ArticleThe Journal of biological chemistry2019
Identification and functional analyses of disease-associated P4-ATPase phospholipid flippase variants in red blood cells.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 33 citations in OpenAlex.
- Fluorescence-Gated Flow Cytometry Approach for Measuring Lipid Flippase Activity in Mammalian Cells.The Journal of membrane biology · 2026Article
- Clinical variability of ATP11C-related hemolytic anemia: expanding the phenotypic and diagnostic spectrum.Blood advances · 2026Article
- HypomorphicHemaSphere · 2026Article
- PfATP2 is a flippase on the Plasmodium falciparum surface that is important for growth and influences parasite sensitivity to antiplasmodial compounds.PLoS pathogens · 2025Article
- ATP8A1-translocated endosomal phosphatidylserine fine-tunes the multivesicular body formation and the endo-lysosomal traffic.iScience · 2025Article
- Substrates, regulation, cellular functions, and disease associations of P4-ATPases.Communications biology · 2025Review
- Article
- Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.Disease models & mechanisms · 2024Article
- Flipping the script: Advances in understanding how and why P4-ATPases flip lipid across membranes.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Calculated haemorheological profile and laboratory parameters in new diagnosed multiple myeloma patients: retrospective analysis according to survival.Therapeutic advances in hematology · 2024Article
- Overproduction of mycotoxin biosynthetic enzymes triggers Fusarium toxisome-shaped structure formation via endoplasmic reticulum remodeling.PLoS pathogens · 2024Article
- Desipramine induces eryptosis in human erythrocytes, an effect blunted by nitric oxide donor sodium nitroprusside and N-acetyl-L-cysteine but enhanced by Calcium depletion.Cell cycle (Georgetown, Tex.) · 2023Article
- Atp8a1 deletion increases the proliferative activity of hematopoietic stem cells by impairing PTEN function.Cellular oncology (Dordrecht, Netherlands) · 2023Article
- Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases.Nature reviews. Molecular cell biology · 2023Review
- The enemy within: lipid asymmetry in intracellular parasite-host interactions.Emerging topics in life sciences · 2023Review
- Physiological and Pathological Functions of TMEM30A: An Essential Subunit of P4-ATPase Phospholipid Flippases.Journal of lipids · 2023Review
- Development of Antifungal Peptides against Cryptococcus neoformans; Leveraging Knowledge about theMicrobiology spectrum · 2022Article
- Of membranes and malaria: phospholipid asymmetry in Plasmodium falciparum-infected red blood cells.Cellular and molecular life sciences : CMLS · 2021Review
- Enzymatic trans-bilayer lipid transport: Mechanisms, efficiencies, slippage, and membrane curvature.Biochimica et biophysica acta. Biomembranes · 2021Review
- Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells.PLoS pathogens · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
ATP-dependent phospholipid flippase activity crucial for generating lipid asymmetry was first detected in red blood cell (RBC) membranes, but the P4-ATPases responsible have not been directly determined. Using affinity-based MS, we show that ATP11C is the only abundant P4-ATPase phospholipid flippase in human RBCs, whereas ATP11C and ATP8A1 are the major P4-ATPases in mouse RBCs. We also found that ATP11A and ATP11B are present at low levels. Mutations in the gene encoding ATP11C are responsible for blood and liver disorders, but the disease mechanisms are not known. Using heterologous expression, we show that the T415N substitution in the phosphorylation motif of ATP11C, responsible for congenital hemolytic anemia, reduces ATP11C expression, increases retention in the endoplasmic reticulum, and decreases ATPase activity by 61% relative to WT ATP11C. The I355K substitution in the transmembrane domain associated with cholestasis and anemia in mice was expressed at WT levels and trafficked to the plasma membrane but was devoid of activity. We conclude that the T415N variant causes significant protein misfolding, resulting in low protein expression, cellular mislocalization, and reduced functional activity. In contrast, the I355K variant folds and traffics normally but lacks key contacts required for activity. We propose that the loss in ATP11C phospholipid flippase activity coupled with phospholipid scramblase activity results in the exposure of phosphatidylserine on the surface of RBCs, decreasing RBC survival and resulting in anemia.
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