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this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.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.
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)
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)
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)
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)
The best-supported primary function of ATP13A1 is ATP-dependent dislocation/extraction of transmembrane helices (polypeptide segments) from the ER membrane.
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)
ATP13A1 function requires its catalytic P-type ATPase activity.
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)
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)
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)
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.
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)
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)
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.
(Advanced Science; publication date: Oct 2022; URL: https://doi.org/10.1002/advs.202203831) (zhang2022theendoplasmicreticulum pages 1-2)
ATP13A1 is implicated as a post-transcriptional determinant of MR1 abundance and MR1-mediated antigen presentation.
(Journal of Biological Chemistry; publication date: Feb 2022; URL: https://doi.org/10.1016/j.jbc.2021.101542) (kulicke2022thep5typeatpase pages 1-3)
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)
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)
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)
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)
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)
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)
| 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.
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.