ATP10

id: P18496
gene_symbol: ATP10
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  ATP10 (Atp10p) is a nuclear-encoded mitochondrial inner membrane protein required
  for assembly of the F0 sector of the mitochondrial F1-F0 ATP synthase complex.
  It functions as a specific assembly factor (chaperone) for Atp6p (subunit 6),
  binding newly synthesized Atp6p on mitochondrial ribosomes and facilitating its
  incorporation into a partially assembled ATPase subcomplex (PMID:14998992).
  Atp10p is not a subunit of the mature ATPase complex itself, nor is it a
  general-purpose chaperone; it acts specifically on Atp6p during the assembly
  process (PMID:2141026). Mutations in ATP10 cause loss of rutamycin sensitivity
  and defective F0 assembly (PMID:2141026).
existing_annotations:
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for mitochondrial inner membrane localization. Atp10p is
      well-established as a mitochondrial inner membrane protein. Ackerman and
      Tzagoloff (PMID:2141026) showed the protein is associated with the
      mitochondrial membrane. Tzagoloff et al. (PMID:14998992) further
      demonstrated that Atp10p is an inner membrane component that interacts
      with newly synthesized Atp6p. UniProt also records subcellular location
      as mitochondrion inner membrane. The IBA annotation is phylogenetically
      consistent and well supported.
    action: ACCEPT
    reason: >-
      Core localization for Atp10p, supported by direct experimental evidence
      (PMID:2141026, PMID:14998992) and phylogenetic inference (IBA). The
      mitochondrial inner membrane is where Atp10p performs its assembly
      factor function.
    supported_by:
      - reference_id: PMID:2141026
        supporting_text: "The protein is associated with the mitochondrial membrane but does not co-fractionate either with F1 or with the rutamycin-sensitive F1-F0 complex."
      - reference_id: PMID:14998992
        supporting_text: "Atp10p was identified as a mitochondrial inner membrane component necessary for the biogenesis of the hydrophobic F(0) sector of the ATPase."

- term:
    id: GO:0033615
    label: mitochondrial proton-transporting ATP synthase complex assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for mitochondrial ATP synthase complex assembly. This is
      the core biological process function of Atp10p. The original
      characterization (PMID:2141026) identified ATP10 as a nuclear gene
      required for assembly of the mitochondrial F1-F0 complex, and the
      follow-up study (PMID:14998992) demonstrated that Atp10p specifically
      assists assembly of Atp6p into the F0 unit. The IBA is phylogenetically
      sound and well-supported by experimental data.
    action: ACCEPT
    reason: >-
      This is the core function of Atp10p. Both original and subsequent studies
      confirm its essential role in ATP synthase assembly, specifically the F0
      sector (PMID:2141026, PMID:14998992).
    supported_by:
      - reference_id: PMID:2141026
        supporting_text: "A yeast nuclear gene (ATP10) is reported whose product is essential for the assembly of a functional mitochondrial ATPase complex."
      - reference_id: PMID:14998992
        supporting_text: "Based on these observations, we propose Atp10p to be an Atp6p-specific chaperone that facilitates the incorporation of Atp6p into an intermediate subcomplex of ATPase subunits."

- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for mitochondrial inner membrane based on UniProt subcellular
      location mapping. This is consistent with the IBA annotation and the
      experimental evidence. UniProt records Atp10p as a mitochondrion inner
      membrane protein. Redundant with the IBA annotation but not incorrect.
    action: ACCEPT
    reason: >-
      Consistent with the well-established inner membrane localization of Atp10p.
      The IEA is a broader qualifier (located_in) compared to the IBA (is_active_in),
      but both correctly place Atp10p at the mitochondrial inner membrane.
    supported_by:
      - reference_id: PMID:2141026
        supporting_text: "The protein is associated with the mitochondrial membrane but does not co-fractionate either with F1 or with the rutamycin-sensitive F1-F0 complex."

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107014
  review:
    summary: >-
      IPI annotation for generic protein binding, from the large-scale inter-species
      PPI study by Zhong et al. (PMID:27107014). The WITH/FROM column indicates
      interaction with UniProtKB:Q6RW13-2 (human AGTRAP isoform 2), a cross-species
      interaction from a yeast two-hybrid screen. This is a xenologous interaction
      with no physiological relevance; AGTRAP is a human angiotensin II receptor-
      associated protein with no known mitochondrial function. The term "protein
      binding" is uninformative per curation guidelines, and the underlying
      interaction is not biologically meaningful for Atp10p function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0005515 (protein binding) is uninformative per curation guidelines. The
      underlying evidence is a cross-species yeast two-hybrid interaction with
      human AGTRAP (Q6RW13-2), which has no physiological relevance to Atp10p
      function. Atp10p's biologically meaningful interaction is with Atp6p
      (PMID:14998992), which is better captured by the process annotation for
      ATP synthase assembly.
    supported_by:
      - reference_id: PMID:27107014
        supporting_text: "systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-interactome network"

- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:2141026
  review:
    summary: >-
      IDA annotation for mitochondrial membrane localization from the original
      characterization by Ackerman and Tzagoloff (PMID:2141026). They showed
      that the Atp10p protein is associated with the mitochondrial membrane
      using antibody detection and fractionation experiments. This is a valid
      but less specific annotation than the mitochondrial inner membrane
      (GO:0005743), which is also annotated with stronger evidence. Since the
      original paper did not specifically demonstrate inner vs. outer membrane
      localization, the broader term is appropriate for the evidence from that
      particular paper.
    action: ACCEPT
    reason: >-
      Valid IDA annotation reflecting the experimental evidence from the
      original characterization. While less specific than the inner membrane
      annotation (GO:0005743), it accurately represents what was demonstrated
      in this particular paper (PMID:2141026). The more specific inner membrane
      localization is supported by later work.
    supported_by:
      - reference_id: PMID:2141026
        supporting_text: "The antibody recognizes a 30-kDa protein present in wild type mitochondria. The protein is associated with the mitochondrial membrane but does not co-fractionate either with F1 or with the rutamycin-sensitive F1-F0 complex."

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: HDA
  original_reference_id: PMID:22842922
  review:
    summary: >-
      HDA annotation for cytoplasm localization from a large-scale proteomics
      study examining protein localization during DNA replication stress
      (PMID:22842922). This is a high-throughput study. While Atp10p is a
      mitochondrial protein, the cytoplasm annotation may reflect detection
      in the broader cytoplasmic compartment (mitochondria are within the
      cytoplasm). However, this is a relatively uninformative localization
      for a protein whose primary function is at the mitochondrial inner
      membrane. The HDA evidence code indicates high-throughput direct assay.
    action: KEEP_AS_NON_CORE
    reason: >-
      The cytoplasm annotation is technically not wrong (mitochondria reside
      within the cytoplasm), but it is uninformative for Atp10p, whose
      well-established localization is the mitochondrial inner membrane. This
      is a high-throughput result that does not add specificity beyond what
      is already captured by the mitochondrion and inner membrane annotations.
    supported_by:
      - reference_id: PMID:22842922
        supporting_text: "high-throughput microscopic screening of the yeast GFP fusion collection to develop a systems-level view of protein reorganization following drug-induced DNA replication stress"

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:24769239
  review:
    summary: >-
      HDA annotation for mitochondrion localization from a quantitative
      mitochondrial proteome study during fermentative and respiratory growth
      (PMID:24769239). Detection of Atp10p in the mitochondrial proteome is
      fully consistent with its known biology as a mitochondrial inner membrane
      assembly factor.
    action: ACCEPT
    reason: >-
      Consistent with the well-established mitochondrial localization of Atp10p.
      Detection in the mitochondrial proteome confirms the known biology. This
      is a broader term than GO:0005743 (inner membrane) but correctly reflects
      the HDA evidence level.
    supported_by:
      - reference_id: PMID:24769239
        supporting_text: "we performed an overall quantitative proteomic and phosphoproteomic study of isolated mitochondria extracted from yeast grown on fermentative (glucose or galactose) and respiratory (lactate) media"

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:16823961
  review:
    summary: >-
      HDA annotation for mitochondrion localization from a comprehensive
      mitochondrial proteomics study (PMID:16823961). Atp10p was detected in
      the yeast mitochondrial proteome, consistent with its known function
      as a mitochondrial assembly factor.
    action: ACCEPT
    reason: >-
      Consistent with known biology. Atp10p is an established mitochondrial
      protein and its detection in high-throughput mitochondrial proteomics
      is expected and correct.
    supported_by:
      - reference_id: PMID:16823961
        supporting_text: "A total of 851 different proteins (PROMITO dataset) were identified by use of multidimensional LC-MS/MS, 1D-SDS-PAGE combined with nano-LC-MS/MS and 2D-PAGE"

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:22842922
  review:
    summary: >-
      HDA annotation for mitochondrion localization from the same DNA replication
      stress proteomics study that also yielded the cytoplasm annotation
      (PMID:22842922). Detection of Atp10p in the mitochondrial fraction is
      expected and consistent with its known biology.
    action: ACCEPT
    reason: >-
      Consistent with the well-established mitochondrial localization. Duplicate
      in terms of GO ID with the other HDA annotations from PMID:24769239 and
      PMID:16823961, but from a different study providing independent HDA
      evidence.
    supported_by:
      - reference_id: PMID:22842922
        supporting_text: "high-throughput microscopic screening of the yeast GFP fusion collection to develop a systems-level view of protein reorganization following drug-induced DNA replication stress"

- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IPI
  original_reference_id: PMID:14998992
  review:
    summary: >-
      IPI annotation for mitochondrial inner membrane localization from Tzagoloff
      et al. (PMID:14998992). The WITH/FROM column indicates SGD:S000007268
      (Atp6p), suggesting the inner membrane localization was inferred from the
      physical interaction between Atp10p and the inner membrane-integrated
      Atp6p. The cross-linking experiments demonstrated that Atp10p interacts
      with Atp6p at the mitochondrial inner membrane. This is strong evidence
      for inner membrane localization.
    action: ACCEPT
    reason: >-
      The IPI evidence demonstrates that Atp10p physically interacts with
      Atp6p (an inner membrane protein) at the mitochondrial inner membrane.
      The cross-linking data from PMID:14998992 provides direct evidence for
      this localization.
    supported_by:
      - reference_id: PMID:14998992
        supporting_text: "Atp10p was identified as a mitochondrial inner membrane component necessary for the biogenesis of the hydrophobic F(0) sector of the ATPase."
      - reference_id: PMID:14998992
        supporting_text: "following its synthesis on mitochondrial ribosomes, subunit 6 of the ATPase (Atp6p) can be cross-linked to Atp10p"

- term:
    id: GO:0033615
    label: mitochondrial proton-transporting ATP synthase complex assembly
  evidence_type: IMP
  original_reference_id: PMID:14998992
  review:
    summary: >-
      IMP annotation for mitochondrial ATP synthase complex assembly from
      Tzagoloff et al. (PMID:14998992). The mutant phenotype evidence shows
      that in an atp10 null mutant, Atp6p is less stable and more rapidly
      degraded, leading to defective F0 assembly. The original paper
      (PMID:2141026) also showed that mutations in ATP10 cause loss of
      rutamycin sensitivity, indicating defective F0 sector. This is the
      core function of Atp10p.
    action: ACCEPT
    reason: >-
      Strong IMP evidence demonstrating that loss of Atp10p leads to
      impaired Atp6p stability and defective ATP synthase assembly. This
      is the central biological process function of Atp10p.
    supported_by:
      - reference_id: PMID:14998992
        supporting_text: "Pulse labeling and chase of mitochondrial translation products in vivo indicate that Atp6p is less stable and more rapidly degraded in an atp10 null mutant than in wild type."
      - reference_id: PMID:2141026
        supporting_text: "Mutations in ATP10 induce a loss of rutamycin sensitivity in the mitochondrial ATPase but do not affect respiratory enzymes. This phenotype has been correlated with a defect in the F0 sector of the ATPase."

- term:
    id: GO:0033615
    label: mitochondrial proton-transporting ATP synthase complex assembly
  evidence_type: IPI
  original_reference_id: PMID:14998992
  review:
    summary: >-
      IPI annotation for mitochondrial ATP synthase complex assembly from
      Tzagoloff et al. (PMID:14998992), with Atp6p (SGD:S000007268) in the
      WITH/FROM column. The physical interaction between Atp10p and Atp6p
      (demonstrated by cross-linking) is directly relevant to the assembly
      process: Atp10p binds newly synthesized Atp6p and facilitates its
      incorporation into an intermediate ATPase subcomplex.
    action: ACCEPT
    reason: >-
      The IPI evidence from cross-linking experiments demonstrates a direct
      physical interaction between Atp10p and Atp6p during the assembly
      process. This interaction is the mechanistic basis for Atp10p's role
      in ATP synthase assembly.
    supported_by:
      - reference_id: PMID:14998992
        supporting_text: "following its synthesis on mitochondrial ribosomes, subunit 6 of the ATPase (Atp6p) can be cross-linked to Atp10p. This interaction is required for the integration of Atp6p into a partially assembled subcomplex of the ATPase."

- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IPI
  original_reference_id: PMID:14998992
  review:
    summary: >-
      IPI annotation for unfolded protein binding from Tzagoloff et al.
      (PMID:14998992), with Atp6p (SGD:S000007268) in the WITH/FROM column.
      The authors proposed that Atp10p functions as an "Atp6p-specific chaperone"
      based on cross-linking experiments showing Atp10p interacts with newly
      synthesized Atp6p. However, Atp10p is not a general unfolded protein
      binder -- it is a highly specific assembly factor for a single client
      (Atp6p). It does not bind a range of unfolded proteins, nor does it
      possess a recognizable chaperone domain. The term GO:0051082 implies
      a broader substrate specificity than what is demonstrated. Atp10p's
      function is better described as stabilizing Atp6p during assembly and
      facilitating its incorporation into the F0 subcomplex, which is an
      assembly factor activity rather than a general chaperone/unfolded protein
      binding activity. This is consistent with how other mitochondrial
      assembly factors (PET100, COX20, SHY1) in this project have been
      handled, where GO:0051082 was marked as over-annotated. GO:0044183
      (protein folding chaperone) is also inappropriate because Atp10p does
      not actively fold proteins. The most appropriate MF annotation would
      be GO:0140777 (protein-containing complex stabilizing activity), which
      captures the stabilization of unassembled subunits during complex
      assembly, analogous to what IBA already provides for the closely
      related ATP11 gene.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Atp10p is a specific assembly factor for Atp6p, not a general unfolded
      protein binder. The literature (PMID:14998992) explicitly describes it
      as an "Atp6p-specific chaperone" with a single known client. GO:0051082
      implies broader substrate binding that is not supported by evidence.
      Atp10p does not possess a recognizable chaperone domain and does not
      actively fold proteins; it stabilizes Atp6p during F0 assembly. This is
      consistent with the handling of other mitochondrial assembly factors in
      the UPB project (PET100, COX20, SHY1), where GO:0051082 was marked as
      over-annotated. GO:0044183 (protein folding chaperone) is also not
      appropriate because Atp10p does not catalyze protein folding. A better MF
      annotation would be GO:0140777 (protein-containing complex stabilizing
      activity), which is already used for the related assembly factor ATP11.
    proposed_replacement_terms:
      - id: GO:0140777
        label: protein-containing complex stabilizing activity
    supported_by:
      - reference_id: PMID:14998992
        supporting_text: "Based on these observations, we propose Atp10p to be an Atp6p-specific chaperone that facilitates the incorporation of Atp6p into an intermediate subcomplex of ATPase subunits."
      - reference_id: PMID:14998992
        supporting_text: "Atp10p was identified as a mitochondrial inner membrane component necessary for the biogenesis of the hydrophobic F(0) sector of the ATPase."
      - reference_id: PMID:2141026
        supporting_text: "These data suggest that the ATP10 product is not a subunit of the ATPase complex but rather is required for the assembly of the F0 sector of the complex."

- term:
    id: GO:0140777
    label: protein-containing complex stabilizing activity
  evidence_type: IPI
  original_reference_id: PMID:14998992
  review:
    summary: >-
      NEW annotation. Atp10p stabilizes newly synthesized Atp6p and facilitates
      its incorporation into an intermediate ATPase subcomplex (PMID:14998992).
      In the absence of Atp10p, Atp6p is less stable and more rapidly degraded.
      This stabilization of an unassembled subunit during complex assembly is
      precisely what GO:0140777 (protein-containing complex stabilizing activity)
      captures. The closely related assembly factor ATP11 already has an IBA
      annotation for this term. This is the most appropriate MF term for Atp10p's
      molecular function.
    action: NEW
    reason: >-
      Atp10p stabilizes newly synthesized Atp6p, preventing its degradation and
      facilitating its incorporation into the ATP synthase F0 sector
      (PMID:14998992). This is a protein-containing complex stabilizing
      activity. The related assembly factor ATP11 already carries this
      annotation via IBA. This term better captures Atp10p's molecular
      function than GO:0051082 (unfolded protein binding), which overstates
      the generality of its binding activity.
    supported_by:
      - reference_id: PMID:14998992
        supporting_text: "Pulse labeling and chase of mitochondrial translation products in vivo indicate that Atp6p is less stable and more rapidly degraded in an atp10 null mutant than in wild type."
      - reference_id: PMID:14998992
        supporting_text: "Based on these observations, we propose Atp10p to be an Atp6p-specific chaperone that facilitates the incorporation of Atp6p into an intermediate subcomplex of ATPase subunits."

references:
- 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: PMID:14998992
  title: Atp10p assists assembly of Atp6p into the F0 unit of the yeast mitochondrial
    ATPase.
  findings:
    - statement: Atp10p cross-links to newly synthesized Atp6p on mitochondrial ribosomes
      supporting_text: "following its synthesis on mitochondrial ribosomes, subunit 6 of the ATPase (Atp6p) can be cross-linked to Atp10p"
    - statement: The Atp10p-Atp6p interaction is required for integration of Atp6p into a partially assembled ATPase subcomplex
      supporting_text: "This interaction is required for the integration of Atp6p into a partially assembled subcomplex of the ATPase"
    - statement: In an atp10 null mutant, Atp6p is less stable and more rapidly degraded
      supporting_text: "Pulse labeling and chase of mitochondrial translation products in vivo indicate that Atp6p is less stable and more rapidly degraded in an atp10 null mutant than in wild type"
    - statement: Authors propose Atp10p is an Atp6p-specific chaperone facilitating Atp6p incorporation into the F0 sector
      supporting_text: "we propose Atp10p to be an Atp6p-specific chaperone that facilitates the incorporation of Atp6p into an intermediate subcomplex of ATPase subunits"
- id: PMID:16823961
  title: 'Toward the complete yeast mitochondrial proteome: multidimensional separation
    techniques for mitochondrial proteomics.'
  findings: []
- id: PMID:2141026
  title: ATP10, a yeast nuclear gene required for the assembly of the mitochondrial
    F1-F0 complex.
  findings:
    - statement: ATP10 encodes a 30 kDa protein essential for assembly of a functional mitochondrial ATPase complex
      supporting_text: "A yeast nuclear gene (ATP10) is reported whose product is essential for the assembly of a functional mitochondrial ATPase complex"
    - statement: Mutations in ATP10 cause loss of rutamycin sensitivity indicating defective F0 sector
      supporting_text: "Mutations in ATP10 induce a loss of rutamycin sensitivity in the mitochondrial ATPase but do not affect respiratory enzymes. This phenotype has been correlated with a defect in the F0 sector of the ATPase"
    - statement: ATP10 product is not a subunit of the ATPase but is required for F0 assembly
      supporting_text: "These data suggest that the ATP10 product is not a subunit of the ATPase complex but rather is required for the assembly of the F0 sector of the complex"
    - statement: The protein is associated with the mitochondrial membrane but does not co-fractionate with F1 or F1-F0
      supporting_text: "The protein is associated with the mitochondrial membrane but does not co-fractionate either with F1 or with the rutamycin-sensitive F1-F0 complex"
- id: PMID:22842922
  title: Dissecting DNA damage response pathways by analysing protein localization
    and abundance changes during DNA replication stress.
  findings: []
- id: PMID:24769239
  title: Quantitative variations of the mitochondrial proteome and phosphoproteome
    during fermentative and respiratory growth in Saccharomyces cerevisiae.
  findings: []
- id: PMID:27107014
  title: An inter-species protein-protein interaction network across vast evolutionary
    distance.
  findings:
    - statement: Cross-species Y2H interaction reported between yeast Atp10p and human AGTRAP isoform 2; not physiologically relevant
      supporting_text: "systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-interactome network"

core_functions:
- description: >-
    Atp10p stabilizes newly synthesized Atp6p during assembly of the F0 sector
    of the mitochondrial ATP synthase. It binds Atp6p after translation on
    mitochondrial ribosomes and facilitates its incorporation into an intermediate
    ATPase subcomplex. In the absence of Atp10p, Atp6p is rapidly degraded.
    This is a protein-containing complex stabilizing activity, not a general
    chaperone or foldase function.
  molecular_function:
    id: GO:0140777
    label: protein-containing complex stabilizing activity
  directly_involved_in:
    - id: GO:0033615
      label: mitochondrial proton-transporting ATP synthase complex assembly
  locations:
    - id: GO:0005743
      label: mitochondrial inner membrane