id: Q5RI15
gene_symbol: COX20
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  COX20 (also known as FAM36A) is a small (118 aa) multi-pass protein of the
  mitochondrial inner membrane that acts as a non-catalytic assembly chaperone
  for cytochrome c oxidase (respiratory chain complex IV, CIV), specific to the
  core catalytic subunit MT-CO2 (COX2). Following its mitochondrial synthesis,
  MT-CO2 engages COX20, which binds and stabilises the newly synthesised protein
  during insertion of its N-proximal transmembrane domain and chaperones it
  through membrane insertion and maturation of its binuclear copper CuA centre by
  the metallochaperones SCO1 and SCO2 (together with COA6, COX18 and TMEM177),
  delivering mature MT-CO2 into the assembling CIV holoenzyme. COX20 has no known
  catalytic activity; its role is to hold and present MT-CO2 to the copper
  metallation machinery. Loss of COX20 causes a severe, isolated CIV deficiency
  in which cells accumulate CIV subassemblies containing COX1/COX4 but lacking
  COX2. Biallelic loss-of-function variants cause mitochondrial complex IV
  deficiency, nuclear type 11 (MC4DN11), an autosomal recessive disorder with
  childhood/adolescent onset presenting with cerebellar ataxia, dystonia,
  choreoathetotic movements, dysarthria and muscle hypotonia.
alternative_products:
- name: '1'
  id: Q5RI15-1
- name: '2'
  id: Q5RI15-2
  sequence_note: VSP_014855
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing COX20 in the mitochondrion. This is
      correct but is the general organelle term; COX20 acts specifically at the
      mitochondrial inner membrane (GO:0005743), which is annotated experimentally.
    action: ACCEPT
    reason: >-
      COX20 is a well-established mitochondrial protein; the IBA annotation is
      accurate at the organelle level, though non-core relative to the more
      precise inner-membrane localization.
    supported_by:
      - reference_id: PMID:29154948
        supporting_text: >-
          Upon synthesis, COX2 engages with COX20 in the inner mitochondrial
          membrane, a scaffold protein that recruits metallochaperones for copper
          delivery to the CuA-Site of COX2.
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation to mitochondrial respiratory chain complex IV
      assembly. This is the core biological process of COX20 and is strongly
      corroborated by human experimental data (IMP) and by conserved function
      across the COX20 family.
    action: ACCEPT
    reason: >-
      Direct experimental evidence in human cells establishes COX20 as required
      for complex IV assembly; the IBA annotation is at the correct level of
      specificity and represents the gene's core function.
    supported_by:
      - reference_id: PMID:23125284
        supporting_text: >-
          These results establish the function of the human gene FAM36A/COX20 in
          complex IV assembly and support a causal role of the gene in complex IV
          deficiency.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (IEA) annotation of inner-membrane localization based on
      InterPro/UniProt-SubCell mapping. This matches the experimentally determined
      subcellular location and the multi-pass topology of the protein.
    action: ACCEPT
    reason: >-
      COX20 is an inner mitochondrial membrane multi-pass protein; the electronic
      inner-membrane assignment agrees with experimental (IDA/EXP) evidence and is
      the core location.
    supported_by:
      - reference_id: file:human/COX20/COX20-uniprot.txt
        supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      Electronic (IEA) InterPro2GO annotation to complex IV assembly, derived from
      the Cox20 InterPro signature (IPR022533). This is consistent with the
      experimentally supported core function.
    action: ACCEPT
    reason: >-
      The InterPro Cox20 family signature reliably predicts a role in cytochrome c
      oxidase assembly; this agrees with the experimental IMP annotations.
    supported_by:
      - reference_id: PMID:24403053
        supporting_text: >-
          We propose that COX20 acts as a chaperone in the early steps of COX2
          maturation, stabilizing the newly synthesized protein and presenting
          COX2 to its metallochaperone module, which in turn facilitates the
          incorporation of mature COX2 into the CIV assembly line.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from the HuRI large-scale binary (yeast two-hybrid)
      interactome map. The listed partners (AQP6, CHIA, CREB3L1, DYNC1H1, ERGIC3,
      FUNDC2, GET1, GJA8, GOLT1A, JAGN1, MAOB, MENT, NCBP2AS2, PGRMC2, SLC10A1,
      SLC10A6, TCEA2, TEX44, TMEM35A, TMX2) are overwhelmingly non-mitochondrial
      secretory/plasma-membrane proteins with no relationship to complex IV
      assembly; these are high-throughput screen hits, not functional partners.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Uninformative "protein binding" from a proteome-wide Y2H screen; the
      interactors are biologically unrelated to COX20's function and the term adds
      no functional information. Retained as over-annotated rather than removed,
      as it derives from experimental IPI evidence.
    supported_by:
      - reference_id: PMID:32296183
        supporting_text: >-
          Here we present a human 'all-by-all' reference interactome map of human
          binary protein interactions, or 'HuRI'.
      - reference_id: PMID:32296183
        supporting_text: >-
          With approximately 53,000 protein-protein interactions, HuRI has
          approximately four times as many such interactions as there are
          high-quality curated interactions from small-scale studies.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA) localization to mitochondrion. Correct but at
      the organelle level; the experimentally resolved location is the inner
      membrane.
    action: ACCEPT
    reason: >-
      Accurate organelle-level localization consistent with all other evidence,
      though non-core relative to the more specific inner-membrane term.
    supported_by:
      - reference_id: PMID:29154948
        supporting_text: >-
          Upon synthesis, COX2 engages with COX20 in the inner mitochondrial
          membrane, a scaffold protein that recruits metallochaperones for copper
          delivery to the CuA-Site of COX2.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput identification of COX20 in the high-confidence human
      mitochondrial proteome (MitoCoP). Confirms mitochondrial residence at the
      organelle level.
    action: ACCEPT
    reason: >-
      COX20 is a bona fide mitochondrial protein captured in a rigorous
      quantitative mitochondrial proteome; consistent with all other evidence,
      non-core relative to the inner-membrane term.
    supported_by:
      - reference_id: PMID:34800366
        supporting_text: >-
          mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP).
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: EXP
  original_reference_id: PMID:29154948
  qualifier: located_in
  review:
    summary: >-
      Experimental localization of COX20 to the mitochondrial inner membrane,
      where it acts as the MT-CO2 assembly scaffold. This is the core subcellular
      location.
    action: ACCEPT
    reason: >-
      Directly demonstrated inner-membrane localization consistent with the
      protein's multi-pass topology and its role in MT-CO2 membrane insertion and
      copper metallation.
    supported_by:
      - reference_id: PMID:29154948
        supporting_text: >-
          Upon synthesis, COX2 engages with COX20 in the inner mitochondrial
          membrane, a scaffold protein that recruits metallochaperones for copper
          delivery to the CuA-Site of COX2.
      - reference_id: PMID:29154948
        supporting_text: residing in the inner membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23125284
  qualifier: enables
  review:
    summary: >-
      "Protein binding" (IPI) recording the physiologically important interaction
      of COX20 with newly synthesised MT-CO2/COX2, demonstrated by co-purification.
      The interaction is central to COX20's function, but the bare GO:0005515 term
      does not convey that; the biology is captured by the complex IV assembly BP.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The MT-CO2 interaction is real and functionally central, but "protein
      binding" is uninformative as a molecular-function annotation. Marked as
      over-annotated (not removed) since it is supported by experimental IPI
      evidence; the functional content is represented by GO:0033617.
    supported_by:
      - reference_id: PMID:23125284
        supporting_text: >-
          We observe co-purification of FAM36A and COX2 proteins, supporting that
          the FAM36A defect hampers the early step of complex IV assembly at the
          incorporation of the COX2 subunit.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24403053
  qualifier: enables
  review:
    summary: >-
      "Protein binding" (IPI) capturing the interactions of COX20 with newly
      synthesised COX2 and with the SCO1/SCO2 metallochaperone module during CIV
      assembly. Functionally important interactions, but the bare term is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Genuine, functionally central interactions (COX2, SCO1/SCO2) supported by
      experimental IPI, but "protein binding" adds no molecular-function
      information; the biology is represented by the complex IV assembly BP.
    supported_by:
      - reference_id: PMID:24403053
        supporting_text: Additionally, we show that SCO1 and SCO2 act on COX20-bound COX2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28330871
  qualifier: enables
  review:
    summary: >-
      "Protein binding" (IPI) for the interactions of COX20 within the MT-CO2
      maturation module (COX2, COX18, SCO1/SCO2/COA6). Functionally central but
      uninformative as a molecular-function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Real, mechanistically important interactions supported by experimental IPI,
      but the bare "protein binding" term conveys no molecular function; captured
      instead by the complex IV assembly BP.
    supported_by:
      - reference_id: PMID:28330871
        supporting_text: >-
          The release of COX18 from this complex coincides with the binding of the
          SCO1-SCO2-COA6 copper metallation module to COX2-COX20 to finalize COX2
          biogenesis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29154948
  qualifier: enables
  review:
    summary: >-
      "Protein binding" (IPI) for the COX20 interaction network including
      TMEM177, COA6, MT-CO2, SCO1 and SCO2 during COX2 biogenesis. Functionally
      relevant but uninformative as a molecular-function annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Physiologically meaningful interactions supported by experimental IPI, but
      "protein binding" provides no molecular-function content; the biology is
      represented by the complex IV assembly BP.
    supported_by:
      - reference_id: PMID:29154948
        supporting_text: >-
          TMEM177 associates with newly synthesized COX2 and SCO2 in a
          COX20-dependent manner.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:23125284
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) localization of COX20 to the mitochondrial inner
      membrane, consistent with its topology and MT-CO2 chaperone role. Core
      location.
    action: ACCEPT
    reason: >-
      Directly demonstrated inner-membrane localization; agrees with the
      multi-pass membrane topology and independent experimental data.
    supported_by:
      - reference_id: PMID:29154948
        supporting_text: residing in the inner membrane
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:24403053
  qualifier: located_in
  review:
    summary: >-
      Direct experimental (IDA) localization of COX20 to the mitochondrial inner
      membrane, where it stabilises MT-CO2 and presents it to the copper
      metallochaperones. Core location.
    action: ACCEPT
    reason: >-
      Independent experimental confirmation of inner-membrane localization,
      consistent with all other evidence and the protein's function.
    supported_by:
      - reference_id: PMID:24403053
        supporting_text: >-
          These cell lines exhibit a severe, isolated CIV deficiency due to
          instability of COX2, a mitochondrion-encoded CIV subunit.
      - reference_id: PMID:29154948
        supporting_text: residing in the inner membrane
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:23125284
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype (IMP) evidence: a homozygous FAM36A/COX20 mutation causes
      complex IV deficiency, with cells accumulating COX1-containing CIV
      subassemblies devoid of COX2. Establishes COX20's core role in CIV assembly.
    action: ACCEPT
    reason: >-
      Loss-of-function in patient cells directly demonstrates that COX20 is
      required for cytochrome c oxidase (complex IV) assembly; this is the core
      biological process.
    supported_by:
      - reference_id: PMID:23125284
        supporting_text: >-
          Cells affected by the mutation accumulate subassemblies of complex IV
          that contain COX1 but are almost devoid of COX2 protein.
      - reference_id: PMID:23125284
        supporting_text: >-
          These results establish the function of the human gene FAM36A/COX20 in
          complex IV assembly and support a causal role of the gene in complex IV
          deficiency.
- term:
    id: GO:0033617
    label: mitochondrial respiratory chain complex IV assembly
  evidence_type: IMP
  original_reference_id: PMID:24403053
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype (IMP) evidence from COX20 knockdown/knockout human cell
      lines showing severe isolated CIV deficiency due to COX2 instability, with
      accumulation of COX1/COX4 subassemblies. Confirms the core assembly role.
    action: ACCEPT
    reason: >-
      Independent loss-of-function evidence establishes COX20 as required for
      complex IV assembly, acting as a chaperone that stabilises MT-CO2 and
      presents it to the copper metallation module.
    supported_by:
      - reference_id: PMID:24403053
        supporting_text: >-
          These cell lines exhibit a severe, isolated CIV deficiency due to
          instability of COX2, a mitochondrion-encoded CIV subunit.
      - reference_id: PMID:24403053
        supporting_text: >-
          We propose that COX20 acts as a chaperone in the early steps of COX2
          maturation, stabilizing the newly synthesized protein and presenting
          COX2 to its metallochaperone module, which in turn facilitates the
          incorporation of mature COX2 into the CIV assembly line.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9865630
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author (TAS) inner-membrane localization associated with
      the reaction in which the metallochaperone inserts copper into MT-CO2. COX20
      operates at the inner membrane in this step. Consistent with experimental
      data.
    action: ACCEPT
    reason: >-
      Curated pathway evidence agreeing with the experimentally determined
      inner-membrane location.
    supported_by:
      - reference_id: PMID:29154948
        supporting_text: >-
          Upon synthesis, COX2 engages with COX20 in the inner mitochondrial
          membrane, a scaffold protein that recruits metallochaperones for copper
          delivery to the CuA-Site of COX2.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9902096
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author (TAS) inner-membrane localization for the reaction
      in which COX18 inserts nascent MT-CO2 into the COX20:TMEM177 chaperone
      complex. COX20 acts at the inner membrane. Consistent with experimental data.
    action: ACCEPT
    reason: >-
      Curated pathway evidence agreeing with the experimentally determined
      inner-membrane location and COX20's chaperone role in MT-CO2 biogenesis.
    supported_by:
      - reference_id: PMID:28330871
        supporting_text: >-
          We demonstrate that COX20 stabilizes COX2 during insertion of its
          N-proximal transmembrane domain
core_functions:
- description: >-
    Non-catalytic inner-membrane assembly chaperone/scaffold that mediates
    incorporation of the core catalytic subunit MT-CO2 (COX2) into cytochrome c
    oxidase (respiratory chain complex IV). COX20 binds and stabilises newly
    synthesised MT-CO2 during membrane insertion and presents it to the
    SCO1/SCO2 metallochaperones for CuA copper delivery, driving cytochrome c
    oxidase assembly.
  directly_involved_in:
    - id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
  locations:
    - id: GO:0005743
      label: mitochondrial inner membrane
  supported_by:
    - reference_id: PMID:24403053
      supporting_text: >-
        We propose that COX20 acts as a chaperone in the early steps of COX2
        maturation, stabilizing the newly synthesized protein and presenting COX2
        to its metallochaperone module, which in turn facilitates the
        incorporation of mature COX2 into the CIV assembly line.
    - reference_id: PMID:23125284
      supporting_text: >-
        These results establish the function of the human gene FAM36A/COX20 in
        complex IV assembly and support a causal role of the gene in complex IV
        deficiency.
    - reference_id: PMID:29154948
      supporting_text: >-
        Upon synthesis, COX2 engages with COX20 in the inner mitochondrial
        membrane, a scaffold protein that recruits metallochaperones for copper
        delivery to the CuA-Site of COX2.
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:23125284
  title: A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome
    c oxidase assembly and is associated with ataxia and muscle hypotonia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Identifies FAM36A/COX20 as required for complex IV assembly; patient
      mutation causes CIV deficiency with COX2-devoid subassemblies. Basis for the
      core BP and inner-membrane annotations.
- id: PMID:24403053
  title: Human COX20 cooperates with SCO1 and SCO2 to mature COX2 and promote the
    assembly of cytochrome c oxidase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes COX20 as a chaperone that stabilises newly synthesised COX2 and
      presents it to SCO1/SCO2 for CuA metallation; knockout causes isolated CIV
      deficiency. Primary support for the core function.
- 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: HIGH
    correctness: VERIFIED
    review_notes: >-
      Places COX20 in the MT-CO2 maturation module; COX20 stabilises COX2 during
      N-proximal TM insertion, then the SCO1-SCO2-COA6 module binds COX2-COX20.
- id: PMID:29154948
  title: The mitochondrial TMEM177 associates with COX20 during COX2 biogenesis.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Describes COX20 as an inner-membrane scaffold that recruits metallochaperones
      for CuA-site copper delivery to COX2; defines the COX20 interaction network.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI proteome-wide binary (Y2H) interactome. Source of many bare
      protein-binding IPIs whose partners are non-mitochondrial and unrelated to
      COX20 function; high-throughput, not functionally informative for this gene.
- 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: >-
      MitoCoP high-confidence mitochondrial proteome; corroborates COX20's
      mitochondrial localization at the organelle level.
- id: Reactome:R-HSA-9865630
  title: Metallochaperone inserts 2Cu2+ into MT-CO2
  findings: []
- id: Reactome:R-HSA-9902096
  title: COX18 inserts nascent MT-CO2 in COX20:TMEM77
  findings: []
- id: file:human/COX20/COX20-uniprot.txt
  title: UniProtKB Q5RI15 (COX20_HUMAN) curated entry
  findings: []