ATP13A1 is a multipass endoplasmic-reticulum membrane P5A-type ATPase that uses an ATP-driven phosphorylated-aspartate cycle to dislocate transmembrane helices. It extracts mistargeted mitochondrial tail-anchored proteins and corrects the orientation of selected ER membrane proteins and atypical signal sequences, allowing folding-competent clients to escape degradation and complete productive membrane insertion or translocation. Demonstrated contexts include ABCG2 topogenesis and delivery of corrected signal-sequence substrates to SEC61. Its membrane-protein biogenesis function also influences organelle protein composition and ion homeostasis; structural and biochemical studies favor polypeptide transport over direct inorganic-cation pumping.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0019829 ATPase-coupled monoatomic cation transmembrane transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: P5A ATPases retain a P-type transport cycle but have a protein-helix substrate pocket distinct from characterized ion pumps. Reason: The original GOA WITH/FROM traces this assertion to PTN001944130. The current PTHR45630 PAINT slice retains transport/dislocase annotations but lacks these old ion-activity assertions. More importantly, PMID:32973005 directly demonstrates ATP13A1-dependent helix extraction and identifies a large membrane-accessible Spf1 pocket lacking the metal-coordination geometry expected for ion pumping. This is mechanistic evidence against the assigned substrate, not merely discovery of a preferred alternative activity. Replace with the experimentally established dislocase function; version drift alone does not prove why PAINT changed. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001944130 Β· PTN001944130 SOURCE STALE OR MISSING Original GOA node recovered directly. The current family slice lacks the old ion activity; structural and biochemical evidence, rather than disappearance alone, supports correcting substrate scope. Proposed replacements: membrane protein dislocase activity Supporting Evidence: PMID:32973005 the structure did not reveal any sites in the pocket of Spf1 that could specifically coordinate a metal ion, arguing against the idea that the P5A-ATPase transports cations PMID:32973005 Thus, ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The ER membrane localization is consistent with experimental human ATP13A1 localization and with the dislocase activity occurring in ER rough microsomes. Reason: ATP13A1 is an ER-resident multi-pass membrane protein and functions at the ER membrane. Supporting Evidence: PMID:24392018 immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. |
| GO:0015662 P-type ion transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: P5A ATPases retain a P-type transport cycle but have a protein-helix substrate pocket distinct from characterized ion pumps. Reason: The original GOA WITH/FROM traces this assertion to PTN000643319. The current PTHR45630 PAINT slice retains transport/dislocase annotations but lacks these old ion-activity assertions. More importantly, PMID:32973005 directly demonstrates ATP13A1-dependent helix extraction and identifies a large membrane-accessible Spf1 pocket lacking the metal-coordination geometry expected for ion pumping. This is mechanistic evidence against the assigned substrate, not merely discovery of a preferred alternative activity. Replace with the experimentally established dislocase function; version drift alone does not prove why PAINT changed. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000643319 Β· PTN000643319 SOURCE STALE OR MISSING Original GOA node recovered directly. The current family slice lacks the old ion activity; structural and biochemical evidence, rather than disappearance alone, supports correcting substrate scope. Proposed replacements: membrane protein dislocase activity Supporting Evidence: PMID:32973005 the structure did not reveal any sites in the pocket of Spf1 that could specifically coordinate a metal ion, arguing against the idea that the P5A-ATPase transports cations PMID:32973005 Thus, ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. |
| GO:0055085 transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: The broad transport, nucleotide-binding or membrane property is compatible with ATP-dependent protein-helix dislocation. Reason: ATP13A1 uses a phosphorylated-aspartate P-type ATPase cycle and ATP binding/hydrolysis at the ER membrane. GO:0140358 describes the P-type transport mechanism without requiring an inorganic ion substrate. Transmembrane transport includes the demonstrated helix/topology movement. The narrower dislocase annotation adds specificity without making these existing broad terms false. Supporting Evidence: PMID:32973005 TM removal required ATP |
| GO:0140567 membrane protein dislocase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATP13A1 extracts transmembrane helices during both localization quality control and productive topology correction. Reason: Direct ATP-dependent removal is established in PMID:32973005. PMID:36283413 shows rescue of folding-competent misoriented ER proteins; PMID:38723633 extends this to ABCG2 topogenesis, and PMID:40498833 supports correction of atypical signal sequences before SEC61 translocation. These productive roles use the dislocation mechanism and should not be excluded by a quality-control-only description. The existing OpenScientist report correctly identifies that false dichotomy. Supporting Evidence: PMID:32973005 Thus, ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. PMID:36283413 Thus, ATP13A1 prevents ERAD of diverse proteins capable of proper folding. |
| GO:0140569 extraction of mislocalized protein from ER membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The IBA biological-process annotation matches direct evidence that ATP13A1 removes misinserted terminal hydrophobic helices from the ER. Reason: This is the specific process ATP13A1 performs in ER membrane protein quality control. Supporting Evidence: PMID:32973005 Together, our data support a QC function for P5A-ATPases in removing misinserted terminal hydrophobic helices from the ER. PMID:36264797 ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs |
| GO:0006874 intracellular calcium ion homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited intracellular calcium-homeostasis role separately from direct calcium transport. Reason: The PTHR45630 IBD at PTN000643319 includes fungal experimental descendants and remains in the current PAINT slice. Structural evidence against a cation-pump mechanism does not show loss of a homeostatic process that could depend on membrane-protein biogenesis. The existing OpenScientist report flags this role as potentially indirect but does not demonstrate target-specific loss. Preserve the phylogenetic process inference as non-core and leave its human mechanism for follow-up. Supporting Evidence: file:human/ATP13A1/ATP13A1-hypotheses/kgap-atp13a1-dislocase-vs-topogenesis/openscientist.md May reflect indirect consequences of ER stress rather than direct CaΒ²βΊ transport |
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | ACCEPT | Summary: The broad transport, nucleotide-binding or membrane property is compatible with ATP-dependent protein-helix dislocation. Reason: ATP13A1 uses a phosphorylated-aspartate P-type ATPase cycle and ATP binding/hydrolysis at the ER membrane. GO:0140358 describes the P-type transport mechanism without requiring an inorganic ion substrate. Transmembrane transport includes the demonstrated helix/topology movement. The narrower dislocase annotation adds specificity without making these existing broad terms false. Supporting Evidence: PMID:32973005 TM removal required ATP |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is a valid mechanistic molecular function for the P5A ATPase cycle that powers transmembrane-helix dislocation. Reason: ATP binding is required for the catalytic cycle underlying ATP13A1 dislocase activity. Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The automated ER membrane location agrees with experimental localization and the ER rough-microsome dislocation assay. Reason: ATP13A1 is correctly localized to the ER membrane. Supporting Evidence: PMID:24392018 immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: The broad transport, nucleotide-binding or membrane property is compatible with ATP-dependent protein-helix dislocation. Reason: ATP13A1 uses a phosphorylated-aspartate P-type ATPase cycle and ATP binding/hydrolysis at the ER membrane. GO:0140358 describes the P-type transport mechanism without requiring an inorganic ion substrate. Transmembrane transport includes the demonstrated helix/topology movement. The narrower dislocase annotation adds specificity without making these existing broad terms false. Supporting Evidence: PMID:32973005 TM removal required ATP |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: ATP hydrolysis is a valid mechanistic activity for ATP13A1; dislocation required ATP and catalytic-dead ATP13A1 failed to rescue activity. Reason: ATP hydrolysis powers the conformational cycle used for TM extraction. Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. |
| GO:0071421 manganese ion transmembrane transport | IEA GO_REF:0000108 | REMOVE | Summary: Direct manganese/cation translocation is not supported by the P5A substrate mechanism. Reason: PMID:24392018 establishes manganese-dependent homeostatic phenotypes, while expressly stating that it cannot prove direct manganese transport. PMID:32973005 provides structural evidence against cation coordination and direct protein-helix dislocation assays. The source mechanism behind these transporter-derived or Reactome process assertions is therefore not sustained. This does not reject manganese or calcium homeostasis as broader biological effects. Supporting Evidence: PMID:24392018 Our results can not prove that Spf1 is the direct transporter of Mn2+ but demonstrate that Spf1 influences Mn2+ homeostasis in the cell. PMID:32973005 the structure did not reveal any sites in the pocket of Spf1 that could specifically coordinate a metal ion, arguing against the idea that the P5A-ATPase transports cations |
| GO:0098655 monoatomic cation transmembrane transport | IEA GO_REF:0000108 | REMOVE | Summary: Direct manganese/cation translocation is not supported by the P5A substrate mechanism. Reason: PMID:24392018 establishes manganese-dependent homeostatic phenotypes, while expressly stating that it cannot prove direct manganese transport. PMID:32973005 provides structural evidence against cation coordination and direct protein-helix dislocation assays. The source mechanism behind these transporter-derived or Reactome process assertions is therefore not sustained. This does not reject manganese or calcium homeostasis as broader biological effects. Supporting Evidence: PMID:24392018 Our results can not prove that Spf1 is the direct transporter of Mn2+ but demonstrate that Spf1 influences Mn2+ homeostasis in the cell. PMID:32973005 the structure did not reveal any sites in the pocket of Spf1 that could specifically coordinate a metal ion, arguing against the idea that the P5A-ATPase transports cations |
| GO:0140358 P-type transmembrane transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: The broad transport, nucleotide-binding or membrane property is compatible with ATP-dependent protein-helix dislocation. Reason: ATP13A1 uses a phosphorylated-aspartate P-type ATPase cycle and ATP binding/hydrolysis at the ER membrane. GO:0140358 describes the P-type transport mechanism without requiring an inorganic ion substrate. Transmembrane transport includes the demonstrated helix/topology movement. The narrower dislocase annotation adds specificity without making these existing broad terms false. Supporting Evidence: PMID:32973005 TM removal required ATP |
| GO:0140567 membrane protein dislocase activity | IEA GO_REF:0000116 | ACCEPT | Summary: ATP13A1 extracts transmembrane helices during both localization quality control and productive topology correction. Reason: Direct ATP-dependent removal is established in PMID:32973005. PMID:36283413 shows rescue of folding-competent misoriented ER proteins; PMID:38723633 extends this to ABCG2 topogenesis, and PMID:40498833 supports correction of atypical signal sequences before SEC61 translocation. These productive roles use the dislocation mechanism and should not be excluded by a quality-control-only description. The existing OpenScientist report correctly identifies that false dichotomy. Supporting Evidence: PMID:32973005 Thus, ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. PMID:36283413 Thus, ATP13A1 prevents ERAD of diverse proteins capable of proper folding. |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | REMOVE | Summary: The GLP-1R interaction-screen row is too generic and does not describe ATP13A1 core molecular function. Reason: The recorded interaction evidence is not disputed, including the tested isoform. Generic protein binding provides no informative molecular function beyond these interactions; remove this uninformative label without inventing a binding-derived function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: The BioPlex AP-MS row is a generic interaction annotation and does not identify an ATP13A1 functional activity. Reason: The recorded interaction evidence is not disputed, including the tested isoform. Generic protein binding provides no informative molecular function beyond these interactions; remove this uninformative label without inventing a binding-derived function. |
| GO:0005515 protein binding | IPI Q9HD20-3 PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The HuRI isoform-specific protein-binding row is a generic binary-interaction annotation and does not establish an isoform-specific ATP13A1 function. Reason: The recorded interaction evidence is not disputed, including the tested isoform. Generic protein binding provides no informative molecular function beyond these interactions; remove this uninformative label without inventing a binding-derived function. |
| GO:0034220 monoatomic ion transmembrane transport | TAS Reactome:R-HSA-936837 | REMOVE | Summary: Direct manganese/cation translocation is not supported by the P5A substrate mechanism. Reason: PMID:24392018 establishes manganese-dependent homeostatic phenotypes, while expressly stating that it cannot prove direct manganese transport. PMID:32973005 provides structural evidence against cation coordination and direct protein-helix dislocation assays. The source mechanism behind these transporter-derived or Reactome process assertions is therefore not sustained. This does not reject manganese or calcium homeostasis as broader biological effects. Supporting Evidence: PMID:24392018 Our results can not prove that Spf1 is the direct transporter of Mn2+ but demonstrate that Spf1 influences Mn2+ homeostasis in the cell. PMID:32973005 the structure did not reveal any sites in the pocket of Spf1 that could specifically coordinate a metal ion, arguing against the idea that the P5A-ATPase transports cations |
| GO:0015410 ABC-type manganese transporter activity | TAS Reactome:R-HSA-5692462 | REMOVE | Summary: ATP13A1 is a P-type ATPase, not an ABC-type manganese transporter. Reason: The Reactome manganese event reflects an early interpretation of homeostatic phenotypes. Its ABC-type molecular-function assignment is additionally incompatible with the observed phosphorylated-aspartate P-type architecture and transport cycle. The ion-coordination pocket distinction in PMID:32973005 provides independent mechanistic evidence against direct cation pumping. Supporting Evidence: PMID:32973005 the structure did not reveal any sites in the pocket of Spf1 that could specifically coordinate a metal ion, arguing against the idea that the P5A-ATPase transports cations |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:24392018 The yeast p5 type ATPase, spf1, regulates manganese transpor... | ACCEPT | Summary: The experimental ER membrane localization from Cohen et al. is valid even though the same paper overinterpreted manganese transport. Reason: ATP13A1 shows an ER-like reticular/perinuclear localization in HeLa cells. Supporting Evidence: PMID:24392018 immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein |
| GO:0140567 membrane protein dislocase activity | IDA PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. | ACCEPT | Summary: ATP13A1 extracts transmembrane helices during both localization quality control and productive topology correction. Reason: Direct ATP-dependent removal is established in PMID:32973005. PMID:36283413 shows rescue of folding-competent misoriented ER proteins; PMID:38723633 extends this to ABCG2 topogenesis, and PMID:40498833 supports correction of atypical signal sequences before SEC61 translocation. These productive roles use the dislocation mechanism and should not be excluded by a quality-control-only description. The existing OpenScientist report correctly identifies that false dichotomy. Supporting Evidence: PMID:32973005 Thus, ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. PMID:36283413 Thus, ATP13A1 prevents ERAD of diverse proteins capable of proper folding. |
| GO:0140569 extraction of mislocalized protein from ER membrane | IDA PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase. | ACCEPT | 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. Reason: ATP13A1 depletion enhances ER misinsertion/mistargeting phenotypes, consistent with its extraction role. Supporting Evidence: PMID:36264797 ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs PMID:32973005 Together, our data support a QC function for P5A-ATPases in removing misinserted terminal hydrophobic helices from the ER. |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Orthology-based ER membrane localization is consistent with human experimental localization and the UniProt-reviewed ER membrane assignment. Reason: ATP13A1 is correctly annotated to the ER membrane. Supporting Evidence: PMID:24392018 immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein |
| GO:0140567 membrane protein dislocase activity | IDA PMID:32973005 The endoplasmic reticulum P5A-ATPase is a transmembrane heli... | ACCEPT | Summary: ATP13A1 extracts transmembrane helices during both localization quality control and productive topology correction. Reason: Direct ATP-dependent removal is established in PMID:32973005. PMID:36283413 shows rescue of folding-competent misoriented ER proteins; PMID:38723633 extends this to ABCG2 topogenesis, and PMID:40498833 supports correction of atypical signal sequences before SEC61 translocation. These productive roles use the dislocation mechanism and should not be excluded by a quality-control-only description. The existing OpenScientist report correctly identifies that false dichotomy. Supporting Evidence: PMID:32973005 Thus, ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. PMID:36283413 Thus, ATP13A1 prevents ERAD of diverse proteins capable of proper folding. |
| GO:0140569 extraction of mislocalized protein from ER membrane | IDA PMID:32973005 The endoplasmic reticulum P5A-ATPase is a transmembrane heli... | ACCEPT | Summary: McKenna et al. directly supports the ER membrane extraction process for misinserted terminal hydrophobic helices. Reason: This is the specific biological process carried out by ATP13A1. Supporting Evidence: PMID:32973005 Together, our data support a QC function for P5A-ATPases in removing misinserted terminal hydrophobic helices from the ER. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5692462 | ACCEPT | Summary: The ER membrane location is correct, but the associated Reactome manganese-transport event should not be used for ATP13A1 molecular-function assertions. Reason: Retain the location term while rejecting manganese/cation transport annotations elsewhere in this review. Supporting Evidence: PMID:24392018 immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: The broad transport, nucleotide-binding or membrane property is compatible with ATP-dependent protein-helix dislocation. Reason: ATP13A1 uses a phosphorylated-aspartate P-type ATPase cycle and ATP binding/hydrolysis at the ER membrane. GO:0140358 describes the P-type transport mechanism without requiring an inorganic ion substrate. Transmembrane transport includes the demonstrated helix/topology movement. The narrower dislocase annotation adds specificity without making these existing broad terms false. Supporting Evidence: PMID:32973005 TM removal required ATP |
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Download this section (compressed HTML)Q: Do any ATP13A1-dependent manganese or lipid/glycosylation phenotypes remain after separating direct transmembrane-helix dislocation from secondary ER stress and secretory-pathway effects?
Suggested experts: McKenna MJ, Shao S, Park E, Schuldiner M
Q: 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?
Q: 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?
Experiment: 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.
Hypothesis: ATP13A1-associated manganese phenotypes are secondary consequences of defective ER membrane-protein quality control rather than direct Mn2+ transport.
Type: reconstitution and cell-rescue assay
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether ATP13A1 is exclusively a membrane-protein dislocase or can also directly promote insertion, secretion, or topogenesis for selected clients remains unresolved.
OPEN BIOLOGYCURATION MF_DARK
What is known: The review accepts ATP13A1's core molecular function as ATP-dependent extraction of misinserted terminal hydrophobic helices from the ER membrane. The open question is whether the GET3/SEC61-linked models represent a separable productive routing activity or a downstream consequence of the accepted dislocase reaction.
Significance: Resolving this gap would determine whether ATP13A1 should remain annotated only to membrane protein dislocase activity and extraction of mislocalized proteins from the ER, or whether additional topogenesis/translocation proofreading processes are warranted.
What would resolve it: Reconstituted assays and cell-rescue experiments with client-specific reporters should test whether ATP13A1 directly enables productive insertion or SEC61 handoff, independently of extracting mislocalized helices.
Provenance (the field's own admissions):
Gap: The human ATP13A1 client spectrum and selection rules are still incompletely defined.
OPEN BIOLOGYCURATION MF_DARK
What is known: The review accepts mistargeted mitochondrial tail-anchored proteins and misinserted terminal hydrophobic helices as supported substrates/classes. It does not infer that all atypical signal sequences, ERAD substrates, EMC clients, or mitochondrial-targeting errors are ATP13A1 clients.
Significance: A resolved substrate code would refine the molecular-function annotation, distinguish ATP13A1 from general ER quality-control factors, and identify which biological-process annotations should be client-specific.
What would resolve it: Proteome-scale client trapping, topology-sensitive reporters, ATPase-dead and pocket-mutant rescue, and GET3/SEC61/EMC/ERAD epistasis should define the sequence, topology, and pathway features that make a human substrate ATP13A1-dependent.
Provenance (the field's own admissions):
Gap: The connection between ATP13A1 membrane-protein quality control and reported immune or developmental phenotypes remains unresolved.
OPEN BIOLOGYCURATION BP_DARK
What is known: The review treats antiviral signaling, MR1/MAIT antigen-presentation, and developmental phenotypes as downstream or context-dependent unless direct ATP13A1 client-specific mechanisms are shown.
Significance: Resolving this gap would determine whether ATP13A1 should be annotated to specific immune or developmental processes, or whether those phenotypes are secondary consequences of ER membrane-protein quality-control failure.
What would resolve it: Client-resolved perturbation and rescue experiments should separate direct ATP13A1-dependent handling of immune/developmental substrates from broad ER stress, mistargeting, and homeostasis effects.
Provenance (the field's own admissions):
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