id: Q8N5M1
gene_symbol: ATPAF2
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATPAF2 (ATP12 homolog) is a mitochondrial molecular chaperone that acts
  as an assembly factor for the F1 catalytic sector of mitochondrial ATP synthase
  (Complex V). Encoded in the nucleus and imported into mitochondria via an N-terminal
  transit peptide, it binds the unassembled F1 alpha subunit (ATP5F1A) during assembly
  and prevents non-productive self-aggregation of the alpha subunit, thereby promoting
  formation of the alpha3-beta3 catalytic core. It is a non-catalytic chaperone (ATP12
  family) rather than an enzyme. It acts at the matrix face of the mitochondrial inner
  membrane. Loss of function causes mitochondrial complex V (ATP synthase) deficiency,
  a severe encephalopathy/encephalomyopathy (MC5DN1) that can present with
  3-methylglutaconic aciduria.
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) inference placing ATPAF2 activity in the mitochondrion.
      Consistent with all experimental and computational evidence; ATPAF2 is imported
      into mitochondria and acts on the F1 sector of ATP synthase.
    action: ACCEPT
    reason: Correct compartment, appropriately general. A more specific location
      (mitochondrial matrix / inner membrane) is captured in core_functions and by
      other annotations.
    supported_by:
    - reference_id: file:human/ATPAF2/ATPAF2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0033615
    label: mitochondrial proton-transporting ATP synthase complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) inference that ATPAF2 is involved in assembly of the
      mitochondrial proton-transporting ATP synthase (Complex V). This is the core
      biological process of the gene, and matches the yeast Atp12p ortholog and human
      experimental data.
    action: ACCEPT
    reason: Specific, well-supported BP capturing the central role of ATPAF2 as an
      F1 assembly factor. This is a core function.
    supported_by:
    - reference_id: PMID:11410595
      supporting_text: proteins required for assembly of the
    - reference_id: PMID:14701807
      supporting_text: Atp12p binds to unassembled
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation from UniProt Subcellular Location mapping. UniProt
      records ATPAF2 as a peripheral inner-membrane protein, consistent with its role
      acting on the soluble F1 sector at the matrix face of the inner membrane.
    action: ACCEPT
    reason: Consistent with the experimentally reported subcellular location; the
      protein is a peripheral membrane protein associated with the inner membrane.
    supported_by:
    - reference_id: file:human/ATPAF2/ATPAF2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Electronic inference (from the protein folding chaperone MF) that ATPAF2
      participates in protein folding. ATPAF2 is a molecular chaperone that binds
      unassembled F1 alpha subunit and suppresses its aggregation, so a folding-related
      BP is reasonable, though the specific assembly BP terms are more informative.
    action: ACCEPT
    reason: Not incorrect; the chaperone assists proper folding/assembly of the F1
      alpha subunit. The more specific and core process is ATP synthase complex
      assembly (GO:0033615).
    supported_by:
    - reference_id: PMID:14701807
      supporting_text: Wild type HuAtp12p suppresses the aggregation of thermally
- term:
    id: GO:0043461
    label: proton-transporting ATP synthase complex assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-to-GO electronic annotation (IPR011419, ATP12 family) assigning
      the general ATP synthase assembly process. Correct but less specific than the
      mitochondrial-specific term GO:0033615.
    action: ACCEPT
    reason: Correct parent-level BP consistent with the ATP12 family assignment;
      redundant with the more specific mitochondrial term but not wrong.
    supported_by:
    - reference_id: PMID:11410595
      supporting_text: proteins required for assembly of the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11410595
  qualifier: enables
  review:
    summary: IPI protein-binding annotation to an F1 subunit (ATP5F1A, P25705). This
      is the physiologically meaningful interaction underlying ATPAF2 function -
      binding the F1 alpha subunit during assembly. However, the bare protein binding
      term is uninformative; the informative molecular function is protein folding
      chaperone (GO:0044183).
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding conveys no functional specificity. The interaction
      is real and biologically relevant (F1 alpha subunit), but the chaperone MF term
      captures the actual function. Retained rather than removed per curation policy.
    supported_by:
    - reference_id: PMID:11410595
      supporting_text: the human proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: Bare protein binding from a large-scale next-generation-sequencing
      interactome (Y2H) dataset. Uninformative and captures partners not established
      as physiological for a mitochondrial matrix assembly chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding from a high-throughput interactome screen;
      no specific function conveyed. Retained per policy.
- 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 human interactome map. Many
      recorded partners (zinc-finger transcription factors, keratins, nuclear
      proteins) are not physiological for a mitochondrial assembly chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-throughput protein binding; no specific function.
      Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: Bare protein binding from an interactome-perturbation study. Uninformative
      and dominated by non-mitochondrial partners.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-throughput protein binding; no specific function.
      Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27499296
  qualifier: enables
  review:
    summary: Protein binding from a mitochondrial protein-interaction mapping (AE-MS)
      study that captured the ATPAF2-ATP5F1A interaction among respiratory chain
      assembly factors. Functionally relevant partner, but the bare protein binding
      term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The interaction (F1 alpha subunit) is physiologically meaningful, but the
      generic protein binding term does not capture the chaperone function
      (GO:0044183). Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Bare protein binding from a proteome-scale interactome/community-detection
      study. Uninformative for molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-throughput protein binding; no specific function.
      Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29892012
  qualifier: enables
  review:
    summary: Bare protein binding from an interactome-perturbation framework. Records
      the ATP5F1B (P06576) interaction, which is physiologically relevant, but the
      generic term conveys no function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; the relevant F1-subunit interaction is
      better captured by the chaperone MF and assembly BP. Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Bare protein binding from a population-scale interaction-disruption
      study. Includes the ATP5F1B interaction but the generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-throughput protein binding; no specific function.
      Retained per policy.
- 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 reference binary interactome (Y2H).
      Large set of partners, most not physiological for a mitochondrial matrix
      chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-throughput protein binding; no specific function.
      Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare protein binding from the BioPlex dual proteome-scale AP-MS network.
      Records the ATP5F1B interaction; the generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; specific function captured elsewhere.
      Retained per policy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Bare protein binding from a multimodal cell-map / interactome study.
      Records the ATP5F1B interaction; the generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative protein binding; no specific function conveyed. Retained
      per policy.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:14701807
  qualifier: enables
  review:
    summary: Direct experimental (IDA) annotation that ATPAF2 is a protein folding
      chaperone. Purified recombinant human Atp12p suppresses aggregation of a model
      substrate (thermally inactivated citrate synthase), and binds unassembled F1
      alpha subunit to prevent non-productive aggregation during F1 assembly. This
      is the core molecular function.
    action: ACCEPT
    reason: Informative, experimentally supported molecular function that captures
      the chaperone activity - far more useful than bare protein binding. This is the
      core MF of ATPAF2.
    supported_by:
    - reference_id: PMID:14701807
      supporting_text: Wild type HuAtp12p suppresses the aggregation of thermally
    - reference_id: PMID:14701807
      supporting_text: Atp12p binds to unassembled
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput proteomics (HTP) detection of ATPAF2 in a high-confidence
      human mitochondrial proteome. Corroborates mitochondrial localization.
    action: ACCEPT
    reason: Consistent with experimental and phylogenetic evidence for mitochondrial
      localization.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: high-confidence human mitochondrial proteome
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IGI
  original_reference_id: PMID:11410595
  qualifier: is_active_in
  review:
    summary: Genetic-interaction (IGI) annotation placing ATPAF2 activity at the
      mitochondrial inner membrane, based on functional analysis of the human ATP12
      relative to yeast atp12/ATP11 (P22135). Consistent with UniProt's peripheral
      inner-membrane assignment; ATPAF2 acts on the F1 sector at the matrix face of
      the inner membrane.
    action: ACCEPT
    reason: Correct localization for a peripheral inner-membrane assembly factor.
    supported_by:
    - reference_id: file:human/ATPAF2/ATPAF2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0033615
    label: mitochondrial proton-transporting ATP synthase complex assembly
  evidence_type: IGI
  original_reference_id: PMID:11410595
  qualifier: involved_in
  review:
    summary: Genetic-interaction (IGI) annotation to the core assembly process, from
      functional characterization of human ATP11/ATP12 showing they function like
      their yeast counterparts in F1 assembly. This is a core function.
    action: ACCEPT
    reason: Well-supported, specific core BP for ATPAF2. Duplicates the IBA entry,
      which is acceptable.
    supported_by:
    - reference_id: PMID:11410595
      supporting_text: the human proteins
    - reference_id: PMID:11410595
      supporting_text: proteins required for assembly of the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28719601
  qualifier: enables
  review:
    summary: IPI protein-binding annotation for the interaction with FMC1 (Q96HJ9),
      a co-factor implicated in mitochondrial ATP synthase F1 assembly, identified via
      co-expression (CLIC). Functionally relevant partner, but the bare protein binding
      term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The FMC1 interaction is biologically plausible in the F1 assembly context,
      but generic protein binding conveys no molecular function. Retained per policy.
    supported_by:
    - reference_id: PMID:28719601
      supporting_text: functional connection between protein C7orf55 (FMC1) and the
        mitochondrial ATP
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: located_in
  review:
    summary: IDA nuclear speck localization from a LIFEdb GFP-fusion screen of an
      overexpressed construct. This contradicts the well-established mitochondrial
      localization of ATPAF2, which carries an N-terminal mitochondrial transit
      peptide and is a validated component of the mitochondrial proteome. Nuclear
      speck localization is a mislocalization artifact of the overexpressed fusion
      protein.
    action: REMOVE
    reason: Inconsistent with the mitochondrial-matrix / inner-membrane biology of
      this transit-peptide-containing assembly chaperone; a GFP-fusion overexpression
      artifact (GO_REF:0000054 automated fusion-localization pipeline), not evidence
      of a physiological nuclear function. This is not an experimental annotation
      whose full text is inaccessible, so removal is appropriate.
    supported_by:
    - reference_id: file:human/ATPAF2/ATPAF2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
- term:
    id: GO:0043461
    label: proton-transporting ATP synthase complex assembly
  evidence_type: NAS
  original_reference_id: PMID:14757859
  qualifier: involved_in
  review:
    summary: Non-traceable author statement (NAS) that ATPAF2/ATP12 is involved in
      ATP synthase assembly, from the clinical report describing the first pathogenic
      mutation in a human nuclear-encoded ATPase assembly gene (causing complex V
      deficiency). Correct process; the disease phenotype directly implicates ATPAF2
      in ATP synthase assembly.
    action: ACCEPT
    reason: Correct BP, supported by disease genetics; loss of ATPAF2 function impairs
      complex V, consistent with an assembly role. Parent-level term redundant with
      the more specific mitochondrial term.
    supported_by:
    - reference_id: PMID:14757859
      supporting_text: the first report of a pathogenic mutation in a human nuclear
    - reference_id: PMID:14757859
      supporting_text: believed to be the cause of the impaired complex V activity
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IC
  original_reference_id: PMID:14701807
  qualifier: located_in
  review:
    summary: Proposed anatomical location. ATPAF2 is a soluble chaperone that binds
      the unassembled F1 alpha subunit and prevents its aggregation; F1 assembly
      occurs on the matrix face of the inner membrane, and UniProt classifies ATPAF2
      as a peripheral (not integral) inner-membrane protein. It therefore functions
      in the mitochondrial matrix compartment. This complements the mitochondrion
      and inner-membrane annotations with the more precise sub-compartment.
    action: NEW
    reason: The existing location annotations (mitochondrion; inner membrane) are
      correct but do not capture that ATPAF2 acts as a soluble matrix-side chaperone
      on the F1 sector. Added to reflect the core_functions location.
    supported_by:
    - reference_id: PMID:14701807
      supporting_text: Atp12p binds to unassembled
    - reference_id: file:human/ATPAF2/ATPAF2-uniprot.txt
      supporting_text: Mitochondrion inner membrane
core_functions:
- description: Molecular chaperone / assembly factor for the F1 catalytic sector of
    mitochondrial ATP synthase (Complex V); binds the unassembled F1 alpha subunit
    (ATP5F1A) at the matrix face of the mitochondrial inner membrane and suppresses
    its non-productive aggregation, promoting formation of the alpha3-beta3 catalytic
    core. Non-catalytic.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0033615
    label: mitochondrial proton-transporting ATP synthase complex assembly
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:14701807
    supporting_text: Atp12p binds to unassembled
  - reference_id: PMID:14701807
    supporting_text: Wild type HuAtp12p suppresses the aggregation of thermally
  - reference_id: PMID:11410595
    supporting_text: proteins required for assembly of the
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: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:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: PMID:11410595
  title: Atp11p and Atp12p are assembly factors for the F(1)-ATPase in human mitochondria.
  findings:
  - statement: Human ATP11 and ATP12 (ATPAF2) were cloned and shown to be assembly
      factors for the F1 component of mitochondrial ATP synthase, functioning like
      their yeast counterparts.
    supporting_text: proteins required for assembly of the
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Establishes human ATP12/ATPAF2 as an F1 assembly
      factor and reports its interaction with an F1 subunit.
- id: PMID:14701807
  title: The molecular chaperone, Atp12p, from Homo sapiens. In vitro studies with
    purified wild type and mutant (E240K) proteins.
  findings:
  - statement: Human Atp12p binds unassembled F1 alpha subunits and prevents their
      non-productive aggregation during F1 assembly; purified recombinant HuAtp12p
      suppresses aggregation of thermally denatured citrate synthase, demonstrating
      chaperone activity.
    supporting_text: Atp12p binds to unassembled
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Direct in vitro demonstration of the chaperone
      molecular function (basis for GO:0044183 IDA).
- id: PMID:14757859
  title: Respiratory chain complex V deficiency due to a mutation in the assembly
    gene ATP12.
  findings:
  - statement: A pathogenic mutation in ATP12 (ATPAF2) causes respiratory chain complex
      V deficiency, the first reported pathogenic mutation in a human nuclear-encoded
      ATPase assembly gene.
    supporting_text: the first report of a pathogenic mutation in a human nuclear
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified. Disease genetics linking ATPAF2 loss of function
      to complex V (ATP synthase) deficiency (MC5DN1).
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome dataset; source of a bare protein-binding
      IPI, not gene-specific functional evidence.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome map; bare protein-binding IPI only.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Interactome-perturbation dataset; bare protein-binding IPI only.
- id: PMID:27499296
  title: Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory
    Chain Function.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Mitochondrial AE-MS interaction map; captures the physiologically
      relevant ATPAF2-ATP5F1A interaction, though annotated only as bare protein binding.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome/community study; bare protein-binding
      IPI only.
- id: PMID:28719601
  title: CLIC, a tool for expanding biological pathways based on co-expression across
    thousands of datasets.
  findings:
  - statement: Co-expression analysis links ATPAF2 to FMC1 (C7orf55), a co-factor in
      mitochondrial ATP synthase F1 assembly.
    supporting_text: functional connection between protein C7orf55 (FMC1) and the
      mitochondrial ATP
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the FMC1 interaction; supports the F1-assembly functional
      context, though the GO annotation is only bare protein binding.
- id: PMID:29892012
  title: An interactome perturbation framework prioritizes damaging missense mutations
    for developmental disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Interactome-perturbation framework; bare protein-binding IPI only.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Population-scale interaction-disruption dataset; bare protein-binding
      IPI only.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI reference binary interactome (Y2H); many non-physiological
      partners; bare protein-binding IPI only.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex AP-MS network; bare protein-binding IPI only.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: ATPAF2 is detected in a high-confidence human mitochondrial proteome,
      corroborating its mitochondrial localization.
    supporting_text: high-confidence human mitochondrial proteome
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports mitochondrial localization (HTP).
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; bare protein-binding IPI only.
- id: file:human/ATPAF2/ATPAF2-uniprot.txt
  title: UniProtKB entry Q8N5M1 (ATPF2_HUMAN)
  findings:
  - statement: >-
      ATPAF2 plays a role in assembly of the F1 component of mitochondrial ATP
      synthase, interacts with an F1 subunit (ATP5F1B) and with FMC1, and localizes
      to the mitochondrial inner membrane as a peripheral membrane protein.
    supporting_text: 'Interacts with ATP5F1B; involved in the assembly of the F1'