Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0019829 ATPase-coupled monoatomic cation transmembrane transporter activity	IBA GO_REF:0000033	MODIFY	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. Reason: Replace the cation-transporter activity with the directly supported dislocase molecular function. Proposed replacements: membrane protein dislocase activity Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. PMID:32973005 arguing against the idea that the P5A-ATPase transports cations
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: 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. Reason: Use the specific ATP13A1 dislocase activity rather than a broad P-type ion transporter term. Proposed replacements: membrane protein dislocase activity Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. PMID:32973005 arguing against the idea that the P5A-ATPase transports cations
GO:0055085 transmembrane transport	IBA GO_REF:0000033	MODIFY	Summary: ATP13A1 performs an ATP-dependent membrane extraction/dislocation reaction, but the broad transmembrane transport process loses the specific mislocalized-protein extraction context. Reason: The narrower biological-process term captures the direct ATP13A1 role in ER membrane quality control. Proposed replacements: extraction of mislocalized protein from ER membrane Supporting Evidence: PMID:32973005 Together, our data support a QC function for P5A-ATPases in removing misinserted terminal hydrophobic helices from the ER.
GO:0140567 membrane protein dislocase activity	IBA GO_REF:0000033	ACCEPT	Summary: The IBA dislocase annotation matches direct human biochemical and cell-biological evidence. Reason: ATP13A1 mediates ATP-dependent removal of mitochondrial transmembrane segments from the ER and is independently described as an ER dislocase. Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. PMID:36264797 ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs
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	REMOVE	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. Reason: Current direct evidence supports transmembrane-helix dislocation; calcium ion homeostasis is not established as an ATP13A1 function. Supporting Evidence: PMID:32973005 arguing against the idea that the P5A-ATPase transports cations
GO:0000166 nucleotide binding	IEA GO_REF:0000002	MODIFY	Summary: ATP13A1 binds nucleotide as a P-type ATPase, but the generic nucleotide-binding term is less informative than ATP binding. Reason: Use the specific ATP-binding term already present in GOA. Proposed replacements: ATP binding
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	MODIFY	Summary: ATP13A1 is a membrane protein, but the generic membrane term is less informative than the experimentally supported ER membrane location. Reason: Replace broad membrane localization with ER membrane. Proposed replacements: endoplasmic reticulum 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: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: The manganese transport inference derives from an older model and is not supported as ATP13A1 direct transport activity after the dislocase study. Reason: Cohen et al. did not prove direct Mn2+ transport, and later structural/biochemical evidence argues against cation transport. Supporting Evidence: PMID:24392018 can not prove that Spf1 is the direct transporter of Mn2+ PMID:32973005 arguing against the idea that the P5A-ATPase transports cations
GO:0098655 monoatomic cation transmembrane transport	IEA GO_REF:0000108	REMOVE	Summary: The broad monoatomic cation transport inference is not defensible for ATP13A1 given the directly supported transmembrane-helix substrate. Reason: Current evidence supports terminal hydrophobic helix dislocation rather than cation transport. Supporting Evidence: PMID:32973005 arguing against the idea that the P5A-ATPase transports cations
GO:0140358 P-type transmembrane transporter activity	IEA GO_REF:0000002	MODIFY	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. Reason: Use membrane protein dislocase activity for the actual physiological substrate class. Proposed replacements: membrane protein dislocase activity Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER.
GO:0140567 membrane protein dislocase activity	IEA GO_REF:0000116	ACCEPT	Summary: The Rhea-derived membrane protein dislocase annotation matches the direct ATP13A1 activity. Reason: ATP13A1 is a transmembrane-helix dislocase acting on misinserted ER membrane proteins. Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER.
GO:0005515 protein binding	IPI PMID:23864651 The identification of novel proteins that interact with the ...	MARK AS OVER ANNOTATED	Summary: The GLP-1R interaction-screen row is too generic and does not describe ATP13A1 core molecular function. Reason: Protein binding is uninformative here and should not be used instead of the specific dislocase activity.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: The BioPlex AP-MS row is a generic interaction annotation and does not identify an ATP13A1 functional activity. Reason: High-throughput protein-binding evidence is not a useful ATP13A1 function term in the presence of specific dislocase evidence.
GO:0005515 protein binding	IPI Q9HD20-3 PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: The HuRI isoform-specific protein-binding row is a generic binary-interaction annotation and does not establish an isoform-specific ATP13A1 function. Reason: Keep the tested isoform metadata, but do not treat generic protein binding as a functional ATP13A1 annotation.
GO:0034220 monoatomic ion transmembrane transport	TAS Reactome:R-HSA-936837	REMOVE	Summary: The Reactome parent ion-transport pathway is an older family-level context and conflicts with the current ATP13A1 dislocase model. Reason: ATP13A1 should not be annotated as a monoatomic ion transporter based on current evidence. Supporting Evidence: PMID:32973005 arguing against the idea that the P5A-ATPase transports cations
GO:0015410 ABC-type manganese transporter activity	TAS Reactome:R-HSA-5692462	REMOVE	Summary: The ABC-type manganese transporter activity annotation is both mechanistically wrong for a P-type ATPase and unsupported after the dislocase study. Reason: Remove this superseded Reactome manganese-transport assertion. Supporting Evidence: PMID:24392018 can not prove that Spf1 is the direct transporter of Mn2+ PMID:32973005 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: The MTCH2 paper independently supports ATP13A1 as an ER dislocase for mislocalized mitochondrial tail-anchored proteins. Reason: This agrees with the direct ATP13A1 biochemical evidence from McKenna et al. Supporting Evidence: PMID:36264797 ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER.
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: McKenna et al. directly supports ATP13A1 membrane protein dislocase activity. Reason: ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER. Supporting Evidence: PMID:32973005 ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER.
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.	MODIFY	Summary: The NK-cell membrane proteome row supports a broad membrane association but is less precise than ER membrane localization. Reason: ATP13A1 is specifically an ER membrane protein, so the generic membrane term should be replaced by ER membrane. Proposed replacements: endoplasmic reticulum 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

Core Functions

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:

membrane protein dislocase activity

Directly Involved In:

extraction of mislocalized protein from ER membrane

Cellular Locations:

endoplasmic reticulum membrane

Supporting Evidence:

PMID:32973005
ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER.
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
file:human/ATP13A1/ATP13A1-deep-research-falcon.md
The best-supported primary function of ATP13A1 is **ATP-dependent dislocation/extraction of transmembrane helices (polypeptide segments)** from the ER membrane.

References

file:human/ATP13A1/ATP13A1-notes.md

ATP13A1 manual review notes

file:human/ATP13A1/ATP13A1-deep-research-falcon.md

Falcon deep research report for ATP13A1

Falcon research supports ATP13A1 as an ER P5A ATPase whose primary function is ATP-dependent transmembrane-helix dislocation rather than classical ion pumping.

"The best-supported primary function of ATP13A1 is **ATP-dependent dislocation/extraction of transmembrane helices (polypeptide segments)** from the ER membrane."

file:human/ATP13A1/ATP13A1-uniprot.txt

UniProtKB record for human ATP13A1

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:19946888

Defining the membrane proteome of NK cells.

This high-throughput membrane proteome study supports membrane association but does not specify ATP13A1 ER function.

"Defining the membrane proteome of NK cells."

PMID:23864651

The identification of novel proteins that interact with the GLP-1 receptor and restrain its activity.

This GLP-1R interactome study provides interaction-screen context, not a specific ATP13A1 molecular function.

"we sought to identify proteins that interact with the GLP-1R using a membrane-based split ubiquitin yeast two-hybrid (MYTH) assay"

PMID:24392018

The yeast p5 type ATPase, spf1, regulates manganese transport into the endoplasmic reticulum.

Human ATP13A1 localizes in a reticular pattern consistent with an ER-resident protein.

"immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein"
The original manganese-homeostasis study did not prove that Spf1 directly transports manganese.

"can not prove that Spf1 is the direct transporter of Mn2+"

PMID:32296183

A reference map of the human binary protein interactome.

HuRI is a proteome-scale binary interaction map, so generic protein-binding rows from it are not informative ATP13A1 functions.

"reference interactome map of human binary protein interactions"

PMID:32973005

The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase.

ATP13A1 mediates ATP-dependent extraction of a mitochondrial transmembrane segment from the ER.

"ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER."
P5A-ATPases remove misinserted terminal hydrophobic helices from the ER as a quality-control function.

"Together, our data support a QC function for P5A-ATPases in removing misinserted terminal hydrophobic helices from the ER."
The P5A substrate-binding pocket lacks a metal coordination site, arguing against cation transport as the direct activity.

"arguing against the idea that the P5A-ATPase transports cations"

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

BioPlex is a proteome-scale AP-MS interaction network, so generic protein-binding rows from it are not informative ATP13A1 functions.

"BioPlex 3.0, the most complete model of the human interactome to date"

PMID:36264797

MTCH2 is a mitochondrial outer membrane protein insertase.

The MTCH2 study independently treats ATP13A1 as an ER dislocase for mislocalized mitochondrial tail-anchored proteins.

"ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs"

Reactome:R-HSA-5692462

ATP13A1 transports Mn2+ from cytosol to ER lumen

Reactome describes an older manganese-transport interpretation that is superseded for ATP13A1 molecular-function review.

"Manganese-transporting ATPase 13A1 (ATP13A1) mediates the transport of manganese (Mn2+) into the endoplasmic reticulum."

Reactome:R-HSA-936837

Ion transport by P-type ATPases

Reactome parent pathway describes P-type ATPases primarily as ion pumps, which is too broad for ATP13A1 after the dislocase evidence.

"Most members of this transporter family pump a large variety of cations"

Suggested Experiments

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

Deep Research

Falcon

(ATP13A1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 21 citations 2 artifacts 2026-06-03T12:59:55.814247

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000009 The requested figures showing the P5A-ATPase/Spf1 dislocase mechanism and phenotypes are as follows: - **Figure 5** presents the pr (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human ATP13A1 (UniProt Q9HD20) — ER P5A-ATPase / transmembrane-helix translocase

0) Target verification (critical)

The UniProt entry Q9HD20 corresponds to human ATP13A1, an endoplasmic reticulum (ER)-resident P5A-type P-type ATPase, orthologous to yeast Spf1 and C. elegans CATP-8; these studies explicitly equate ATP13A1 with the conserved ER P5A-ATPase whose function is now best described as a transmembrane-helix dislocase/translocase involved in protein targeting fidelity and quality control. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 8-9, mckenna2020theendoplasmicreticulum pages 2-4, li2024thestructureand pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 P5A-ATPases and “orphan” P-type ATPases

P-type ATPases are primary active transporters that couple ATP hydrolysis to substrate movement via a covalent phosphoenzyme intermediate (Post–Albers cycle). Historically, most known P-type ATPases transport ions (e.g., Na+/K+) or lipids (P4 flippases). P5A-ATPases were long considered “orphan” P-type ATPases because their transported substrate was unclear. (mckenna2020theendoplasmicreticulum pages 1-2, li2024thestructureand pages 1-2)

1.2 A “transmembrane helix dislocase”

A dislocase (here) is an ATP-driven membrane machine that extracts/dislocates transmembrane helices (TMs) or TM-like polypeptide segments from the lipid bilayer, thereby correcting topogenesis/targeting errors and protecting organelle identity. McKenna et al. provided strong evidence that P5A-ATPases establish polypeptides (TM helices) as a distinct class of P-type ATPase substrate. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 8-9)

1.3 Tail-anchored (TA) proteins and targeting surveillance

Tail-anchored proteins have a single C-terminal TM. Because ER and mitochondrial outer membrane targeting signals overlap in physicochemical properties, TA proteins can mistarget; surveillance systems extract those that land in the wrong membrane. A 2023 review summarizes ATP13A1/Spf1 as an ER factor that extracts mistargeted TA proteins to maintain targeting specificity. (mckenna2020theendoplasmicreticulum pages 2-4)

2) Molecular function: substrate specificity, directionality, and catalytic mechanism

2.1 Primary molecular function and substrate

The best-supported primary function of ATP13A1 is ATP-dependent dislocation/extraction of transmembrane helices (polypeptide segments) from the ER membrane.

Direct TM engagement: Site-specific crosslinking detected UV-dependent adducts between a mitochondrial TA protein TM and ATP13A1, supporting direct physical interaction with TM substrates. (mckenna2020theendoplasmicreticulum pages 2-4)
Substrate classes: Mistargeted mitochondrial TA proteins (e.g., OMP25, MAVS, MAOB are among the candidates discussed) and other misinserted/misoriented terminal helices (including certain signal sequences/type II TMs) are implicated as clients. (mckenna2020theendoplasmicreticulum pages 4-6)

2.2 Direction: ER membrane → cytosol/soluble capture

In reconstituted extraction assays using ER-derived vesicles/microsomes, ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER, with dislocated substrates captured by cytosolic chaperone components (e.g., SGTA in the assay design), consistent with extraction from membrane into the cytosolic/soluble pool. (mckenna2020theendoplasmicreticulum pages 2-4)

2.3 Catalysis is required (P-type ATPase chemistry)

ATP13A1 function requires its catalytic P-type ATPase activity.

In knockout-rescue experiments, extraction/phenotypes are rescued by WT ATP13A1 but not by a catalytically inactive phosphorylation-site mutant (e.g., D533A). (mckenna2020theendoplasmicreticulum pages 2-4)
A hydrolysis-deficient mutant (e.g., D533N) can stabilize substrate interaction in mechanistic assays, consistent with cycle-dependent substrate handling. (yang2025atp13a1engagessec61 pages 6-7)

3) Subcellular localization and where ATP13A1 acts

ATP13A1 is an ER membrane protein whose core function is executed at the ER as part of membrane-protein targeting fidelity/quality control. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 8-9, kulicke2022thep5typeatpase pages 10-12)

4) Mechanistic/structural insights (with recent emphasis)

4.1 Structural basis for polypeptide/TM handling (foundational)

McKenna et al. determined cryo-EM structures of the yeast ortholog Spf1 in multiple conformations and inferred a mechanism applicable to ATP13A1: a large, membrane-accessible substrate-binding pocket alternates accessibility toward lumen vs cytosol and remains laterally accessible from the bilayer, consistent with an ATP-driven alternating-access dislocation mechanism for helices. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 8-9)

4.2 2024 structural advance: transport intermediates and “Plug-domain”

A 2024 Nature Communications study reports multiple intermediates of the P5A transport cycle (E1→E2… states) and identifies a membrane-spanning cleft that can hold polypeptide cargo in E2P/E2.Pi states, alongside a Plug-domain that gates a cytosol-facing cavity in E1 and is displaced in phosphorylated intermediates. This work supports a mechanistic framework for how P5A-ATPases couple the P-type cycle to movement of polypeptide cargo within/through the membrane. (Publication date: Nov 2024; URL: https://doi.org/10.1038/s41467-024-53757-6) (li2024thestructureand pages 1-2)

4.3 Human structural/mechanistic work linking to Sec61 (latest in corpus; 2025)

A 2025 study reports cryo-EM structures of human ATP13A1 (3.40–3.87 Å) and proposes ATP13A1 can recognize certain atypical/misoriented signal sequences and facilitate their productive ER translocation by engaging SEC61.

The substrate pocket is described as conserved and electronegative (including residues like E492/E496) and accommodates an α-helical substrate. (yang2025atp13a1engagessec61 pages 6-7)
Mutations in pocket residues (e.g., E492/E496, L499) impair function in reported assays. (yang2025atp13a1engagessec61 pages 6-7)

Although outside the requested 2023–2024 window, this provides “latest mechanistic” context currently available in the retrieved corpus. (Publication date: Jun 2025; URL: https://doi.org/10.1126/sciadv.adt1346) (yang2025atp13a1engagessec61 pages 1-2, yang2025atp13a1engagessec61 pages 6-7)

5) Biological roles and pathways

5.1 ER proteome safeguarding and organelle identity

ATP13A1 is a quality control factor that limits persistence of ectopically localized mitochondrial TMs in the ER. Loss of P5A-ATPase activity causes accumulation/mislocalization of mitochondrial TA proteins to the ER and broader ER dysfunction phenotypes in model systems, consistent with a safeguarding role for ER identity and proteostasis. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 2-4, mckenna2020theendoplasmicreticulum pages 4-6)

5.2 Innate immunity: MAVS/RIG-I pathway support

A 2022 study identified ATP13A1 in a genome-wide CRISPR–Cas9 screen as a regulator of the RIG-I pathway, concluding that ATP13A1 deficiency abolishes RIG-I-mediated antiviral responses due to compromised MAVS stability.

Screen scale/statistic: The screen used GeCKO v2 with 123,411 sgRNAs targeting ~19,050 genes, and downstream experiments used standard significance thresholds (e.g., p < 0.01 to p < 0.0001). (zhang2022theendoplasmicreticulum pages 11-14)
Mechanistic assays: ATP13A1 loss impaired IRF3 dimerization (native PAGE) and affected MAVS aggregation (SDD-AGE), linking ATP13A1 to MAVS activation/stability. (zhang2022theendoplasmicreticulum pages 11-14)
In vivo phenotype: Homozygous Atp13a1 knockout mice show developmental retardation/embryonic lethality, motivating conditional knockouts; myeloid-specific Atp13a1-deficient mice were viable but susceptible to RNA virus infection. (zhang2022theendoplasmicreticulum pages 1-2)

(Advanced Science; publication date: Oct 2022; URL: https://doi.org/10.1002/advs.202203831) (zhang2022theendoplasmicreticulum pages 1-2)

5.3 Antigen presentation: MR1/MAIT axis

ATP13A1 is implicated as a post-transcriptional determinant of MR1 abundance and MR1-mediated antigen presentation.

Genetic discovery: A gene-trap screen in near-haploid HAP1 cells identified ATP13A1 among the most significant positive regulators of MR1 surface expression. (kulicke2022thep5typeatpase pages 1-3)
Causal validation: CRISPR knockout of ATP13A1 in HAP1.MR1 and THP-1 caused a profound reduction in MR1 protein and a selective defect in MR1-mediated antigen presentation (with little effect on classical MHC I). (kulicke2022thep5typeatpase pages 1-3, kulicke2022thep5typeatpase pages 10-12)
Kinetic interpretation: Pulse-chase labeling suggested reduced MR1 levels essentially immediately after synthesis (within minutes), interpreted as altered nascent synthesis rate or very early co-/post-translational stability rather than later accelerated degradation. (kulicke2022thep5typeatpase pages 10-12)

(Journal of Biological Chemistry; publication date: Feb 2022; URL: https://doi.org/10.1016/j.jbc.2021.101542) (kulicke2022thep5typeatpase pages 1-3)

6) Recent developments (prioritizing 2023–2024)

6.1 2024: expanded structural cycle and cargo cleft model

The 2024 P5A structural work strengthens the mechanistic picture that P5A-ATPases can hold polypeptide cargo in a membrane-spanning cleft during phosphorylated intermediates, and introduces a Plug-domain concept for gating. (li2024thestructureand pages 1-2)

6.2 2024: pathway extension to GET3/SEC61 (preprint)

A 2024 bioRxiv preprint proposes a substrate-specific translocation proofreading pathway in which atypical signal sequences insert in reverse orientation, are dislocated by ATP13A1, transferred to GET3, and then delivered to SEC61 for further translocation. (Publication date: Feb 2024; URL: https://doi.org/10.1101/2024.02.12.579870) (yang2024atp13a1engagesget3 pages 1-5)

6.3 2023: synthesis of TA surveillance frameworks

A 2023 review describes ATP13A1/Spf1/CATP-8 as part of TA-protein surveillance that removes mistargeted TA proteins from ER (and analogs from mitochondria), reflecting a consolidation of the “surveillance extractor” concept across systems. (Publication date: Jan 2023; URL: https://doi.org/10.59717/j.xinn-life.2023.100013) (mckenna2020theendoplasmicreticulum pages 2-4)

7) Current applications and real-world implementations

Organelle targeting fidelity and membrane proteostasis research: ATP13A1 knockout/rescue systems and in vitro extraction assays are now used as a testbed for understanding how cells correct mislocalization/topology errors for α-helical membrane proteins, complementing insertion factors (e.g., Sec61/EMC) with “removal/rectification” machinery. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 2-4)
Innate immunity host-factor studies: ATP13A1 is a host factor whose loss destabilizes MAVS and blunts RIG-I signaling; conditional mouse knockouts provide an in vivo model for cell-type-specific susceptibility to RNA viruses. (zhang2022theendoplasmicreticulum pages 11-14, zhang2022theendoplasmicreticulum pages 1-2)
Immunology tools for MR1/MAIT biology: ATP13A1 perturbation (gene-trap and CRISPR KO in HAP1/THP-1) is used to dissect mechanisms controlling MR1 protein abundance and MR1-restricted antigen presentation, with specificity relative to classical MHC I. (kulicke2022thep5typeatpase pages 10-12, kulicke2022thep5typeatpase pages 1-3)

8) Expert interpretation and synthesis

ATP13A1 appears to be an “ER membrane proofreading ATPase”: rather than pumping a small molecule, it uses the P-type ATPase cycle to recognize and move problematic hydrophobic polypeptide segments (mislocalized TA proteins; misoriented signal sequences) out of the ER membrane (and potentially toward downstream pathways such as re-targeting or productive translocation). This reframes ATP13A1’s “substrate specificity” from ions/lipids to defined classes of membrane helices plus short flanking segments and emphasizes interplay with targeting factors and the Sec61 translocon. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 8-9, yang2025atp13a1engagessec61 pages 6-7, li2024thestructureand pages 1-2)

A key open question raised by structural work is whether ATP13A1 is strictly a dislocase or can also facilitate insertion/secretion/topogenesis for selected clients under some contexts; the 2024 structural analysis explicitly notes insertion/secretion cannot be excluded, while the 2024–2025 pathway models propose coupling to GET3/SEC61 for substrate-specific routing. (yang2024atp13a1engagesget3 pages 1-5, li2024thestructureand pages 1-2)

9) Quantitative/statistical highlights (from cited studies)

Cryo-EM resolution (human ATP13A1): 3.40–3.87 Å, enabling residue-level identification of substrate-pocket interactions with signal sequences. (yang2025atp13a1engagessec61 pages 1-2)
CRISPR screen scale (innate immunity study): GeCKO v2 library with 123,411 sgRNAs targeting ~19,050 genes. (zhang2022theendoplasmicreticulum pages 11-14)
Early MR1 biosynthesis timepoints: pulse-chase experiments examined MR1 fate within minutes of translation (e.g., first ~4 min window noted), consistent with ATP13A1 acting at/near cotranslational stages. (kulicke2022thep5typeatpase pages 10-12)

10) Disease associations (curated and emerging)

Open Targets lists ATP13A1 disease associations including neurodegenerative disease and Respiratory Syncytial Virus Infection, with evidence derived from CRISPRi survival datasets linked to PubMed ID 34031600 in the Open Targets evidence rows (association scores modest for most diseases except a higher neurodegenerative disease score in that dataset context). These should be interpreted as hypothesis-generating rather than definitive causal human genetics. (OpenTargets Search: -ATP13A1)

Visual evidence from primary literature

Cropped panels from McKenna et al. (Science 2020) include: (i) immunofluorescence mislocalization phenotype in ATP13A1 KO cells, (ii) cryo-EM views of the outward-open substrate pocket with putative TM density, and (iii) a proposed mechanistic model for TM dislocation across the ATPase cycle. (mckenna2020theendoplasmicreticulum media 0773d66a, mckenna2020theendoplasmicreticulum media a4a225ef, mckenna2020theendoplasmicreticulum media c903e7d2)

Summary table (evidence map)

Aspect	Summary
Identity	• ATP13A1 matches human UniProt Q9HD20 and is the ER-resident P5A-ATPase. • It is the only P5A ATPase in human/mouse and is orthologous to yeast Spf1 and worm CATP-8. (mckenna2020theendoplasmicreticulum pages 1-2, li2024thestructureand pages 1-2, zhang2022theendoplasmicreticulum pages 1-2)
Localization	• Predominantly localized to the endoplasmic reticulum membrane. • Functions at the ER in membrane protein targeting, topology correction, and quality control. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 8-9, li2024thestructureand pages 1-2)
Primary molecular function & substrate	• Best-supported function is ATP-dependent dislocation/extraction of transmembrane helices or polypeptide segments from the ER membrane, not classical ion pumping. • Substrates include mistargeted mitochondrial tail-anchored proteins, misinserted terminal helices, and some atypical or misoriented signal sequences. • Supported direction is ER membrane to cytosolic/soluble pool during extraction. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 8-9, mckenna2020theendoplasmicreticulum pages 2-4, yang2025atp13a1engagessec61 pages 6-7)
Mechanism & structure	• Cryo-EM studies show a large membrane-accessible substrate pocket/cleft that alternates between cytosol- and lumen-facing states in a canonical P-type ATPase cycle. • Substrate preference favors moderately hydrophobic helices with short luminal hydrophilic or basic flanks; large luminal domains are disfavored. • Recent structures highlight an electronegative pocket and a Plug-domain/gating element; residues such as E492/E496 and L499 contribute to substrate engagement. (mckenna2020theendoplasmicreticulum pages 8-9, mckenna2020theendoplasmicreticulum pages 2-4, yang2025atp13a1engagessec61 pages 6-7, li2024thestructureand pages 1-2, mckenna2020theendoplasmicreticulum media 0773d66a)
Key experimental systems & assays	• Core systems include human ATP13A1 knockout cells, yeast Spf1, and worm CATP-8. • Evidence comes from site-specific crosslinking, cell-free reconstitution and extraction assays, proteomics, immunofluorescence mislocalization assays, and cryo-EM. • Catalytic dependence was shown by rescue with WT but not phosphorylation-site mutants such as D533A or D533N. (mckenna2020theendoplasmicreticulum pages 1-2, mckenna2020theendoplasmicreticulum pages 2-4, mckenna2020theendoplasmicreticulum pages 4-6, yang2025atp13a1engagessec61 pages 6-7, mckenna2020theendoplasmicreticulum media a4a225ef)
Phenotypes & pathways (protein targeting QC, MAVS antiviral, MR1 antigen presentation)	• Protein targeting QC: ATP13A1 loss causes ER accumulation or mislocalization of mitochondrial tail-anchored proteins and broader ER proteostasis defects. • MAVS antiviral pathway: deficiency compromises MAVS stability, IRF3 activation, and antiviral responses; myeloid-specific knockout mice are more susceptible to RNA virus infection. • MR1 antigen presentation: ATP13A1 knockout lowers MR1 protein and surface expression and selectively impairs MR1-mediated MAIT-cell activation with little effect on classical MHC I. (mckenna2020theendoplasmicreticulum pages 1-2, zhang2022theendoplasmicreticulum pages 11-14, zhang2022theendoplasmicreticulum pages 1-2, kulicke2022thep5typeatpase pages 10-12, kulicke2022thep5typeatpase pages 1-3, kulicke2021thep5atpaseatp13a1 pages 13-17)
Key recent developments 2024-2025	• 2024 structural work strengthened the model that P5A-ATPases transport polypeptide or helix cargo through a membrane-spanning cleft and identified a possible Plug-domain role. • 2025 work proposed that human ATP13A1 can transfer atypical signal-sequence substrates to SEC61, extending its role to substrate-specific translocation proofreading. • Recent expert perspectives place ATP13A1 among ER accessory factors that improve fidelity of membrane protein insertion and organelle identity. (yang2025atp13a1engagessec61 pages 1-2, yang2025atp13a1engagessec61 pages 6-7, li2024thestructureand pages 1-2)
Open questions	• Whether ATP13A1 acts only as a dislocase or can also directly support insertion, secretion, or topogenesis for selected substrates remains unresolved. • The full human substrate spectrum, selection rules, and integration with GET3, SEC61, EMC, ERAD, and mitochondrial targeting pathways are still being defined. • It remains unclear which immune and developmental phenotypes are direct client-specific effects versus secondary consequences of ER homeostasis failure. (yang2025atp13a1engagessec61 pages 1-2, yang2024atp13a1engagesget3 pages 1-5, li2024thestructureand pages 1-2)

Table: This table summarizes the current functional annotation of human ATP13A1 (UniProt Q9HD20), including identity, localization, molecular function, mechanism, experimental evidence, phenotypes, and recent advances. It provides a compact evidence map for the major claims about ATP13A1.

Key primary references (URLs and publication dates)

McKenna MJ et al. Science (Sep 2020). “The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase.” https://doi.org/10.1126/science.abc5809 (mckenna2020theendoplasmicreticulum pages 1-2)
Li P et al. Nature Communications (Nov 2024). “The structure and function of P5A-ATPases.” https://doi.org/10.1038/s41467-024-53757-6 (li2024thestructureand pages 1-2)
Yang X et al. bioRxiv (Feb 2024). “ATP13A1 engages GET3 to facilitate substrate-specific translocation.” https://doi.org/10.1101/2024.02.12.579870 (yang2024atp13a1engagesget3 pages 1-5)
Zhang R et al. Advanced Science (Oct 2022). “The Endoplasmic Reticulum ATP13A1 is Essential for MAVS‐Mediated Antiviral Innate Immunity.” https://doi.org/10.1002/advs.202203831 (zhang2022theendoplasmicreticulum pages 1-2)
Kulicke CA et al. Journal of Biological Chemistry (Feb 2022). “The P5-type ATPase ATP13A1 modulates MR1-mediated antigen presentation.” https://doi.org/10.1016/j.jbc.2021.101542 (kulicke2022thep5typeatpase pages 1-3)

Limitations of this report (transparency)

The tool-accessible corpus contained strong 2024 structural work and 2023 surveillance synthesis, but fewer tool-retrievable 2023–2024 review articles explicitly focused on ATP13A1 than expected; therefore, some “expert opinion” sections rely primarily on interpretation from primary mechanistic/structural studies (plus one targeted 2023 review) rather than multiple independent recent reviews. (mckenna2020theendoplasmicreticulum pages 2-4, li2024thestructureand pages 1-2)

References

(mckenna2020theendoplasmicreticulum pages 1-2): Michael J. McKenna, Sue Im Sim, Alban Ordureau, Lianjie Wei, J. Wade Harper, Sichen Shao, and Eunyong Park. The endoplasmic reticulum p5a-atpase is a transmembrane helix dislocase. Science, Sep 2020. URL: https://doi.org/10.1126/science.abc5809, doi:10.1126/science.abc5809. This article has 161 citations and is from a highest quality peer-reviewed journal.
(mckenna2020theendoplasmicreticulum pages 8-9): Michael J. McKenna, Sue Im Sim, Alban Ordureau, Lianjie Wei, J. Wade Harper, Sichen Shao, and Eunyong Park. The endoplasmic reticulum p5a-atpase is a transmembrane helix dislocase. Science, Sep 2020. URL: https://doi.org/10.1126/science.abc5809, doi:10.1126/science.abc5809. This article has 161 citations and is from a highest quality peer-reviewed journal.
(mckenna2020theendoplasmicreticulum pages 2-4): Michael J. McKenna, Sue Im Sim, Alban Ordureau, Lianjie Wei, J. Wade Harper, Sichen Shao, and Eunyong Park. The endoplasmic reticulum p5a-atpase is a transmembrane helix dislocase. Science, Sep 2020. URL: https://doi.org/10.1126/science.abc5809, doi:10.1126/science.abc5809. This article has 161 citations and is from a highest quality peer-reviewed journal.
(li2024thestructureand pages 1-2): Ping Li, Viktoria Bågenholm, Per Hägglund, Karin Lindkvist-Petersson, Kaituo Wang, and Pontus Gourdon. The structure and function of p5a-atpases. Nature Communications, Nov 2024. URL: https://doi.org/10.1038/s41467-024-53757-6, doi:10.1038/s41467-024-53757-6. This article has 7 citations and is from a highest quality peer-reviewed journal.
(mckenna2020theendoplasmicreticulum pages 4-6): Michael J. McKenna, Sue Im Sim, Alban Ordureau, Lianjie Wei, J. Wade Harper, Sichen Shao, and Eunyong Park. The endoplasmic reticulum p5a-atpase is a transmembrane helix dislocase. Science, Sep 2020. URL: https://doi.org/10.1126/science.abc5809, doi:10.1126/science.abc5809. This article has 161 citations and is from a highest quality peer-reviewed journal.
(yang2025atp13a1engagessec61 pages 6-7): Xiaoyan Yang, Yi Li, Chengxi Yang, Tingting Li, Zhiyu Fang, Zhigang Feng, Jun Liao, and Yan Zou. Atp13a1 engages sec61 to facilitate substrate-specific translocation. Jun 2025. URL: https://doi.org/10.1126/sciadv.adt1346, doi:10.1126/sciadv.adt1346. This article has 2 citations and is from a highest quality peer-reviewed journal.
(kulicke2022thep5typeatpase pages 10-12): Corinna A. Kulicke, Erica De Zan, Zeynep Hein, Claudia Gonzalez-Lopez, Swapnil Ghanwat, Natacha Veerapen, Gurdyal S. Besra, Paul Klenerman, John C. Christianson, Sebastian Springer, Sebastian M. Nijman, Vincenzo Cerundolo, and Mariolina Salio. The p5-type atpase atp13a1 modulates major histocompatibility complex i-related protein 1 (mr1)-mediated antigen presentation. Feb 2022. URL: https://doi.org/10.1016/j.jbc.2021.101542, doi:10.1016/j.jbc.2021.101542. This article has 13 citations and is from a domain leading peer-reviewed journal.
(yang2025atp13a1engagessec61 pages 1-2): Xiaoyan Yang, Yi Li, Chengxi Yang, Tingting Li, Zhiyu Fang, Zhigang Feng, Jun Liao, and Yan Zou. Atp13a1 engages sec61 to facilitate substrate-specific translocation. Jun 2025. URL: https://doi.org/10.1126/sciadv.adt1346, doi:10.1126/sciadv.adt1346. This article has 2 citations and is from a highest quality peer-reviewed journal.
(zhang2022theendoplasmicreticulum pages 11-14): Rui Zhang, Xianteng Hou, Changwan Wang, Jiaxin Li, Junyan Zhu, Yingbo Jiang, and Fajian Hou. The endoplasmic reticulum atp13a1 is essential for mavs‐mediated antiviral innate immunity. Advanced Science, Oct 2022. URL: https://doi.org/10.1002/advs.202203831, doi:10.1002/advs.202203831. This article has 14 citations and is from a peer-reviewed journal.
(zhang2022theendoplasmicreticulum pages 1-2): Rui Zhang, Xianteng Hou, Changwan Wang, Jiaxin Li, Junyan Zhu, Yingbo Jiang, and Fajian Hou. The endoplasmic reticulum atp13a1 is essential for mavs‐mediated antiviral innate immunity. Advanced Science, Oct 2022. URL: https://doi.org/10.1002/advs.202203831, doi:10.1002/advs.202203831. This article has 14 citations and is from a peer-reviewed journal.
(kulicke2022thep5typeatpase pages 1-3): Corinna A. Kulicke, Erica De Zan, Zeynep Hein, Claudia Gonzalez-Lopez, Swapnil Ghanwat, Natacha Veerapen, Gurdyal S. Besra, Paul Klenerman, John C. Christianson, Sebastian Springer, Sebastian M. Nijman, Vincenzo Cerundolo, and Mariolina Salio. The p5-type atpase atp13a1 modulates major histocompatibility complex i-related protein 1 (mr1)-mediated antigen presentation. Feb 2022. URL: https://doi.org/10.1016/j.jbc.2021.101542, doi:10.1016/j.jbc.2021.101542. This article has 13 citations and is from a domain leading peer-reviewed journal.
(yang2024atp13a1engagesget3 pages 1-5): Xiaoyan Yang, Tingting Li, Zhiyu Fang, Zhigang Feng, and Yan Zou. Atp13a1 engages get3 to facilitate substrate-specific translocation. bioRxiv, Feb 2024. URL: https://doi.org/10.1101/2024.02.12.579870, doi:10.1101/2024.02.12.579870. This article has 2 citations.
(OpenTargets Search: -ATP13A1): Open Targets Query (-ATP13A1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(mckenna2020theendoplasmicreticulum media 0773d66a): Michael J. McKenna, Sue Im Sim, Alban Ordureau, Lianjie Wei, J. Wade Harper, Sichen Shao, and Eunyong Park. The endoplasmic reticulum p5a-atpase is a transmembrane helix dislocase. Science, Sep 2020. URL: https://doi.org/10.1126/science.abc5809, doi:10.1126/science.abc5809. This article has 161 citations and is from a highest quality peer-reviewed journal.
(mckenna2020theendoplasmicreticulum media a4a225ef): Michael J. McKenna, Sue Im Sim, Alban Ordureau, Lianjie Wei, J. Wade Harper, Sichen Shao, and Eunyong Park. The endoplasmic reticulum p5a-atpase is a transmembrane helix dislocase. Science, Sep 2020. URL: https://doi.org/10.1126/science.abc5809, doi:10.1126/science.abc5809. This article has 161 citations and is from a highest quality peer-reviewed journal.
(mckenna2020theendoplasmicreticulum media c903e7d2): Michael J. McKenna, Sue Im Sim, Alban Ordureau, Lianjie Wei, J. Wade Harper, Sichen Shao, and Eunyong Park. The endoplasmic reticulum p5a-atpase is a transmembrane helix dislocase. Science, Sep 2020. URL: https://doi.org/10.1126/science.abc5809, doi:10.1126/science.abc5809. This article has 161 citations and is from a highest quality peer-reviewed journal.
(kulicke2021thep5atpaseatp13a1 pages 13-17): Corinna A. Kulicke, Erica De Zan, Zeynep Hein, Claudia Gonzalez-Lopez, Swapnil Ghanwat, Natacha Veerapen, Gurdyal S. Besra, Paul Klenerman, John C. Christianson, Sebastian Springer, Sebastian Nijman, Vincenzo Cerundolo, and Mariolina Salio. The p5-atpase atp13a1 modulates mr1-mediated antigen presentation. bioRxiv, May 2021. URL: https://doi.org/10.1101/2021.05.26.445708, doi:10.1101/2021.05.26.445708. This article has 0 citations.

Artifacts

Edison artifact artifact-00

Citations

mckenna2020theendoplasmicreticulum pages 2-4
mckenna2020theendoplasmicreticulum pages 4-6
li2024thestructureand pages 1-2
zhang2022theendoplasmicreticulum pages 11-14
zhang2022theendoplasmicreticulum pages 1-2
mckenna2020theendoplasmicreticulum pages 1-2
mckenna2020theendoplasmicreticulum pages 8-9
https://doi.org/10.1038/s41467-024-53757-6
https://doi.org/10.1126/sciadv.adt1346
https://doi.org/10.1002/advs.202203831
https://doi.org/10.1016/j.jbc.2021.101542
https://doi.org/10.1101/2024.02.12.579870
https://doi.org/10.59717/j.xinn-life.2023.100013
https://doi.org/10.1126/science.abc5809
https://doi.org/10.1126/science.abc5809,
https://doi.org/10.1038/s41467-024-53757-6,
https://doi.org/10.1126/sciadv.adt1346,
https://doi.org/10.1016/j.jbc.2021.101542,
https://doi.org/10.1002/advs.202203831,
https://doi.org/10.1101/2024.02.12.579870,
https://doi.org/10.1101/2021.05.26.445708,

📚 Additional Documentation

Notes

(ATP13A1-notes.md)

ATP13A1 notes

2026-06-03 - Proteostasis PN review pass

just fetch-gene human ATP13A1 created the review stub, UniProt record, GOA table, cached publications, Reactome entries, and PANTHER family data. Falcon deep research was attempted with perplexity-lite fallback; the wrapper reported a Falcon timeout after 600 seconds and the fallback failed with a Perplexity quota/401 error, but ATP13A1-deep-research-falcon.md was written and incorporated into this review.
ATP13A1 is best treated as an ER membrane P5A-type P-type ATPase whose direct function is ATP-dependent transmembrane-helix dislocation. McKenna et al. report that ATP13A1 directly interacts with mitochondrial tail-anchored protein transmembrane segments and that "ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER" [PMID:32973005 The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase].
The same paper supports the biological-process annotation to extraction of mislocalized proteins from the ER membrane: ATP13A1 knockout increased ER/secretory-pathway mislocalization of mitochondrial tail-anchored reporters, rescue required wild-type but not catalytic-dead ATP13A1, and the authors conclude a quality-control role in "removing misinserted terminal hydrophobic helices from the ER" PMID:32973005.
The later MTCH2 study independently uses ATP13A1 as the ER-side dislocase in the mitochondrial tail-anchored protein targeting system, stating that MTCH2 depletion effects were enhanced by depleting "ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs" [PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase].
ER membrane localization is supported by the early human ATP13A1 work: "immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein" [PMID:24392018 The yeast p5 type ATPase, spf1, regulates manganese transport into the endoplasmic reticulum].
Manganese/cation transport annotations should be removed or modified conservatively. Cohen et al. linked yeast Spf1 and human ATP13A1 to manganese-dependent cellular phenotypes, but they explicitly state that their results "can not prove that Spf1 is the direct transporter of Mn2+" PMID:24392018. McKenna et al. later found a large membrane-accessible substrate pocket and state that its structure argues "against the idea that the P5A-ATPase transports cations" PMID:32973005.
Reactome:R-HSA-5692462 still asserts "ATP13A1 transports Mn2+ from cytosol to ER lumen"; this appears to reflect the superseded 2013 interpretation and should not drive GO review decisions for ATP13A1 molecular function.

PN projection decision

The PN projection report has one candidate addition for ATP13A1: GO:0015031 protein transport, propagated from ER proteostasis | Protein transport | Removal of misinserted transmembrane proteins.
Working curation conclusion: do not add the broad parent GO:0015031 protein transport candidate. ATP13A1 already has the narrower, directly supported GO:0140567 membrane protein dislocase activity and GO:0140569 extraction of mislocalized protein from ER membrane annotations, and adding protein transport would be less informative than the reviewed dislocase/extraction terms.

Pn Notes

(ATP13A1-pn-notes.md)

ATP13A1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9HD20
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1382)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP13A1/ATP13A1-ai-review.yaml
AIGR review HTML: present - genes/human/ATP13A1/ATP13A1-ai-review.html
Gene notes: present - genes/human/ATP13A1/ATP13A1-notes.md
GOA TSV: present - genes/human/ATP13A1/ATP13A1-goa.tsv
UniProt record: present - genes/human/ATP13A1/ATP13A1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP13A1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP13A1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/ATP13A1/ATP13A1-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 14; MARK_AS_OVER_ANNOTATED: 3; MODIFY: 7; REMOVE: 5

PN Consistency Summary

Consistency: Deep research (falcon), review YAML, and PN are mutually consistent on the modern model: ATP13A1 is a P5A-ATPase transmembrane-helix dislocase (GO:0140567 / GO:0140569), not a cation pump. The review aggressively (and defensibly) REMOVEs the legacy Mn2+/cation-transport annotations (GO:0071421, GO:0098655, GO:0034220, GO:0015410, GO:0006874) and MODIFYs the P-type-transporter terms to dislocase. No internal contradictions.
PN story / NEW pressure: The PN leaf names exactly the gene's core role ("removal of misinserted TM proteins") and is left no_mapping (correct — too heterogeneous). No NEW GO pressure: the specific role is already fully captured by existing GO:0140567 + GO:0140569 (both ACCEPTed, with IDA support). proposed_new_terms is empty. Already captured.
Evidence alignment: PN dossier carries no reference titles for this gene; review anchors on PMID:32973005 (P5A dislocase), PMID:36264797 (MTCH2/ER dislocase), PMID:24392018 (ER localization). No divergence to reconcile.
Verdict: CONSISTENT — no NEW term warranted; PN class projection (protein transport) is broader-but-harmless. No edits required.

Full Consistency Review

UniProt: Q9HD20 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: ER proteostasis|Protein transport|Removal of misinserted transmembrane proteins (group, no_mapping); PN-node mapping: propagating term comes from the parent class ER proteostasis|Protein transport = mapped, ok_for_propagation_to_go, GO:0015031 protein transport (new_to_goa, confirmed absent from goa.tsv).
Consistency: Deep research (falcon), review YAML, and PN are mutually consistent on the modern model: ATP13A1 is a P5A-ATPase transmembrane-helix dislocase (GO:0140567 / GO:0140569), not a cation pump. The review aggressively (and defensibly) REMOVEs the legacy Mn2+/cation-transport annotations (GO:0071421, GO:0098655, GO:0034220, GO:0015410, GO:0006874) and MODIFYs the P-type-transporter terms to dislocase. No internal contradictions.
PN story / NEW pressure: The PN leaf names exactly the gene's core role ("removal of misinserted TM proteins") and is left no_mapping (correct — too heterogeneous). No NEW GO pressure: the specific role is already fully captured by existing GO:0140567 + GO:0140569 (both ACCEPTed, with IDA support). proposed_new_terms is empty. Already captured.
Mapping strategy: Gene does not change the node. The only projected term, GO:0015031 protein transport, derives from the broad class node and is far broader than the gene's dislocase function — it is a generic umbrella, not a claim about ATP13A1's specific activity. Acceptable as a class-level propagation but uninformative for this gene; the gene-specific terms live in the review, not the projection.
Evidence alignment: PN dossier carries no reference titles for this gene; review anchors on PMID:32973005 (P5A dislocase), PMID:36264797 (MTCH2/ER dislocase), PMID:24392018 (ER localization). No divergence to reconcile.
Verdict: CONSISTENT — no NEW term warranted; PN class projection (protein transport) is broader-but-harmless. No edits required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP13A1/ATP13A1-ai-review.yaml
PN workbook rows: 1

PN row 1: ER proteostasis | Protein transport | Removal of misinserted transmembrane proteins

UniProt: Q9HD20
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Protein transport|Removal of misinserted transmembrane proteins
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [class] ER proteostasis|Protein transport
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
  rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

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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

ATP13A1

Gene Description

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human ATP13A1 (UniProt Q9HD20) — ER P5A-ATPase / transmembrane-helix translocase

0) Target verification (critical)

1) Key concepts and definitions (current understanding)

1.1 P5A-ATPases and “orphan” P-type ATPases

1.2 A “transmembrane helix dislocase”

1.3 Tail-anchored (TA) proteins and targeting surveillance

2) Molecular function: substrate specificity, directionality, and catalytic mechanism

2.1 Primary molecular function and substrate

2.2 Direction: ER membrane → cytosol/soluble capture

2.3 Catalysis is required (P-type ATPase chemistry)

3) Subcellular localization and where ATP13A1 acts

4) Mechanistic/structural insights (with recent emphasis)

4.1 Structural basis for polypeptide/TM handling (foundational)

4.2 2024 structural advance: transport intermediates and “Plug-domain”

4.3 Human structural/mechanistic work linking to Sec61 (latest in corpus; 2025)

5) Biological roles and pathways

5.1 ER proteome safeguarding and organelle identity

5.2 Innate immunity: MAVS/RIG-I pathway support

5.3 Antigen presentation: MR1/MAIT axis

6) Recent developments (prioritizing 2023–2024)

6.1 2024: expanded structural cycle and cargo cleft model

6.2 2024: pathway extension to GET3/SEC61 (preprint)

6.3 2023: synthesis of TA surveillance frameworks

7) Current applications and real-world implementations

8) Expert interpretation and synthesis

9) Quantitative/statistical highlights (from cited studies)

10) Disease associations (curated and emerging)

Visual evidence from primary literature

Summary table (evidence map)

Key primary references (URLs and publication dates)

Limitations of this report (transparency)

Artifacts

Citations

📚 Additional Documentation

Notes

ATP13A1 notes

2026-06-03 - Proteostasis PN review pass

PN projection decision

Pn Notes

ATP13A1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Protein transport | Removal of misinserted transmembrane proteins

Projected GO annotations (1)

Note

📄 View Raw YAML