to oxygen
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  in_complex:
    id: GO:0045277
    label: respiratory chain complex IV
  supported_by:
  - reference_id: PMID:30030519
    supporting_text: assigned the NDUFA4 subunit into complex-IV
  - reference_id: file:human/COX5A/COX5A-uniprot.txt
    supporting_text: 'a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded
      in'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19393246
  title: Knockdown of human COX17 affects assembly and supramolecular organization
    of cytochrome c oxidase.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:26759378
  title: The mammalian homologue of yeast Afg1 ATPase (lactation elevated 1) mediates
    degradation of nuclear-encoded complex IV subunits.
  findings: []
- id: PMID:2853101
  title: Subunit Va of human and bovine cytochrome c oxidase is highly conserved.
  findings: []
- id: PMID:30030519
  title: Structure of the intact 14-subunit human cytochrome c oxidase.
  findings: []
- id: PMID:31536960
  title: Rewiring of the Human Mitochondrial Interactome during Neuronal Reprogramming
    Reveals Regulators of the Respirasome and Neurogenesis.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: Reactome:R-HSA-163214
  title: Electron transfer from reduced cytochrome c to molecular oxygen
  findings: []
- id: Reactome:R-HSA-9709406
  title: CO binds to Cytochrome c oxidase
  findings: []
- id: Reactome:R-HSA-9838627
  title: AFG3L2 binds mitochondrial inner membrane proteins
  findings: []
- id: Reactome:R-HSA-9839113
  title: AFG3L2 degrades mitochondrial inner membrane proteins
  findings: []
- id: Reactome:R-HSA-9865412
  title: TIMM21 carries COX4, COX5A, COX6C to MT-CO1:MITRAC
  findings: []
- id: Reactome:R-HSA-9865449
  title: Metallochaperone inserts Cu2+ into MT-CO1
  findings: []
- id: Reactome:R-HSA-9865579
  title: MT-CO1 and MT-CO2 complexes associate, installing heme moieties
  findings: []
- id: Reactome:R-HSA-9865663
  title: MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex
  findings: []
- id: file:human/COX5A/COX5A-uniprot.txt
  title: UniProtKB P20674 (COX5A_HUMAN) - Cytochrome c oxidase subunit 5A, mitochondrial
  findings: []