Affinage

ATP11A

Phospholipid-transporting ATPase IH · UniProt P98196

Length
1134 aa
Mass
129.8 kDa
Annotated
2026-06-09
14 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ATP11A is a P4-type ATPase phospholipid flippase that translocates phosphatidylserine from the outer to the inner leaflet of the plasma membrane to establish and maintain transbilayer lipid asymmetry (PMID:34403372, PMID:35476530). Its substrate selectivity is dictated by transmembrane residues: a Q84E substitution opens the substrate entry site to phosphatidylcholine, producing aberrant PtdCho flipping that depletes outer-leaflet PtdCho, raises sphingomyelin, and perturbs cholesterol homeostasis and cell growth (PMID:34403372), while residues Y300 and D913 are required for flippase activity and for correct Golgi and plasma membrane localization in complex with its beta-subunit TMEM30A (PMID:32596364). This flippase activity is developmentally essential across multiple tissues: ATP11A (with ATP11C) drives the phosphatidylserine exposure needed for syncytiotrophoblast fusion in the placental labyrinth, and Atp11a-null embryos die with thin-walled heart ventricles (PMID:35476530); conditional loss disrupts uterine epithelial integrity, gland progenitor specification, and pregnancy success (PMID:40261925); and it sustains spiral ganglion neurons of the auditory nerve, where loss-of-function causes auditory neuropathy in mice and humans carrying a splice-altering deletion that abolishes PtdSer flipping (PMID:36300302). In zebrafish, loss of atp11a reduces stereocilia and sensory hair cells and impairs photoreceptor outer segments with mitochondrial fission defects, linking flippase activity to sensory cell maintenance and energy homeostasis (PMID:40223426). Beyond its lipid-transport role, ATP11A is reported to bind the Numb PRRL isoform and promote epithelial-to-mesenchymal transition in pancreatic cancer cells (PMID:35345586).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2005 Medium

    Before its biochemical activity was defined, ATP11A was linked to a cellular phenotype: its expression level modulates leukemia cell survival under targeted-drug pressure, establishing it as a functionally relevant gene.

    Evidence Overexpression and siRNA knockdown with drug sensitivity assays in Bcr/Abl-positive lymphoblastic leukemia cells

    PMID:15860663

    Open questions at the time
    • No mechanism connecting ATP11A to drug resistance proposed
    • Flippase activity not yet established as the relevant function
    • No in vivo validation
  2. 2020 Medium

    Established that ATP11A requires its beta-subunit TMEM30A and specific transmembrane residues (Y300, D913) for both correct Golgi/plasma membrane trafficking and phosphatidylserine flippase activity, defining structural determinants of function.

    Evidence Mutagenesis, fluorescence localization, and PS flippase assays with TMEM30A co-expression

    PMID:32596364

    Open questions at the time
    • Single-lab study
    • Mechanism by which residues couple transport to localization not resolved
    • No structural model
  3. 2021 High

    Defined the substrate specificity logic of ATP11A by showing it selectively flips phosphatidylserine and that a single Q84E mutation at the substrate entry site permits aberrant phosphatidylcholine flipping with downstream effects on membrane lipid composition and cell physiology.

    Evidence In vitro flippase assays, molecular dynamics simulations, MALDI-IMS, and a knockin mouse model

    PMID:34403372

    Open questions at the time
    • Physiological context where Q84-type gain-of-function arises not defined
    • Full transport cycle structure not resolved
  4. 2022 High

    Showed that ATP11A flippase activity is developmentally essential, driving phosphatidylserine-dependent syncytiotrophoblast fusion in the placenta and being required for embryonic survival.

    Evidence Atp11a-null mouse embryos, histology, EM, TUNEL, and PS flippase/fusion assays in BeWo cells with siRNA

    PMID:35476530

    Open questions at the time
    • Molecular link between PS exposure and the fusion machinery not detailed
    • Cause of cardiac ventricular defect not mechanistically resolved
  5. 2022 Medium

    Proposed a non-canonical role for ATP11A in cancer, binding the Numb PRRL isoform to drive a TGFβ-dependent Numb–ZEB1/Snail2 EMT program.

    Evidence Co-immunoprecipitation, Western blot, overexpression/knockdown and rescue, invasion/migration assays in pancreatic cancer cells

    PMID:35345586

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Whether the interaction depends on flippase activity is unknown
    • Direct versus indirect binding not established
  6. 2023 High

    Connected loss of ATP11A flippase activity to human auditory neuropathy, identifying a deletion that creates a cryptic last exon abolishing PtdSer transport and recapitulating the phenotype in conditional knockout mice.

    Evidence Whole-genome sequencing, in vitro flippase assay, immunohistochemistry, conditional KO mouse, and auditory electrophysiology

    PMID:36300302

    Open questions at the time
    • How PS asymmetry loss leads to spiral ganglion neuron dysfunction not defined
    • Cell-autonomous versus systemic contribution not separated
  7. 2025 High

    Extended ATP11A's essential role to uterine biology, showing its loss disrupts epithelial tight junctions, gland progenitor specification, and receptivity, causing pregnancy failure.

    Evidence Conditional uterine knockout mouse, immunofluorescence, transcriptional profiling, morphological analysis

    PMID:40261925

    Open questions at the time
    • Mechanism linking phospholipid asymmetry to junction and progenitor defects unresolved
    • Whether defects are flippase-dependent not formally tested
  8. 2025 Medium

    Demonstrated conservation of ATP11A's requirement in sensory cell and photoreceptor maintenance, linking its loss to defective stereocilia, hair cells, outer segments, and mitochondrial energy homeostasis.

    Evidence Loss-of-function zebrafish mutant with confocal/EM imaging and mitochondrial analysis

    PMID:40223426

    Open questions at the time
    • Mechanistic link between flippase activity and mitochondrial fission unknown
    • Single-lab study
    • Whether mitochondrial phenotype is primary or secondary unclear
  9. 2024 Low

    Reported that ATP11A promotes gastric cancer cell migration, invasion and EMT via Hippo pathway inactivation.

    Evidence Migration/invasion/proliferation assays and Western blot of EMT and Hippo markers with knockdown/overexpression in gastric cancer cells

    PMID:39247595

    Open questions at the time
    • No direct mechanistic link between flippase activity and Hippo signaling established
    • Single method set (pathway-marker Westerns)
    • No in vivo validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ATP11A's phospholipid-flipping activity is mechanistically coupled to its diverse tissue-specific roles — EMT signaling, mitochondrial homeostasis, junction integrity, and neuronal function — remains unresolved.
  • No causal chain from membrane PS asymmetry to downstream signaling pathways
  • Whether cancer-associated functions require catalytic activity untested
  • No high-resolution structure of the ATP11A–TMEM30A complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0008289 lipid binding 2 GO:0140657 ATP-dependent activity 2 GO:0016787 hydrolase activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-382551 Transport of small molecules 2
Partners
NUMBTMEM30A

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, maintaining asymmetric PtdSer distribution. A Q84E substitution in the first transmembrane segment causes aberrant PtdCho flipping; molecular dynamics simulations showed this mutation allows PtdCho binding at the substrate entry site. Aberrant PtdCho flipping decreased PtdCho in the outer leaflet and increased sphingomyelin, altering cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. In vitro flippase activity assays, molecular dynamics simulations, MALDI-IMS, knockin mouse model The Journal of clinical investigation High 34403372
2022 ATP11A (and ATP11C) function as flippases at the plasma membrane to translocate phosphatidylserine from the outer to inner leaflet. Atp11a-null mouse embryos die at ~E14.5 with thin-walled heart ventricles. Atp11a is expressed in mouse placenta (but not Atp11c), and its loss causes poor development of the labyrinthine layer with unfused trophoblasts (syncytiotrophoblast formation failure). In BeWo cells, combined loss of ATP11A and ATP11C eliminated PS flipping and cell fusion upon forskolin treatment. Knockout mouse model, immunohistochemistry, electron microscopy, TUNEL assay, PS flippase assay in BeWo cells, siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 35476530
2020 ATP11A localizes to the Golgi and plasma membrane when co-expressed with its beta-subunit TMEM30A. Residues Y300 and D913 (corresponding to functionally critical residues in the related flippase ATP8A2) are required for correct Golgi/plasma membrane localization and PS flippase activity; Y300F mutation also reduces ATP11A expression levels. Mutagenesis, fluorescence microscopy (subcellular localization), PS flippase activity assay, co-expression with TMEM30A BioMed research international Medium 32596364
2023 A 5500 bp deletion in ATP11A activates a cryptic splice site forming an alternative last exon, causing the altered C-terminus to lose flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and cochlear nucleus in mice; conditional Atp11a knockout mice show progressive reduction of spiral ganglion neuron compound action potential, recapitulating auditory neuropathy. Whole-genome sequencing, in vitro functional flippase assay, immunohistochemistry, conditional knockout mouse model, auditory electrophysiology Human molecular genetics High 36300302
2022 ATP11A binds specifically to the Numb PRRL isoform (by immunoprecipitation), positively regulates Numb PRRL, Snail2, and ZEB1 protein expression, and promotes epithelial-to-mesenchymal transition (EMT) in pancreatic cancer cells via a TGFβ-dependent Numb PRRL–ZEB1/Snail2 pathway. Knockdown of Numb PRRL suppresses the ATP11A-mediated enhancement of ZEB1/Snail2. Immunoprecipitation, Western blot, overexpression/knockdown, rescue assay, invasion/migration assays PeerJ Medium 35345586
2025 Genetic ablation of Atp11a in mouse uterine epithelium causes loss of tight junctions, disrupted luminal epithelial morphology, incomplete luminal epithelial cell specification (retention of gland-restricted FOXA2 marker), and depletion of gland progenitor cells (SOX9, PAX8, LGR5, PROM1). This results in uterine receptivity deficits and frequent pregnancy failure. Heterozygous Atp11a loss increases incidence of abnormal placental trophoblast differentiation and developmental heart defects in embryos. Conditional knockout mouse, immunofluorescence, transcriptional profiling, morphological analysis Proceedings of the National Academy of Sciences of the United States of America High 40261925
2025 Loss-of-function atp11a mutant zebrafish display reduced stereocilia in the larval ear and reduced hair cells in sensory neuromasts. Photoreceptors in atp11a mutants show reduced outer segments (worsened by light exposure) and mitochondrial fission with increased mitochondrial number, suggesting defects in energy homeostasis. Loss-of-function zebrafish mutant, confocal microscopy, hair cell counting, electron/fluorescence microscopy of mitochondria Journal of cell science Medium 40223426
2024 ATP11A promotes migration, invasion, proliferation, and EMT in gastric cancer cells by inactivating the Hippo pathway, as evidenced by changes in Hippo pathway markers upon ATP11A knockdown/overexpression. Transwell/wound healing/CCK8/colony formation assays, Western blot for EMT and Hippo pathway markers, siRNA knockdown and overexpression Journal of Cancer Low 39247595
2005 Overexpression of ATP11A confers protection of Bcr/Abl-positive lymphoblastic leukemia cells against farnesyltransferase inhibitors (SCH66336/lonafarnib, FTI-276, GGTI-298) and imatinib mesylate, while siRNA-mediated knockdown of endogenous ATP11A sensitizes cells to these drugs. Overexpression, siRNA knockdown, drug sensitivity assays Blood Medium 15860663

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes. The Journal of clinical investigation 37 34403372
2010 ATP11A is a novel predictive marker for metachronous metastasis of colorectal cancer. Oncology reports 26 20043114
2005 Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a. Blood 26 15860663
2022 Inefficient development of syncytiotrophoblasts in the Atp11a-deficient mouse placenta. Proceedings of the National Academy of Sciences of the United States of America 25 35476530
2022 Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene. Human genetics 19 35278131
2022 ATP11A promotes EMT by regulating Numb PRRL in pancreatic cancer cells. PeerJ 15 35345586
2023 A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2. Human molecular genetics 10 36300302
2020 Disease Mutation Study Identifies Critical Residues for Phosphatidylserine Flippase ATP11A. BioMed research international 6 32596364
2025 De novo heterozygous missense variants in ATP11A are associated with refractory focal epilepsy. Journal of medical genetics 4 40185629
2025 Phospholipid flippase ATP11A brokers uterine epithelial integrity and function. Proceedings of the National Academy of Sciences of the United States of America 4 40261925
2021 DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study. Genes 4 33808877
2020 Expression of three P4-phospholipid flippases-atp11a, atp11b, and atp11c in zebrafish (Danio rerio). Gene expression patterns : GEP 4 32344036
2024 ATP11A Promotes Epithelial-mesenchymal Transition in Gastric Cancer Cells via the Hippo Pathway. Journal of Cancer 1 39247595
2025 The P4-phospholipid flippase Atp11a is required for maintenance of eye and ear structure in zebrafish. Journal of cell science 0 40223426

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