Affinage

ATP11C

Phospholipid-transporting ATPase IG · UniProt Q8NB49

Length
1132 aa
Mass
129.5 kDa
Annotated
2026-06-09
26 papers in source corpus 18 papers cited in narrative 17 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

ATP11C is a P4-type ATPase aminophospholipid flippase that, in complex with its essential subunit CDC50A, actively translocates phosphatidylserine and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflet of the plasma membrane, thereby establishing and maintaining membrane lipid asymmetry across erythrocytes, leukocytes, and hepatocytes (PMID:21423173, PMID:21423172, PMID:26944472, PMID:40812423). Cryo-EM structures captured across the transport cycle define a phosphorylation-driven catalytic mechanism in which domain movements couple to phospholipid binding, with an invariant Lys880 serving as the pivot for helix bending and dephosphorylation, and the substrate-binding pocket (Q79, S91, N352) dictating head-group selectivity such that engineered changes expand specificity from PS/PE to phosphatidylcholine (PMID:32997992, PMID:41237907); native-membrane structures further show local bilayer distortion around transmembrane helix 2 that facilitates lipid release (PMID:34922944). Surface activity of ATP11C is dynamically controlled: a C-terminal di-leucine motif (SVRPLL) drives Ca2+/PKC-triggered clathrin-mediated endocytosis, while the splice variant ATP11C-b is anchored to a polarized membrane domain through direct binding of its C-terminal LLxY motif to ezrin (PMID:29123098, PMID:31371488, PMID:34528675). Loss of ATP11C function causes defective B lymphopoiesis through a block in the pre-B to immature B cell differentiation switch, X-linked congenital hemolytic anemia, and X-linked intrahepatic cholestasis arising from a hepatocyte-intrinsic defect in which ATP11C is required for basolateral localization and stability of bile-salt uptake transporters (OATP1B2/1A1/1A4, NTCP) (PMID:21423173, PMID:21423172, PMID:21518881, PMID:26944472, PMID:26926206, PMID:36753036). Disease-associated mutations act through loss of function, either by ER retention and proteasomal degradation (T418N) or reduced protein expression and ATPase activity (L789F) (PMID:31253392, PMID:37671681).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2011 High

    Established that ATP11C is an aminophospholipid flippase whose PS-translocating activity is required for B lymphopoiesis, linking a biophysical lipid-transport function to a developmental program.

    Evidence ENU mutagenesis mouse genetics with PS translocation flow cytometry and transgenic rescue in pro-B cells

    PMID:21423172 PMID:21423173

    Open questions at the time
    • Did not resolve why only B cells arrest despite flippase activity in other lineages
    • Molecular structure and catalytic mechanism not addressed
  2. 2011 High

    Showed the cholestasis phenotype originates from a non-hematopoietic liver defect, establishing ATP11C as a hepatic factor preventing bile-acid toxicity.

    Evidence Bone marrow chimeras, bile acid measurements, and dietary cholic acid challenge in mutant mice

    PMID:21518881

    Open questions at the time
    • Mechanism connecting flippase activity to bile-acid handling unresolved
    • Identity of affected hepatic transporters not yet known
  3. 2015 Medium

    Defined the hepatic mechanism: ATP11C deficiency reduces sinusoidal organic-anion uptake and OATP transporter levels at the basolateral membrane without affecting canalicular secretion.

    Evidence In vivo pharmacokinetics with radiolabeled substrates, isolated hepatocyte uptake, and liver plasma membrane fractionation/western blot

    PMID:26399598

    Open questions at the time
    • Whether transporter loss is degradation or mistrafficking not yet distinguished
    • Single lab
  4. 2015 Medium

    Confirmed ATP11C as the essential PS flippase in a cultured cell line via mutation identification and functional rescue, generalizing its role beyond immune and hepatic cells.

    Evidence Mutation sequencing and exogenous wild-type rescue with fluorescent PS-analog uptake in CHO-K1/UPS-1 cells

    PMID:26420878

    Open questions at the time
    • Does not address regulation or structural basis
    • Single lab
  5. 2016 High

    Established ATP11C as the principal erythrocyte PS flippase and causally linked its loss to X-linked congenital hemolytic anemia in humans.

    Evidence Patient genetics with PS internalization and PS exposure assays in patient-derived erythrocytes

    PMID:26944472

    Open questions at the time
    • Mechanism linking PS exposure to hemolysis not fully dissected
    • Effect on protein stability not addressed in this study
  6. 2016 Medium

    Showed flippase activity is broad across leukocyte subsets yet only B cell development is blocked, sharpening the lineage-specificity question.

    Evidence Flow cytometry with fluorescent PS/PE analogs in leukocytes from knockout mice with viability gating

    PMID:26799398

    Open questions at the time
    • Lineage-specific dependence remains unexplained
    • Single lab
  7. 2016 High

    Resolved the hepatic mechanism by showing ATP11C is required for basolateral localization of bile-salt uptake transporters, with their loss driven by proteasomal degradation.

    Evidence Immunofluorescence, western blot, in vivo pharmacokinetics, and bortezomib proteasome-inhibitor rescue in deficient mice

    PMID:26926206

    Open questions at the time
    • How a flippase governs transporter trafficking mechanistically unresolved
    • Direct physical interaction with transporters not shown
  8. 2017 High

    Revealed dynamic regulation of surface ATP11C: a C-terminal di-leucine motif drives Ca2+/PKC-triggered clathrin-mediated endocytosis downstream of Gq-coupled receptors.

    Evidence Live-cell imaging, endocytosis and PKC-activation assays, di-leucine motif mutagenesis, clathrin inhibition, and Gq receptor stimulation

    PMID:29123098

    Open questions at the time
    • Physiological contexts triggering this endocytosis in vivo not defined
    • Adaptor proteins reading the motif not identified
  9. 2019 Medium

    Showed splice-variant C-termini determine subcellular distribution, with ATP11C-b targeted to a polarized membrane domain via an LLXY motif and resistant to PKC-induced endocytosis.

    Evidence Fluorescence microscopy of splice variants and LLXY motif mutagenesis with PKC-activation assays

    PMID:31371488

    Open questions at the time
    • Binding partner mediating polarized targeting not yet identified
    • Single lab
  10. 2019 Medium

    Defined a disease mutation mechanism distinct from catalytic loss: T418N causes ER retention and proteasomal degradation, preventing plasma-membrane trafficking.

    Evidence Patient erythrocyte immunoblotting, mutant transfection, immunofluorescence localization, and proteasome-inhibitor rescue

    PMID:31253392

    Open questions at the time
    • Whether CDC50A folding interaction is altered not fully resolved
    • Single lab
  11. 2020 High

    Provided the structural basis for transport by capturing six states of the cycle, defining phosphorylation-coupled domain movements, head-group recognition, and the Lys880 dephosphorylation pivot.

    Evidence Single-particle cryo-EM in multiple conformational states with functional residue validation

    PMID:32997992

    Open questions at the time
    • Role of native lipid environment in the cycle not addressed
    • Splice-variant and regulatory C-terminus not resolved structurally
  12. 2021 High

    Showed in a native lipid environment that the enzyme distorts the inner membrane around TM2 in a phosphointermediate, providing a physical basis for phospholipid release into the bilayer.

    Evidence Cryo-EM of Nanodisc-reconstituted ATP11C with ATPase activity measurement

    PMID:34922944

    Open questions at the time
    • Kinetics of membrane deformation during transport not measured
    • Single lab
  13. 2021 Medium

    Identified ezrin as the direct partner anchoring polarized ATP11C-b, and showed ATP11C-b reciprocally controls localization of active ERM proteins.

    Evidence Co-immunoprecipitation, LLxY motif mutagenesis, ERM knockdown, and knockout/rescue microscopy

    PMID:34528675

    Open questions at the time
    • Structural detail of the LLxY-ezrin interface not defined
    • Single lab
  14. 2023 Medium

    Pinpointed ATP11C's role in B cell development to the IL-7-withdrawal-driven pre-B to immature B differentiation switch rather than proliferation.

    Evidence CRISPR/Cas9 knockout in a pre-B cell line with PS flippase, proliferation, and differentiation assays

    PMID:36753036

    Open questions at the time
    • Signaling link between lipid asymmetry and the differentiation switch unresolved
    • Single lab
  15. 2023 Medium

    Demonstrated a human L789F variant acts by reducing protein expression and PS-stimulated ATPase activity, confirming loss-of-function as the basis of hemolytic anemia.

    Evidence Patient RBC ghost immunoblotting, PS flippase assay, and recombinant HEK293T expression with ATPase measurement

    PMID:37671681

    Open questions at the time
    • Whether reduced expression reflects misfolding or degradation not dissected
    • Single lab
  16. 2025 Medium

    Established CDC50A as an essential subunit for ATP11C activity and linked ATP11C-maintained PS asymmetry to enveloped virus replication and release.

    Evidence CRISPR knockout, PS flipping and viral replication assays, CDC50A D193G/K319E mutagenesis, and virus-like particle assays

    PMID:40812423

    Open questions at the time
    • Direct structural role of CDC50A residues in catalysis not resolved
    • Single lab
  17. 2025 High

    Structurally defined the determinants of substrate specificity by showing Q79E with conformational shifts of Ser91 and Asn352 reshape the pocket to admit the bulky choline head group, expanding selectivity to PC.

    Evidence Cryo-EM of the Q79E mutant in the PC-occluded E2-Pi state with PS/PC ATPase assays and mutagenesis

    PMID:41237907

    Open questions at the time
    • Whether native ATP11C ever transports PC physiologically not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How lipid asymmetry generated by ATP11C is transduced into specific cell-fate and trafficking outcomes (B cell differentiation switch, basolateral transporter retention) remains mechanistically undefined.
  • No molecular link between cytoplasmic PS enrichment and downstream signaling identified
  • Physical basis for ATP11C control of partner transporter trafficking unknown
  • Lineage-specific developmental dependence unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 4 GO:0008289 lipid binding 3 GO:0016787 hydrolase activity 3 GO:0140657 ATP-dependent activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1430728 Metabolism 2 R-HSA-382551 Transport of small molecules 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CDC50AEZRINNTCPOATP1B2
Complex memberships
ATP11C-CDC50A flippase complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 ATP11C functions as an aminophospholipid flippase that internalizes phosphatidylserine in pro-B cells; loss-of-function mutations cause defective PS translocation and developmental arrest of B lymphopoiesis, establishing a direct link between flippase activity and B cell differentiation. Mouse genetics (ENU mutagenesis), flow cytometry for PS translocation, transgenic rescue experiments (pre-rearranged Ig, Bcl-2, IL-7 transgenes) Nature immunology High 21423172 21423173
2011 ATP11C mutations cause X-linked intrahepatic cholestasis in mice, originating from a non-hematopoietic (liver) cell defect; mutant mice show elevated serum cholic acid and are hypersensitive to dietary cholic acid supplementation, establishing ATP11C as a hepatic transporter preventing cholestasis. Mouse genetics, liver function tests, bile acid measurements, dietary supplementation challenge, bone marrow chimeras to distinguish hematopoietic vs. non-hematopoietic origin Proceedings of the National Academy of Sciences of the United States of America High 21518881
2016 ATP11C is the major phosphatidylserine flippase in human erythrocytes; a loss-of-function mutation reduces PS internalization 10-fold and causes X-linked congenital hemolytic anemia, establishing ATP11C as the principal erythrocyte flippase. Patient genetics, PS internalization assay in patient erythrocytes vs. controls, flow cytometry for PS exposure Haematologica High 26944472
2016 ATP11C mediates significant flippase activity (PS and PE internalization) in all murine leukocyte subsets; loss of ATP11C results in increased PS exposure on viable pro-B and developing T cells, but only B cell development is blocked. Flow cytometry with fluorescent PS/PE analogs in leukocyte subsets from ATP11C-deficient mice, 7-AAD viability gating PloS one Medium 26799398
2016 ATP11C localizes to the basolateral membrane of central hepatocytes and is required for basolateral localization of multiple bile salt uptake transporters (OATP1B2, OATP1A1, OATP1A4, NTCP); its loss causes proteasome-dependent degradation of these transporters and impairs hepatic uptake of unconjugated bile salts. Immunofluorescence, western blotting, pharmacokinetic analysis with radiolabeled substrates, proteasome inhibitor rescue (bortezomib) in ATP11C-deficient mice Hepatology (Baltimore, Md.) High 26926206
2015 A nonsense mutation in ATP11C is responsible for the PS uptake defect in UPS-1 cells; exogenous expression of wild-type ATP11C restores PS flipping, establishing ATP11C as the essential flippase for PS in CHO-K1 cells. mRNA quantification, mutation identification by sequencing, rescue by exogenous ATP11C expression, fluorescent PS analog uptake assay Journal of lipid research Medium 26420878
2015 ATP11C deficiency in mice impairs hepatic sinusoidal uptake of organic anions and reduces expression of OATP transporters in liver plasma membranes, without affecting biliary secretion or canalicular transporter expression. In vivo pharmacokinetic analysis with radiolabeled substrates, isolated hepatocyte uptake assays, liver plasma membrane fractionation and western blotting Molecular pharmacology Medium 26399598
2017 ATP11C is internalized from the plasma membrane via clathrin-mediated endocytosis upon Ca2+-mediated PKC activation; a di-leucine motif (SVRPLL) in the cytoplasmic C-terminus of ATP11C becomes functional upon PKC activation, and this regulation is triggered by Ca2+ signaling through Gq-coupled receptors. ATP11A does not undergo the same endocytosis. Live-cell imaging, endocytosis assays, PKC activation experiments, mutagenesis of di-leucine motif, pharmacological inhibition of clathrin-mediated endocytosis, Gq-coupled receptor stimulation Nature communications High 29123098
2020 Cryo-EM structures of ATP11C in six states at 3.0–4.0 Å resolution reveal the complete transport cycle: phosphorylation-driven domain movements couple with phospholipid binding; three phospholipid-bound states detail head group recognition and acyl chain accommodation in transmembrane grooves; invariant Lys880 and surrounding hydrogen-bond network serve as a pivot for helix bending and dephosphorylation. Single-particle cryo-EM, structure determination in five conformational states Cell reports High 32997992
2019 The C-terminal cytoplasmic region determines splice variant-specific localization: ATP11C-a distributes over the entire plasma membrane, while ATP11C-b localizes to a polarized membrane region; LLXY residues in the ATP11C-b C-terminus are critical for polarized localization. ATP11C-b and ATP11C-a do not undergo endocytosis upon PKC activation, in contrast to ATP11C-a. Fluorescence microscopy of splice variant localization in polarized and non-polarized cells, site-directed mutagenesis of LLXY motif, PKC activation assays Journal of cell science Medium 31371488
2019 The ATP11C T418N disease-causing mutation reduces flippase activity by causing ER retention and proteasome-mediated degradation rather than catalytic inactivation: mutant protein fails to traffic to the plasma membrane even in the presence of CDC50A, and is partially rescued by proteasome inhibitors. Monoclonal antibody generation, immunoblotting of patient erythrocyte membranes, transfection of mutant vs. wild-type in cultured cells, immunofluorescence for localization, proteasome inhibitor rescue, PS flippase activity assay Biochemical and biophysical research communications Medium 31253392
2021 Cryo-EM of ATP11C reconstituted in Nanodiscs reveals distended inner membrane around transmembrane helix 2 in the BeF-stabilized intermediate, suggesting local membrane perturbation facilitates phospholipid release to the lipid bilayer; membrane boundary varies with enzyme conformational state. Single-particle cryo-EM at 3.4 Å and 3.9 Å of Nanodisc-reconstituted ATP11C, ATPase activity measurement The Journal of biological chemistry High 34922944
2021 The polarized localization of ATP11C-b at the plasma membrane is mediated through direct interaction with ezrin; the LLxY motif in the ATP11C-b C-terminus is required for both ezrin binding and polarized localization. ERM proteins (especially ezrin) contribute to ATP11C-b polarization, and ATP11C-b loss causes mislocalization of C-terminally phosphorylated (active) ERM proteins, restored only by ATP11C-b but not ATP11C-a. Co-immunoprecipitation, mutagenesis of LLxY motif, ERM knockdown, fluorescence microscopy, ATP11C knockout with rescue experiments Journal of cell science Medium 34528675
2023 ATP11C loss in pre-B cells does not impair IL-7-dependent proliferation but is required for differentiation of pre-B cells into immature B cells upon IL-7 withdrawal, indicating ATP11C-mediated lipid asymmetry controls the switch from proliferation to differentiation. CRISPR/Cas9 knockout of ATP11C in pre-B cell line, PS flippase activity assay, proliferation and differentiation assays in vitro Immunologic research Medium 36753036
2025 Cryo-EM structure of the ATP11C Q79E mutant in the PC-occluded E2-Pi state reveals a reshaped substrate binding pocket: Q79E mutation plus conformational changes in Ser91 and Asn352 create additional space accommodating the bulky choline headgroup, thereby expanding substrate specificity from PS/PE to include PC. Cryo-EM structure determination, ATPase activity assay with PS and PC substrates, site-directed mutagenesis The Journal of biological chemistry High 41237907
2025 The ATP11C-CDC50A complex maintains PS in the inner membrane leaflet; CRISPR knockout of ATP11C reduces PS flipping efficiency, impairs Newcastle disease virus (NDV) replication, and disrupts virion release; CDC50A mutations D193G/K319E compromise ATP11C activity and reduce PS redistribution by 60%, establishing CDC50A as an essential subunit for ATP11C function. CRISPR/Cas9 knockout, PS flipping assay, viral replication quantification, CDC50A site-directed mutagenesis, virus-like particle production assay The Journal of biological chemistry Medium 40812423
2023 A missense variant ATP11C p.Leu789Phe reduces ATP11C protein expression by 58% in patient RBC ghosts and reduces PS flippase activity to 26% of normal; recombinant mutant expression in HEK293T cells confirms reduced protein expression (27%) and decreased PS-stimulated ATPase activity (57%), establishing loss-of-function as the mechanism causing hemolytic anemia. Patient RBC ghost immunoblotting, PS flippase activity assay, recombinant protein expression in HEK293T cells, ATPase activity measurement American journal of hematology Medium 37671681

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 ATP11C is critical for the internalization of phosphatidylserine and differentiation of B lymphocytes. Nature immunology 119 21423173
2011 The P4-type ATPase ATP11C is essential for B lymphopoiesis in adult bone marrow. Nature immunology 81 21423172
2016 ATP11C is a major flippase in human erythrocytes and its defect causes congenital hemolytic anemia. Haematologica 76 26944472
2020 Transport Cycle of Plasma Membrane Flippase ATP11C by Cryo-EM. Cell reports 58 32997992
2011 X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C. Proceedings of the National Academy of Sciences of the United States of America 51 21518881
2017 Phospholipid flippase ATP11C is endocytosed and downregulated following Ca2+-mediated protein kinase C activation. Nature communications 46 29123098
2016 ATP11C Facilitates Phospholipid Translocation across the Plasma Membrane of All Leukocytes. PloS one 21 26799398
2016 ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes. Hepatology (Baltimore, Md.) 21 26926206
2015 ATP11C mutation is responsible for the defect in phosphatidylserine uptake in UPS-1 cells. Journal of lipid research 20 26420878
2015 Impaired Hepatic Uptake by Organic Anion-Transporting Polypeptides Is Associated with Hyperbilirubinemia and Hypercholanemia in Atp11c Mutant Mice. Molecular pharmacology 19 26399598
2021 Cryo-EM of the ATP11C flippase reconstituted in Nanodiscs shows a distended phospholipid bilayer inner membrane around transmembrane helix 2. The Journal of biological chemistry 15 34922944
2019 The cytoplasmic C-terminal region of the ATP11C variant determines its localization at the polarized plasma membrane. Journal of cell science 9 31371488
2015 ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function. Digestive diseases (Basel, Switzerland) 9 26045263
2023 A novel missense variant in ATP11C is associated with reduced red blood cell phosphatidylserine flippase activity and mild hereditary hemolytic anemia. American journal of hematology 8 37671681
2019 ATP11C T418N, a gene mutation causing congenital hemolytic anemia, reduces flippase activity due to improper membrane trafficking. Biochemical and biophysical research communications 7 31253392
2021 The interaction of ATP11C-b with ezrin contributes to its polarized localization. Journal of cell science 5 34528675
2020 Expression of three P4-phospholipid flippases-atp11a, atp11b, and atp11c in zebrafish (Danio rerio). Gene expression patterns : GEP 4 32344036
2023 Case of Congenital Hemolytic Anemia with ATP11C and ANK1 Variants. Children (Basel, Switzerland) 3 37892263
2025 Not-So-Rare Defects of RBC Lipidic Composition: Four New Cases of Flippase Deficiency Due to ATP11C Mutations. International journal of molecular sciences 2 40869043
2021 The ratio of ATP11C/PLSCR1 mRNA transcripts has clinical significance in sickle cell anemia. Annals of hematology 2 34651249
2025 Newcastle disease virus exploits the phospholipid flippase ATP11c-CDC50A complex to promote viral infection. The Journal of biological chemistry 1 40812423
2025 Cryo-EM structure of the ATP11C Q79E mutant reveals the structural basis for altered Phospholipid recognition. The Journal of biological chemistry 1 41237907
2023 ATP11C promotes the differentiation of pre-B cells into immature B cells but does not affect their IL-7-dependent proliferation. Immunologic research 1 36753036
2026 Hypomorphic ATP11c is a novel regulator of decreased efficacy of transfused red blood cells in humans and mice. HemaSphere 0 41523080
2026 Clinical variability of ATP11C-related hemolytic anemia: expanding the phenotypic and diagnostic spectrum. Blood advances 0 42018644
2026 Beyond Gilbert's syndrome: hyperbilirubinaemia due to combined UGT1A1 mutation associated with an ATP11C variant. Revista espanola de enfermedades digestivas 0 42024132

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