id: Q5JTJ3
gene_symbol: COA6
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: COA6 (cytochrome c oxidase assembly factor 6 homolog; formerly C1orf31)
  is a small (~14 kDa) mitochondrial intermembrane-space/inner-membrane assembly factor
  for respiratory chain complex IV (cytochrome c oxidase). It has a twin CX9C motif
  and adopts a CHCH (coiled-coil-helix-coiled-coil-helix) fold typical of IMS redox
  proteins, and is imported via the MIA disulfide-relay pathway. COA6 acts as a
  thiol-disulfide oxidoreductase/copper-relay factor that, together with SCO1, SCO2
  and COX20, mediates copper delivery to and CuA-site metallation of the newly
  synthesized mtDNA-encoded subunit MT-CO2/COX2. It transiently binds the copper
  center of nascent COX2 and reduces the copper-coordinating disulfides of its client
  proteins SCO1 and COX2 to permit copper loading; it is not itself a physiological
  copper-binding protein. Loss of COA6 destabilizes newly synthesized COX2 and blocks
  complex IV assembly. Biallelic loss-of-function variants cause mitochondrial complex
  IV deficiency nuclear type 13 (fatal infantile hypertrophic cardioencephalomyopathy
  with lactic acidosis).
alternative_products:
- name: '1'
  id: Q5JTJ3-1
- name: '2'
  id: Q5JTJ3-2
  sequence_note: VSP_023656
- name: '3'
  id: Q5JTJ3-3
  sequence_note: VSP_023655
existing_annotations:
- term:
    id: GO:0015035
    label: protein-disulfide reductase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) propagation of thiol-disulfide oxidoreductase activity.
      This is directly supported by experimental structural/biochemical work showing
      COA6 acts as a thiol-disulfide oxidoreductase on SCO1 and COX2 to enable copper
      binding.
    action: ACCEPT
    reason: The IBA is corroborated by direct experimental evidence (PMID:31851937)
      that COA6 exhibits thiol-disulfide oxidoreductase activity toward its client
      proteins SCO1 and COX2 in the copper-delivery pathway to complex IV. This is
      the core molecular function of COA6.
    supported_by:
    - reference_id: PMID:31851937
      supporting_text: COA6 adopts a coiled-coil-helix-coiled-coil-helix (CHCH) domain,
        preferentially interacts with SCO1, and exhibits thiol-disulfide oxidoreductase
        activity both in vitro and in vivo, with SCO1 and COX2 being its client proteins.
- term:
    id: GO:0008535
    label: respiratory chain complex IV assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment of a role in complex IV assembly, well
      supported by experimental data across yeast, zebrafish and human cells.
    action: ACCEPT
    reason: Complex IV assembly is a well-established, experimentally supported role
      for COA6. This is a valid (if less specific than GO:0033617) BP term; retained
      as a correct annotation. The more specific mitochondrial term GO:0033617 is
      the core BP.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: shown its requirement for respiratory complex IV biogenesis
        in yeast, zebrafish and human cells
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) mitochondrial localization. Correct but broad; the
      informative localization is the intermembrane space (GO:0005758).
    action: ACCEPT
    reason: COA6 is an evolutionarily conserved mitochondrial protein; mitochondrial
      localization is well established. Broad but not incorrect.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: we have identified a conserved mitochondrial protein, C1orf31/COA6
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro2GO electronic mapping to mitochondrion. Correct but broad.
    action: ACCEPT
    reason: Consistent with experimental localization data; broad but correct.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: we have identified a conserved mitochondrial protein, C1orf31/COA6
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt SubCell mapping to mitochondrial intermembrane space, matching
      the curated experimental subcellular location.
    action: ACCEPT
    reason: This is the informative, specific localization. COA6 is a twin-CX9C IMS
      protein imported by the MIA pathway; UniProt records IMS localization from
      experimental data (PubMed:25339201, 25959673).
    supported_by:
    - reference_id: file:human/COA6/COA6-uniprot.txt
      supporting_text: 'Mitochondrion intermembrane space'
- term:
    id: GO:0008535
    label: respiratory chain complex IV assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO electronic mapping to complex IV assembly, consistent with
      experimental evidence.
    action: ACCEPT
    reason: Correct BP; duplicates the experimentally supported assembly role. Core
      BP is the more specific GO:0033617.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: shown its requirement for respiratory complex IV biogenesis
        in yeast, zebrafish and human cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare protein-binding IPI from a high-throughput binary (HuRI) interactome
      screen, with partners (TTC19, DTX2, CABP2) that are not part of the COX2
      copper-delivery module.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Uninformative ''protein binding'' term. The interactors reported here
      (UniProtKB:Q6DKK2 TTC19, Q86UW9 DTX2, Q9NPB3 CABP2) are high-throughput yeast
      two-hybrid hits with no established role in COA6/complex IV biology and likely
      represent indirect or non-physiological interactions. Per curation guidelines,
      bare protein binding is not retained as an informative function.'
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence localization to mitochondrion. Correct but broad.
    action: ACCEPT
    reason: Direct immunofluorescence evidence for mitochondrial localization; broad
      but correct. The specific compartment is the intermembrane space.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: we have identified a conserved mitochondrial protein, C1orf31/COA6
- term:
    id: GO:0015035
    label: protein-disulfide reductase activity
  evidence_type: IDA
  original_reference_id: PMID:31851937
  qualifier: enables
  review:
    summary: Direct experimental demonstration that COA6 has thiol-disulfide
      oxidoreductase activity toward client proteins SCO1 and COX2, enabling copper
      binding at the CuA site. This is the core molecular function of COA6.
    action: ACCEPT
    reason: Structural (NMR) and biochemical evidence show COA6 adopts a CHCH redox
      fold and reduces the copper-coordinating disulfides of SCO1 and COX2, both
      in vitro and in vivo. This directly grounds the disulfide-reductase MF and is
      the mechanistically informative activity of COA6.
    supported_by:
    - reference_id: PMID:31851937
      supporting_text: COA6 adopts a coiled-coil-helix-coiled-coil-helix (CHCH) domain,
        preferentially interacts with SCO1, and exhibits thiol-disulfide oxidoreductase
        activity both in vitro and in vivo, with SCO1 and COX2 being its client proteins.
    - reference_id: PMID:31851937
      supporting_text: COA6 can reduce the copper-coordinating
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IGI
  original_reference_id: PMID:31851937
  qualifier: involved_in
  review:
    summary: Genetic-interaction evidence for a role in mitochondrial complex IV
      assembly, consistent with COA6's function in the copper-delivery pathway to
      COX2.
    action: ACCEPT
    reason: Core biological process. COA6's oxidoreductase/copper-relay activity is
      required for CuA-site maturation of COX2 during complex IV assembly.
    supported_by:
    - reference_id: PMID:31851937
      supporting_text: COA6 and SCO2 act as disulfide reductases during the stepwise
        transfer of Cu from Cox17 to the CuA site
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:24549041
  qualifier: involved_in
  review:
    summary: Loss-of-function (yeast/zebrafish/human) evidence that COA6 is required
      for complex IV biogenesis. Core biological process.
    action: ACCEPT
    reason: COA6 knockdown/knockout impairs respiratory complex IV assembly across
      species, and copper supplementation rescues the yeast defect, placing COA6 in
      the copper-delivery pathway for CcO assembly.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: shown its requirement for respiratory complex IV biogenesis
        in yeast, zebrafish and human cells
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:25959673
  qualifier: involved_in
  review:
    summary: Loss-of-COA6 experiments show it is specifically required for COX2
      biogenesis during cytochrome c oxidase assembly. Core biological process.
    action: ACCEPT
    reason: COA6 is specifically required for COX2 maturation; its absence causes
      rapid turnover of newly synthesized COX2 and reduced CcO levels, defining COA6
      as a constituent of the mitochondrial copper relay system.
    supported_by:
    - reference_id: PMID:25959673
      supporting_text: COA6 is specifically
        required for COX2 biogenesis
    - reference_id: PMID:25959673
      supporting_text: define COA6 as a constituent of the
        mitochondrial copper relay system, linking defects in COX2 metallation to
        cardiac cytochrome c oxidase deficiency
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:26160915
  qualifier: involved_in
  review:
    summary: COA6 knockout in HEK293T causes complex IV deficiency via impaired COX2
      biogenesis and accumulation of assembly intermediates. Core biological process.
    action: ACCEPT
    reason: Complete loss of COA6 profoundly impairs complex IV biogenesis through
      defective maturation of the copper-bound COX2 subunit, directly supporting the
      assembly-factor role.
    supported_by:
    - reference_id: PMID:26160915
      supporting_text: caused by impaired biogenesis of the copper-bound mitochondrial
        DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly
        intermediates
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteome localization to mitochondrion.
      Correct but broad.
    action: ACCEPT
    reason: Consistent with all other localization evidence; broad but correct.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: human mitochondrial proteome
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: EXP
  original_reference_id: PMID:25959673
  qualifier: located_in
  review:
    summary: Experimental evidence for intermembrane-space localization. This is the
      informative, specific subcellular location of COA6.
    action: ACCEPT
    reason: COA6 is a twin-CX9C IMS protein imported via the MIA pathway; IMS
      localization is the mechanistically relevant compartment where it engages the
      COX2 copper-delivery machinery. UniProt curates IMS from this reference.
    supported_by:
    - reference_id: file:human/COA6/COA6-uniprot.txt
      supporting_text: 'Mitochondrion intermembrane space'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29381136
  qualifier: enables
  review:
    summary: IPI with COX16 (UniProtKB:Q9P0S2), a COX2 metallation/assembly factor.
      The interaction is biologically meaningful but the bare 'protein binding' term
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'The COA6-COX16 interaction is part of the COX2 copper-delivery module,
      but per curation guidelines the generic ''protein binding'' term conveys no
      functional information; the underlying biology is captured by the complex IV
      assembly BP and the disulfide-reductase MF.'
    supported_by:
    - reference_id: PMID:29381136
      supporting_text: Patient mimicking amino acid exchanges in SCO1 and COA6 impact
        COX16 association with these metallochaperones.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28330871
  qualifier: enables
  review:
    summary: IPI with COX20 (UniProtKB:Q5RI15), the COX2-specific chaperone. Meaningful
      module partner but bare 'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'COA6 interacts with COX20 within the COX2 maturation module; however
      generic ''protein binding'' is not retained as an informative function. The
      biology is captured by the assembly-factor BP/MF.'
    supported_by:
    - reference_id: PMID:28330871
      supporting_text: COA6
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29154948
  qualifier: enables
  review:
    summary: IPI with COX20 (UniProtKB:Q5RI15); COA6 co-isolates with COX20 within
      the COX2 biogenesis complex. Bare 'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'COA6 was efficiently co-isolated with COX20 as part of the COX2 maturation
      module, but generic ''protein binding'' is not an informative MF; the assembly
      role is captured elsewhere.'
    supported_by:
    - reference_id: PMID:29154948
      supporting_text: as well as COA6 and TMEM177, were efficiently co-isolated with
        COX20
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IDA
  original_reference_id: PMID:26160915
  qualifier: enables
  review:
    summary: In vitro evidence that COA6 has the capacity to bind copper. Later
      structural/biochemical work shows COA6 is not a physiological copper-binding
      protein and instead acts as a disulfide reductase in the copper relay.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'PMID:26160915 reported that COA6 "has the capacity to bind copper" in
      vitro. However, the definitive structural study (PMID:31851937) demonstrated
      that COA6 is not a Cu-binding protein under physiological conditions and that
      its activity is independent of metalation state, functioning instead as a
      thiol-disulfide oxidoreductase. Copper ion binding therefore over-states the
      physiological function; retained (not removed) as it reflects a real experimental
      observation, but flagged as over-annotation.'
    supported_by:
    - reference_id: PMID:26160915
      supporting_text: COA6 has the capacity to bind copper and can associate with
        newly translated
    - reference_id: PMID:31851937
      supporting_text: We further demonstrate that COA6 is not a Cu-binding protein
        under physiological conditions and that its enzymatic activity is independent
        of metalation state.
- term:
    id: GO:0008535
    label: respiratory chain complex IV assembly
  evidence_type: IDA
  original_reference_id: PMID:25959673
  qualifier: involved_in
  review:
    summary: Direct evidence for a role in complex IV (cytochrome c oxidase) assembly
      via COX2 biogenesis. Core biological process.
    action: ACCEPT
    reason: COA6 is specifically required for COX2 biogenesis during cytochrome c
      oxidase assembly; the more specific mitochondrial term GO:0033617 is the core
      BP.
    supported_by:
    - reference_id: PMID:25959673
      supporting_text: COA6 is specifically
        required for COX2 biogenesis
- term:
    id: GO:0008535
    label: respiratory chain complex IV assembly
  evidence_type: IDA
  original_reference_id: PMID:26160915
  qualifier: involved_in
  review:
    summary: Direct evidence that COA6 is a complex IV assembly factor critical for
      COX2 biogenesis. Core biological process.
    action: ACCEPT
    reason: COA6 loss impairs biogenesis of the copper-bound COX2 subunit and causes
      accumulation of complex IV assembly intermediates; the more specific term
      GO:0033617 is the core BP.
    supported_by:
    - reference_id: PMID:26160915
      supporting_text: caused by impaired biogenesis of the copper-bound mitochondrial
        DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly
        intermediates
- term:
    id: GO:0005758
    label: mitochondrial intermembrane space
  evidence_type: IDA
  original_reference_id: PMID:25339201
  qualifier: located_in
  review:
    summary: Direct experimental localization of COA6 to the mitochondrial
      intermembrane space. Informative, specific subcellular location.
    action: ACCEPT
    reason: IMS localization is the mechanistically relevant compartment; UniProt
      curates this location from PubMed:25339201 (full text). This is the specific
      CC that should be retained as core localization.
    supported_by:
    - reference_id: file:human/COA6/COA6-uniprot.txt
      supporting_text: 'Mitochondrion intermembrane space'
- term:
    id: GO:0008535
    label: respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:24549041
  qualifier: involved_in
  review:
    summary: Loss-of-function evidence (yeast/zebrafish/human) for a required role
      in complex IV biogenesis. Core biological process.
    action: ACCEPT
    reason: COA6 is required for respiratory complex IV biogenesis across species,
      with copper supplementation rescuing the defect; the more specific mitochondrial
      term GO:0033617 is the core BP.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: shown its requirement for respiratory complex IV biogenesis
        in yeast, zebrafish and human cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26160915
  qualifier: enables
  review:
    summary: IPI with SCO1 (UniProtKB:O75880), a copper chaperone and client of COA6's
      disulfide-reductase activity. Meaningful module partner but bare 'protein binding'
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'COA6 associates with the copper chaperone SCO1, one of its oxidoreductase
      clients; however the generic ''protein binding'' term is uninformative and the
      biology is captured by the disulfide-reductase MF and complex IV assembly BP.'
    supported_by:
    - reference_id: PMID:26160915
      supporting_text: COA6 has the capacity to bind copper and can associate with
        newly translated COX2 and the mitochondrial copper chaperone SCO1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959673
  qualifier: enables
  review:
    summary: IPI with SCO2 (UniProtKB:O43819) and MT-CO2/COX2 (UniProtKB:P00403),
      the copper-relay partner and client of COA6. Bare 'protein binding' is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'COA6 interacts with SCO2 and transiently with the copper-containing
      catalytic domain of newly synthesized COX2, within the copper relay system;
      the generic ''protein binding'' term is uninformative and the biology is captured
      by the assembly-factor MF/BP.'
    supported_by:
    - reference_id: PMID:25959673
      supporting_text: COA6 interacts transiently with the copper-containing catalytic
        domain of newly synthesized COX2
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: RNA binding assigned from a global mRNA-interactome capture screen. No
      dedicated evidence that COA6 is a bona fide RNA-binding protein or that RNA
      binding relates to its function.
    action: MARK_AS_OVER_ANNOTATED
    reason: 'This annotation derives from a high-throughput mRNA-bound proteome atlas
      (PMID:22658674). COA6 is a mitochondrial IMS copper-relay/disulfide-reductase
      complex IV assembly factor with no established RNA-binding role; the term is
      an over-annotation likely reflecting nonspecific capture.'
    supported_by:
    - reference_id: PMID:22658674
      supporting_text: Insights into RNA biology from an atlas of mammalian mRNA-binding
        proteins.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer of mitochondrial localization from mouse
      ortholog. Correct but broad.
    action: ACCEPT
    reason: Consistent with experimental localization; broad but correct.
    supported_by:
    - reference_id: PMID:24549041
      supporting_text: we have identified a conserved mitochondrial protein, C1orf31/COA6
core_functions:
- description: Thiol-disulfide oxidoreductase that reduces the copper-coordinating
    disulfides of its client proteins (the copper chaperone SCO1 and the cytochrome
    c oxidase subunit MT-CO2/COX2), enabling copper loading during CuA-site metallation.
  molecular_function:
    id: GO:0015035
    label: protein-disulfide reductase activity
  supported_by:
  - reference_id: PMID:31851937
    supporting_text: COA6 adopts a coiled-coil-helix-coiled-coil-helix (CHCH) domain,
      preferentially interacts with SCO1, and exhibits thiol-disulfide oxidoreductase
      activity both in vitro and in vivo, with SCO1 and COX2 being its client proteins.
- description: Acts as a copper-relay/assembly factor in the mitochondrial intermembrane
    space that mediates copper delivery to and maturation of the mtDNA-encoded subunit
    MT-CO2/COX2, together with SCO1, SCO2 and COX20, and is thereby required for
    biogenesis of respiratory chain complex IV (cytochrome c oxidase).
  directly_involved_in:
  - id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  locations:
  - id: GO:0005758
    label: mitochondrial intermembrane space
  supported_by:
  - reference_id: PMID:25959673
    supporting_text: define COA6 as a constituent of the
      mitochondrial copper relay system, linking defects in COX2 metallation to
      cardiac cytochrome c oxidase deficiency
  - reference_id: PMID:26160915
    supporting_text: caused by impaired biogenesis of the copper-bound mitochondrial
      DNA-encoded subunit COX2 and subsequent accumulation of complex IV assembly
      intermediates
proposed_new_terms: []
suggested_questions:
- question: Does COA6 have a distinct client specificity (SCO1 vs SCO2 vs COX2) in
    vivo, and how is its disulfide-reductase activity re-oxidized within the MIA/IMS
    redox network?
- question: Is the reported in vitro copper-binding capacity of COA6 ever physiologically
    relevant (e.g. transiently during copper hand-off), or is it purely an artifact
    of the reduced apo-protein?
suggested_experiments:
- description: Structure-guided mutagenesis of the CX9C cysteines to separate COA6's
    import (MIA-dependent) requirement from its catalytic disulfide-reductase activity,
    tested by COX2 metallation and complex IV assembly rescue in COA6-knockout cells.
- description: Quantitative redox-state measurement of SCO1/SCO2/COX2 cysteines in
    the presence and absence of COA6 to establish the directionality and kinetics of
    the copper relay.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: file:human/COA6/COA6-uniprot.txt
  title: UniProtKB entry COA6_HUMAN (Q5JTJ3)
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput mRNA-interactome atlas; source of the RNA-binding
      HDA over-annotation, not evidence of a bona fide RNA-binding function for COA6.
- id: PMID:24549041
  title: Copper supplementation restores cytochrome c oxidase assembly defect in a
    mitochondrial disease model of COA6 deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes conserved requirement of COA6 for complex IV biogenesis
      and links it to the mitochondrial copper-delivery pathway; copper rescue.
- id: PMID:25339201
  title: Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic
    cardiomyopathy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Clinical/functional characterization of a COA6-deficient patient;
      supports IMS localization (full text) and disease association (MC4DN13).
- id: PMID:25959673
  title: Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c
    oxidase assembly links two mitochondrial cardiomyopathies.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Defines COA6 as a constituent of the mitochondrial copper relay
      system required specifically for COX2 biogenesis; SCO2 and COX2 interactions.
- id: PMID:26160915
  title: COA6 is a mitochondrial complex IV assembly factor critical for biogenesis
    of mtDNA-encoded COX2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: COA6 knockout impairs COX2 biogenesis and complex IV assembly;
      reports in vitro copper-binding capacity and SCO1 association.
- id: PMID:28330871
  title: Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently
    as a membrane insertase within the subunit 2 maturation module.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Places COA6 within the COX2 maturation module; source of a
      COX20-interaction IPI (over-annotated as bare protein binding).
- id: PMID:29154948
  title: The mitochondrial TMEM177 associates with COX20 during COX2 biogenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: COA6 co-isolates with COX20 in the COX2 biogenesis complex; source
      of a COX20-interaction IPI.
- id: PMID:29381136
  title: COX16 promotes COX2 metallation and assembly during respiratory complex IV
    biogenesis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: COA6-COX16 association within the COX2 copper-delivery module;
      source of a COX16-interaction IPI.
- id: PMID:31851937
  title: COA6 Is Structurally Tuned to Function as a Thiol-Disulfide Oxidoreductase
    in Copper Delivery to Mitochondrial Cytochrome c Oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive structural/biochemical study establishing COA6's CHCH
      fold and thiol-disulfide oxidoreductase activity toward SCO1/COX2; shows COA6
      is not a physiological copper-binding protein.
- 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 interactome; source of protein-binding
      IPIs to TTC19/DTX2/CABP2 that are not part of the COX2 module (over-annotated).
- 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-throughput mitochondrial proteome; corroborates mitochondrial
      localization of COA6.