id: Q9HD20
gene_symbol: ATP13A1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ATP13A1 is a multi-pass endoplasmic-reticulum membrane P5A-type P-type ATPase
  that functions as an ATP-dependent transmembrane-helix dislocase. It recognizes moderately
  hydrophobic terminal transmembrane segments, especially mistargeted mitochondrial tail-anchored
  proteins and related terminal helices, and extracts them from the ER membrane to help maintain
  organelle protein localization and ER membrane protein quality control. Early work connected
  the yeast ortholog Spf1 and human ATP13A1 to manganese-dependent ER phenotypes, but later
  biochemical and structural studies support transmembrane-helix dislocation rather than direct
  cation transport as the principal molecular function.
alternative_products:
- name: A
  id: Q9HD20-1
- name: B
  id: Q9HD20-2
  sequence_note: VSP_000434, VSP_000435
- name: C
  id: Q9HD20-3
  sequence_note: VSP_000433
existing_annotations:
- term:
    id: GO:0019829
    label: ATPase-coupled monoatomic cation transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: The old phylogenetic cation-transporter assignment reflects the P-type ATPase
      family and older Spf1 manganese interpretation, but ATP13A1 is now directly supported
      as a transmembrane-helix dislocase rather than a monoatomic cation pump.
    action: MODIFY
    reason: Replace the cation-transporter activity with the directly supported dislocase
      molecular function.
    proposed_replacement_terms:
    - id: GO:0140567
      label: membrane protein dislocase activity
    additional_reference_ids:
    - PMID:32973005
    - file:human/ATP13A1/ATP13A1-notes.md
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
    - reference_id: PMID:32973005
      supporting_text: arguing against the idea that the P5A-ATPase transports cations
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: The ER membrane localization is consistent with experimental human ATP13A1 localization
      and with the dislocase activity occurring in ER rough microsomes.
    action: ACCEPT
    reason: ATP13A1 is an ER-resident multi-pass membrane protein and functions at the ER
      membrane.
    additional_reference_ids:
    - PMID:24392018
    - PMID:32973005
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
        the nucleus of the cell as would be expected from an ER resident protein
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
- term:
    id: GO:0015662
    label: P-type ion transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: The P-type ATPase family assignment is real, but the ion-transporter wording
      is misleading for ATP13A1 because the directly supported substrate is a terminal transmembrane
      helix, not an ion.
    action: MODIFY
    reason: Use the specific ATP13A1 dislocase activity rather than a broad P-type ion transporter
      term.
    proposed_replacement_terms:
    - id: GO:0140567
      label: membrane protein dislocase activity
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
    - reference_id: PMID:32973005
      supporting_text: arguing against the idea that the P5A-ATPase transports cations
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ATP13A1 performs an ATP-dependent membrane extraction/dislocation reaction, but
      the broad transmembrane transport process loses the specific mislocalized-protein extraction
      context.
    action: MODIFY
    reason: The narrower biological-process term captures the direct ATP13A1 role in ER membrane
      quality control.
    proposed_replacement_terms:
    - id: GO:0140569
      label: extraction of mislocalized protein from ER membrane
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: Together, our data support a QC function for P5A-ATPases in removing
        misinserted terminal hydrophobic helices from the ER.
- term:
    id: GO:0140567
    label: membrane protein dislocase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: The IBA dislocase annotation matches direct human biochemical and cell-biological
      evidence.
    action: ACCEPT
    reason: ATP13A1 mediates ATP-dependent removal of mitochondrial transmembrane segments
      from the ER and is independently described as an ER dislocase.
    additional_reference_ids:
    - PMID:32973005
    - PMID:36264797
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
    - reference_id: PMID:36264797
      supporting_text: ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs
- term:
    id: GO:0140569
    label: extraction of mislocalized protein from ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: The IBA biological-process annotation matches direct evidence that ATP13A1 removes
      misinserted terminal hydrophobic helices from the ER.
    action: ACCEPT
    reason: This is the specific process ATP13A1 performs in ER membrane protein quality control.
    additional_reference_ids:
    - PMID:32973005
    - PMID:36264797
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: Together, our data support a QC function for P5A-ATPases in removing
        misinserted terminal hydrophobic helices from the ER.
    - reference_id: PMID:36264797
      supporting_text: ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs
- term:
    id: GO:0006874
    label: intracellular calcium ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: The calcium-homeostasis propagation appears to be an older P5A/P-type-family
      inference and is not supported by the ATP13A1-specific dislocase evidence.
    action: REMOVE
    reason: Current direct evidence supports transmembrane-helix dislocation; calcium ion
      homeostasis is not established as an ATP13A1 function.
    additional_reference_ids:
    - PMID:32973005
    - file:human/ATP13A1/ATP13A1-notes.md
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: arguing against the idea that the P5A-ATPase transports cations
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP13A1 binds nucleotide as a P-type ATPase, but the generic nucleotide-binding
      term is less informative than ATP binding.
    action: MODIFY
    reason: Use the specific ATP-binding term already present in GOA.
    proposed_replacement_terms:
    - id: GO:0005524
      label: ATP binding
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP binding is a valid mechanistic molecular function for the P5A ATPase cycle
      that powers transmembrane-helix dislocation.
    action: ACCEPT
    reason: ATP binding is required for the catalytic cycle underlying ATP13A1 dislocase activity.
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: The automated ER membrane location agrees with experimental localization and
      the ER rough-microsome dislocation assay.
    action: ACCEPT
    reason: ATP13A1 is correctly localized to the ER membrane.
    additional_reference_ids:
    - PMID:24392018
    - PMID:32973005
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
        the nucleus of the cell as would be expected from an ER resident protein
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: ATP13A1 is a membrane protein, but the generic membrane term is less informative
      than the experimentally supported ER membrane location.
    action: MODIFY
    reason: Replace broad membrane localization with ER membrane.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    additional_reference_ids:
    - PMID:24392018
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
        the nucleus of the cell as would be expected from an ER resident protein
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: ATP hydrolysis is a valid mechanistic activity for ATP13A1; dislocation required
      ATP and catalytic-dead ATP13A1 failed to rescue activity.
    action: ACCEPT
    reason: ATP hydrolysis powers the conformational cycle used for TM extraction.
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
- term:
    id: GO:0071421
    label: manganese ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: The manganese transport inference derives from an older model and is not supported
      as ATP13A1 direct transport activity after the dislocase study.
    action: REMOVE
    reason: Cohen et al. did not prove direct Mn2+ transport, and later structural/biochemical
      evidence argues against cation transport.
    additional_reference_ids:
    - PMID:24392018
    - PMID:32973005
    - Reactome:R-HSA-5692462
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: can not prove that Spf1 is the direct transporter of Mn2+
    - reference_id: PMID:32973005
      supporting_text: arguing against the idea that the P5A-ATPase transports cations
- term:
    id: GO:0098655
    label: monoatomic cation transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: The broad monoatomic cation transport inference is not defensible for ATP13A1
      given the directly supported transmembrane-helix substrate.
    action: REMOVE
    reason: Current evidence supports terminal hydrophobic helix dislocation rather than cation
      transport.
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: arguing against the idea that the P5A-ATPase transports cations
- term:
    id: GO:0140358
    label: P-type transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic P-type transmembrane transporter activity is directionally related to
      ATP13A1 as a P-type ATPase, but it is too broad relative to the specific dislocase activity.
    action: MODIFY
    reason: Use membrane protein dislocase activity for the actual physiological substrate
      class.
    proposed_replacement_terms:
    - id: GO:0140567
      label: membrane protein dislocase activity
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
- term:
    id: GO:0140567
    label: membrane protein dislocase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: The Rhea-derived membrane protein dislocase annotation matches the direct ATP13A1
      activity.
    action: ACCEPT
    reason: ATP13A1 is a transmembrane-helix dislocase acting on misinserted ER membrane proteins.
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23864651
  qualifier: enables
  review:
    summary: The GLP-1R interaction-screen row is too generic and does not describe ATP13A1
      core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein binding is uninformative here and should not be used instead of the specific
      dislocase activity.
    additional_reference_ids:
    - PMID:23864651
    - PMID:32973005
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: The BioPlex AP-MS row is a generic interaction annotation and does not identify
      an ATP13A1 functional activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein-binding evidence is not a useful ATP13A1 function term
      in the presence of specific dislocase evidence.
    additional_reference_ids:
    - PMID:33961781
    - PMID:32973005
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  isoform: Q9HD20-3
  review:
    summary: The HuRI isoform-specific protein-binding row is a generic binary-interaction
      annotation and does not establish an isoform-specific ATP13A1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Keep the tested isoform metadata, but do not treat generic protein binding as
      a functional ATP13A1 annotation.
    additional_reference_ids:
    - PMID:32296183
    - PMID:32973005
- term:
    id: GO:0034220
    label: monoatomic ion transmembrane transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-936837
  qualifier: involved_in
  review:
    summary: The Reactome parent ion-transport pathway is an older family-level context and
      conflicts with the current ATP13A1 dislocase model.
    action: REMOVE
    reason: ATP13A1 should not be annotated as a monoatomic ion transporter based on current
      evidence.
    additional_reference_ids:
    - Reactome:R-HSA-936837
    - PMID:32973005
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: arguing against the idea that the P5A-ATPase transports cations
- term:
    id: GO:0015410
    label: ABC-type manganese transporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5692462
  qualifier: enables
  review:
    summary: The ABC-type manganese transporter activity annotation is both mechanistically
      wrong for a P-type ATPase and unsupported after the dislocase study.
    action: REMOVE
    reason: Remove this superseded Reactome manganese-transport assertion.
    additional_reference_ids:
    - Reactome:R-HSA-5692462
    - PMID:24392018
    - PMID:32973005
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: can not prove that Spf1 is the direct transporter of Mn2+
    - reference_id: PMID:32973005
      supporting_text: arguing against the idea that the P5A-ATPase transports cations
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:24392018
  qualifier: located_in
  review:
    summary: The experimental ER membrane localization from Cohen et al. is valid even though
      the same paper overinterpreted manganese transport.
    action: ACCEPT
    reason: ATP13A1 shows an ER-like reticular/perinuclear localization in HeLa cells.
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
        the nucleus of the cell as would be expected from an ER resident protein
- term:
    id: GO:0140567
    label: membrane protein dislocase activity
  evidence_type: IDA
  original_reference_id: PMID:36264797
  qualifier: enables
  review:
    summary: The MTCH2 paper independently supports ATP13A1 as an ER dislocase for mislocalized
      mitochondrial tail-anchored proteins.
    action: ACCEPT
    reason: This agrees with the direct ATP13A1 biochemical evidence from McKenna et al.
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:36264797
      supporting_text: ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
- term:
    id: GO:0140569
    label: extraction of mislocalized protein from ER membrane
  evidence_type: IDA
  original_reference_id: PMID:36264797
  qualifier: involved_in
  review:
    summary: The MTCH2 paper supports the extraction process by showing ATP13A1 acts as the
      ER dislocase for mislocalized mitochondrial tail-anchored proteins in the targeting
      system.
    action: ACCEPT
    reason: ATP13A1 depletion enhances ER misinsertion/mistargeting phenotypes, consistent
      with its extraction role.
    additional_reference_ids:
    - PMID:32973005
    supported_by:
    - reference_id: PMID:36264797
      supporting_text: ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs
    - reference_id: PMID:32973005
      supporting_text: Together, our data support a QC function for P5A-ATPases in removing
        misinserted terminal hydrophobic helices from the ER.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Orthology-based ER membrane localization is consistent with human experimental
      localization and the UniProt-reviewed ER membrane assignment.
    action: ACCEPT
    reason: ATP13A1 is correctly annotated to the ER membrane.
    additional_reference_ids:
    - PMID:24392018
    - PMID:32973005
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
        the nucleus of the cell as would be expected from an ER resident protein
- term:
    id: GO:0140567
    label: membrane protein dislocase activity
  evidence_type: IDA
  original_reference_id: PMID:32973005
  qualifier: enables
  review:
    summary: McKenna et al. directly supports ATP13A1 membrane protein dislocase activity.
    action: ACCEPT
    reason: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER.
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
        ER.
- term:
    id: GO:0140569
    label: extraction of mislocalized protein from ER membrane
  evidence_type: IDA
  original_reference_id: PMID:32973005
  qualifier: involved_in
  review:
    summary: McKenna et al. directly supports the ER membrane extraction process for misinserted
      terminal hydrophobic helices.
    action: ACCEPT
    reason: This is the specific biological process carried out by ATP13A1.
    supported_by:
    - reference_id: PMID:32973005
      supporting_text: Together, our data support a QC function for P5A-ATPases in removing
        misinserted terminal hydrophobic helices from the ER.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5692462
  qualifier: located_in
  review:
    summary: The ER membrane location is correct, but the associated Reactome manganese-transport
      event should not be used for ATP13A1 molecular-function assertions.
    action: ACCEPT
    reason: Retain the location term while rejecting manganese/cation transport annotations
      elsewhere in this review.
    additional_reference_ids:
    - PMID:24392018
    - PMID:32973005
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
        the nucleus of the cell as would be expected from an ER resident protein
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: The NK-cell membrane proteome row supports a broad membrane association but is
      less precise than ER membrane localization.
    action: MODIFY
    reason: ATP13A1 is specifically an ER membrane protein, so the generic membrane term should
      be replaced by ER membrane.
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    additional_reference_ids:
    - PMID:24392018
    - PMID:32973005
    supported_by:
    - reference_id: PMID:24392018
      supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
        the nucleus of the cell as would be expected from an ER resident protein
references:
- id: file:human/ATP13A1/ATP13A1-notes.md
  title: ATP13A1 manual review notes
- id: file:human/ATP13A1/ATP13A1-deep-research-falcon.md
  title: Falcon deep research report for ATP13A1
  findings:
  - statement: Falcon research supports ATP13A1 as an ER P5A ATPase whose primary function
      is ATP-dependent transmembrane-helix dislocation rather than classical ion pumping.
    supporting_text: The best-supported primary function of ATP13A1 is **ATP-dependent dislocation/extraction
      of transmembrane helices (polypeptide segments)** from the ER membrane.
- id: file:human/ATP13A1/ATP13A1-uniprot.txt
  title: UniProtKB record for human ATP13A1
- 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:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings:
  - statement: This high-throughput membrane proteome study supports membrane association
      but does not specify ATP13A1 ER function.
    supporting_text: Defining the membrane proteome of NK cells.
- id: PMID:23864651
  title: The identification of novel proteins that interact with the GLP-1 receptor and restrain
    its activity.
  findings:
  - statement: This GLP-1R interactome study provides interaction-screen context, not a specific
      ATP13A1 molecular function.
    supporting_text: we sought to identify proteins that interact with the GLP-1R using a
      membrane-based split ubiquitin yeast two-hybrid (MYTH) assay
- id: PMID:24392018
  title: The yeast p5 type ATPase, spf1, regulates manganese transport into the endoplasmic
    reticulum.
  findings:
  - statement: Human ATP13A1 localizes in a reticular pattern consistent with an ER-resident
      protein.
    supporting_text: immunohistochemistry of HeLa cells reveals a reticular pattern surrounding
      the nucleus of the cell as would be expected from an ER resident protein
  - statement: The original manganese-homeostasis study did not prove that Spf1 directly transports
      manganese.
    supporting_text: can not prove that Spf1 is the direct transporter of Mn2+
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: HuRI is a proteome-scale binary interaction map, so generic protein-binding
      rows from it are not informative ATP13A1 functions.
    supporting_text: reference interactome map of human binary protein interactions
- id: PMID:32973005
  title: The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase.
  findings:
  - statement: ATP13A1 mediates ATP-dependent extraction of a mitochondrial transmembrane
      segment from the ER.
    supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
      ER.
  - statement: P5A-ATPases remove misinserted terminal hydrophobic helices from the ER as
      a quality-control function.
    supporting_text: Together, our data support a QC function for P5A-ATPases in removing
      misinserted terminal hydrophobic helices from the ER.
  - statement: The P5A substrate-binding pocket lacks a metal coordination site, arguing against
      cation transport as the direct activity.
    supporting_text: arguing against the idea that the P5A-ATPase transports cations
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings:
  - statement: BioPlex is a proteome-scale AP-MS interaction network, so generic protein-binding
      rows from it are not informative ATP13A1 functions.
    supporting_text: BioPlex 3.0, the most complete model of the human interactome to date
- id: PMID:36264797
  title: MTCH2 is a mitochondrial outer membrane protein insertase.
  findings:
  - statement: The MTCH2 study independently treats ATP13A1 as an ER dislocase for mislocalized
      mitochondrial tail-anchored proteins.
    supporting_text: ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs
- id: Reactome:R-HSA-5692462
  title: ATP13A1 transports Mn2+ from cytosol to ER lumen
  findings:
  - statement: Reactome describes an older manganese-transport interpretation that is superseded
      for ATP13A1 molecular-function review.
    supporting_text: Manganese-transporting ATPase 13A1 (ATP13A1) mediates the transport of
      manganese (Mn2+) into the endoplasmic reticulum.
- id: Reactome:R-HSA-936837
  title: Ion transport by P-type ATPases
  findings:
  - statement: Reactome parent pathway describes P-type ATPases primarily as ion pumps, which
      is too broad for ATP13A1 after the dislocase evidence.
    supporting_text: Most members of this transporter family pump a large variety of cations
core_functions:
- description: ATP13A1 uses its P5A-type P-type ATPase cycle to extract misinserted terminal
    transmembrane helices, especially mistargeted mitochondrial tail-anchored proteins, from
    the endoplasmic reticulum membrane.
  molecular_function:
    id: GO:0140567
    label: membrane protein dislocase activity
  directly_involved_in:
  - id: GO:0140569
    label: extraction of mislocalized protein from ER membrane
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:32973005
    supporting_text: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the
      ER.
  - reference_id: PMID:32973005
    supporting_text: Together, our data support a QC function for P5A-ATPases in removing
      misinserted terminal hydrophobic helices from the ER.
  - reference_id: PMID:36264797
    supporting_text: ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs
  - reference_id: file:human/ATP13A1/ATP13A1-deep-research-falcon.md
    supporting_text: The best-supported primary function of ATP13A1 is **ATP-dependent dislocation/extraction
      of transmembrane helices (polypeptide segments)** from the ER membrane.
proposed_new_terms: []
suggested_questions:
- question: Do any ATP13A1-dependent manganese or lipid/glycosylation phenotypes remain after
    separating direct transmembrane-helix dislocation from secondary ER stress and secretory-pathway
    effects?
  experts:
  - McKenna MJ
  - Shao S
  - Park E
  - Schuldiner M
- question: Are ATP13A1-dependent MAVS/RIG-I antiviral signaling and MR1/MAIT antigen-presentation
    phenotypes direct client-specific consequences of ATP13A1 substrate handling, or indirect
    effects of ER membrane-protein quality-control stress?
  experts: []
- question: Does the emerging ATP13A1-Sec61 model represent a distinct translocation-proofreading
    role that should receive future GO process annotation, or a mechanistic variant of ATP13A1
    membrane protein dislocation?
  experts: []
suggested_experiments:
- hypothesis: ATP13A1-associated manganese phenotypes are secondary consequences of defective
    ER membrane-protein quality control rather than direct Mn2+ transport.
  description: Compare purified or reconstituted ATP13A1 dislocation activity with direct
    Mn2+ flux assays, using wild-type, catalytic-dead, and substrate-pocket mutants, while
    measuring ER stress and misinserted transmembrane-helix accumulation in matched rescue
    cells.
  experiment_type: reconstitution and cell-rescue assay