id: P24311
gene_symbol: COX7B
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: COX7B (cytochrome c oxidase subunit 7B, mitochondrial; polypeptide VIIb)
  is a small, nuclear-encoded structural subunit of mitochondrial respiratory Complex
  IV (cytochrome c oxidase, COX/CIV), the terminal enzyme of the electron transport
  chain. Complex IV comprises a mitochondrially encoded catalytic core (MT-CO1, MT-CO2,
  MT-CO3) that carries out the reduction of oxygen to water, together with nuclear-encoded
  supernumerary subunits, of which COX7B is one. COX7B is a non-catalytic subunit that
  surrounds and supports the catalytic core and contributes to assembly and stability
  of the holoenzyme; it is a single-pass protein of the mitochondrial inner membrane
  (matrix-facing N-terminus, transmembrane helix, intermembrane-space C-terminus) synthesized
  as an 80-residue precursor with a cleaved mitochondrial transit peptide. Through its
  role in Complex IV it participates in mitochondrial electron transport from cytochrome
  c to oxygen and in oxidative phosphorylation. In humans COX7B is X-linked, and deleterious
  mutations cause an X-linked disorder, linear skin defects with multiple congenital
  anomalies (LSDMCA2), within the microphthalmia-with-linear-skin-defects (MLS/MIDAS)
  spectrum, an unconventional mitochondrial disease with a prominent neurodevelopmental
  phenotype.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: COX7B is a subunit of mitochondrial Complex IV and localizes to the mitochondrion.
      This phylogenetic (IBA) mitochondrial annotation is correct but general; the precise
      location is the mitochondrial inner membrane (GO:0005743).
    action: ACCEPT
    reason: Correct localization to the mitochondrion, consistent with COX7B being a
      cytochrome c oxidase subunit of the inner membrane. Retained as a correct but
      non-core (broad) cellular component; the specific inner-membrane term captures
      the core localization.
    supported_by:
    - reference_id: PMID:8382530
      supporting_text: Isolation of a cDNA specifying subunit VIIb of human cytochrome
        c oxidase.
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: COX7B is a constitutive structural subunit of respiratory chain complex
      IV (cytochrome c oxidase). This phylogenetic annotation captures the core cellular
      component/complex membership of the gene.
    action: ACCEPT
    reason: Complex IV membership is the defining property of COX7B, supported by structural
      and biochemical evidence that it is one of the 11 nuclear-encoded supernumerary
      subunits of the 14-subunit human cytochrome c oxidase. GO:0045277 is the current,
      non-obsolete term for this complex.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: the intact monomeric complex-IV contains 14 subunits
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: COX7A2 (or COX7A1), COX7B, COX7C, COX8A and COXFA4, which are
        encoded
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: COX7B is a single-pass protein of the mitochondrial inner membrane, where
      Complex IV resides. This UniProt subcellular-location mapping is accurate and
      represents the core cellular component.
    action: ACCEPT
    reason: The inner mitochondrial membrane is the precise, experimentally supported
      localization of COX7B and of the whole cytochrome c oxidase complex.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Single-pass membrane protein
    - reference_id: PMID:30030519
      supporting_text: CIV is the terminal oxidase of the electron transport chain in
        mitochondria
- 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: As a subunit of Complex IV, COX7B participates in mitochondrial electron
      transport from cytochrome c to oxygen. This InterPro2GO mapping (from the COX7B/VIIb
      family signature) assigns the correct core biological process.
    action: ACCEPT
    reason: GO:0006123 is the process carried out by the complex to which COX7B belongs
      and is the appropriate core BP for this structural subunit.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: It accepts electrons from cytochrome c to reduce the oxygen to
        water
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: This ARBA machine-learning annotation places COX7B in the generic 'membrane'
      component. It is not wrong (COX7B is an integral membrane protein) but is far
      more general than the well-supported mitochondrial inner membrane term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic 'membrane' term is uninformative given the precise, experimentally
      supported mitochondrial inner membrane localization (GO:0005743). Retained but
      flagged as over-general.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Single-pass membrane protein
- term:
    id: GO:1902600
    label: proton transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: This annotation is inferred by an inter-ontology logical link from the
      cytochrome-c oxidase activity of Complex IV (the complex pumps protons across
      the inner membrane). Proton pumping is a property of the mtDNA-encoded catalytic
      core; COX7B is a non-catalytic structural subunit that does not itself translocate
      protons.
    action: KEEP_AS_NON_CORE
    reason: Complex IV does contribute to proton transmembrane transport, so the annotation
      is not incorrect at the complex level, but for the individual non-catalytic COX7B
      subunit this is a peripheral, complex-level property rather than a core function.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: pumps two protons from the matrix side to the intermembrane space
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: A single high-throughput binary (yeast two-hybrid) interaction with GNMT
      (Q14749) reported in the HuRI human interactome map. Bare 'protein binding' provides
      no informative molecular function, and this cytosolic-methyltransferase partner
      has no clear relationship to an inner-membrane Complex IV subunit.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative 'protein binding' from a single large-scale Y2H screen; it
      does not capture COX7B's actual molecular function (structural subunit of Complex
      IV). Retained (not removed) per policy on high-throughput IPI protein-binding
      annotations, but flagged as over-annotation.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions,
        or 'HuRI'
- term:
    id: GO:0006119
    label: oxidative phosphorylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: Complex IV, and hence COX7B, participates in oxidative phosphorylation
      by contributing to the electron transport chain that builds the proton-motive
      force driving ATP synthase. This UniPathway-based mapping is correct but broader
      than the specific electron-transport process.
    action: ACCEPT
    reason: Correct higher-level biological process for a Complex IV subunit; kept as
      a correct, non-core (broader) BP relative to GO:0006123.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Energy metabolism; oxidative phosphorylation
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: electrochemical gradient over the inner membrane
- 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 (CPX-6123) NAS annotation of the core electron-transport
      process for a Complex IV subunit, based on the intact 14-subunit human cytochrome
      c oxidase structure. Duplicates the InterPro IEA assignment of the same core BP.
    action: ACCEPT
    reason: Correct core biological process for COX7B as a Complex IV subunit; consistent
      with the structural characterization of the complex.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: It accepts electrons from cytochrome c to reduce the oxygen to
        water
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:30030519
  qualifier: located_in
  review:
    summary: ComplexPortal IDA localization to the mitochondrial membrane, from the
      cryo-EM structure of human Complex IV. Correct, though broader than the mitochondrial
      inner membrane term that specifies COX7B's exact location.
    action: ACCEPT
    reason: Accurate mitochondrial-membrane localization supported by structural data;
      retained as a correct but non-core (broader) cellular component relative to GO:0005743.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: CIV is the terminal oxidase of the electron transport chain in
        mitochondria
- term:
    id: GO:0045277
    label: respiratory chain complex IV
  evidence_type: IPI
  original_reference_id: PMID:30030519
  qualifier: part_of
  review:
    summary: ComplexPortal IPI membership of respiratory chain complex IV, established
      by the intact 14-subunit human cytochrome c oxidase structure in which COX7B is
      resolved as a subunit. This is the core complex membership for COX7B.
    action: ACCEPT
    reason: Directly supported structural evidence that COX7B is part of complex IV;
      GO:0045277 is the current term for the complex.
    supported_by:
    - reference_id: PMID:30030519
      supporting_text: the intact monomeric complex-IV contains 14 subunits
- term:
    id: GO:0045333
    label: cellular respiration
  evidence_type: NAS
  original_reference_id: PMID:30030519
  qualifier: involved_in
  review:
    summary: ComplexPortal NAS annotation to cellular respiration, the broad process
      encompassing the electron transport chain and oxidative phosphorylation to which
      Complex IV contributes.
    action: ACCEPT
    reason: Correct high-level biological process for a Complex IV subunit; retained
      as a correct, non-core (broad) BP relative to the specific cytochrome-c-to-oxygen
      electron transport term.
    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 (structural) localization of COX7B to the mitochondrial inner
      membrane, consistent with UniProt topology (matrix-facing N-terminus, single transmembrane
      helix, intermembrane-space C-terminus). This is the core cellular component.
    action: ACCEPT
    reason: The mitochondrial inner membrane is the precise, experimentally supported
      localization of COX7B within Complex IV.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Single-pass membrane protein
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput detection of COX7B in the high-confidence human mitochondrial
      proteome. Correct mitochondrial localization, though general relative to the inner-membrane
      term.
    action: ACCEPT
    reason: Supports mitochondrial localization of COX7B; retained as a correct but
      non-core (broad) cellular component.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: human mitochondrial proteome
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-163214
  qualifier: located_in
  review:
    summary: Reactome traceable-author-statement localization of COX7B to the mitochondrial
      inner membrane in the context of electron transfer from reduced cytochrome c to
      molecular oxygen. Consistent with the core localization.
    action: ACCEPT
    reason: Correct inner-membrane localization from a curated pathway resource; consistent
      with experimental and structural evidence.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Single-pass membrane protein
- 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 localization of COX7B to the mitochondrial inner membrane
      (in the CO-binding-to-cytochrome-c-oxidase reaction context). Consistent with
      the core localization.
    action: ACCEPT
    reason: Correct inner-membrane localization from a curated pathway resource.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Single-pass membrane protein
- 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 localization of COX7B to the mitochondrial inner membrane
      (Complex IV assembly context, MT-CO1/MT-CO2 heme installation). Consistent with
      the core localization.
    action: ACCEPT
    reason: Correct inner-membrane localization from a curated pathway resource.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Single-pass membrane protein
- 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 localization of COX7B to the mitochondrial inner membrane
      (Complex IV assembly context in which COX7B binds the holo-MT-CO1,2 complex).
      Consistent with the core localization.
    action: ACCEPT
    reason: Correct inner-membrane localization from a curated pathway resource; the
      assembly context is consistent with COX7B being a supernumerary subunit added
      during Complex IV biogenesis.
    supported_by:
    - reference_id: file:human/COX7B/COX7B-uniprot.txt
      supporting_text: Single-pass membrane protein
- term:
    id: GO:0007417
    label: central nervous system development
  evidence_type: IMP
  original_reference_id: PMID:23122588
  qualifier: involved_in
  review:
    summary: COX7B knockdown in medaka recapitulates the microphthalmia-with-linear-skin-lesions
      (MLS) phenotype with microcephaly and microphthalmia, demonstrating that Complex
      IV activity is required for vertebrate CNS development. This is a downstream developmental
      consequence of loss of cytochrome c oxidase activity rather than a distinct molecular
      role of COX7B.
    action: KEEP_AS_NON_CORE
    reason: The developmental/neurodevelopmental phenotype is a genuine, experimentally
      supported organismal consequence of COX7B loss-of-function (its disease mechanism),
      but it reflects the general requirement for Complex IV activity in energy metabolism,
      not a core molecular function of this structural subunit. Retained as an important
      non-core annotation.
    supported_by:
    - reference_id: PMID:23122588
      supporting_text: essential function of complex IV activity in vertebrate CNS development
    - reference_id: PMID:23122588
      supporting_text: COX7B encodes a poorly characterized structural subunit of cytochrome
        c oxidase
- term:
    id: GO:0004129
    label: cytochrome-c oxidase activity
  evidence_type: TAS
  original_reference_id: PMID:8382530
  qualifier: enables
  review:
    summary: This legacy TAS annotation assigns the whole-complex catalytic cytochrome-c
      oxidase activity to COX7B. COX7B is a non-catalytic supernumerary subunit; the
      oxygen-reduction chemistry is performed by the mtDNA-encoded catalytic core (MT-CO1,
      MT-CO2). The cited paper reports the cDNA of the nuclear-encoded structural subunit
      VIIb, not that COX7B itself catalyzes the reaction.
    action: MODIFY
    reason: COX7B does not itself enable cytochrome-c oxidase catalysis; its molecular
      function is structural, contributing to the integrity and assembly of the complex
      that performs catalysis. Replace the catalytic MF with structural molecule activity
      (GO:0005198). The catalytic activity is retained at the complex level via contributes_to
      in core_functions.
    proposed_replacement_terms:
    - id: GO:0005198
      label: structural molecule activity
    supported_by:
    - reference_id: PMID:8382530
      supporting_text: the last remaining uncharacterized nuclear-encoded
    - reference_id: PMID:23122588
      supporting_text: COX7B encodes a poorly characterized structural subunit of cytochrome
        c oxidase
core_functions:
- description: Structural (non-catalytic) subunit of mitochondrial respiratory Complex
    IV (cytochrome c oxidase) that contributes to assembly and stability of the holoenzyme,
    supporting electron transport from cytochrome c to oxygen in the mitochondrial inner
    membrane.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  supported_by:
  - reference_id: PMID:23122588
    supporting_text: COX7B encodes a poorly characterized structural subunit of cytochrome
      c oxidase
  - reference_id: PMID:30030519
    supporting_text: the intact monomeric complex-IV contains 14 subunits
  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
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:23122588
  title: Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional
    mitochondrial disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary paper establishing COX7B as a structural subunit of cytochrome
      c oxidase indispensable for COX assembly, COX activity, and mitochondrial respiration;
      links loss-of-function to LSDMCA2/MLS and to a CNS-development requirement via
      medaka knockdown.
- id: PMID:30030519
  title: Structure of the intact 14-subunit human cytochrome c oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cryo-EM structure of the intact 14-subunit human cytochrome c oxidase;
      supports COX7B complex-IV membership, inner-membrane localization, and the electron-transport
      function of the complex.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI high-throughput binary Y2H interactome; source of the single
      uninformative 'protein binding' (COX7B-GNMT) IPI, not a functional study of COX7B.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: High-confidence human mitochondrial proteome; corroborates mitochondrial
      localization of COX7B.
- id: PMID:8382530
  title: Isolation of a cDNA specifying subunit VIIb of human cytochrome c oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original isolation of the human COX7B (subunit VIIb) cDNA, establishing
      it as a nuclear-encoded structural subunit of cytochrome c oxidase (80-aa precursor,
      24-aa leader). Abstract-only in cache; supports structural-subunit identity, not
      catalysis.
- 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-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/COX7B/COX7B-uniprot.txt
  title: UniProtKB entry P24311 (COX7B_HUMAN)
  findings: []