ArticleProceedings of the National Academy of Sciences of the United States of America2014
Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 65 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
65 citing papers in PubMed, 118 citations in OpenAlex.
- Mechanism of Phosphatidylserine Lipid Scrambling by Human SERINC3, an HIV-1 Restriction Factor.bioRxiv : the preprint server for biology · 2025Article
- Substrates, regulation, cellular functions, and disease associations of P4-ATPases.Communications biology · 2025Review
- Membrane Surface Charge, Phospholipids, and Protein Localization.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Substrate specificity controlled by the exit site of human P4-ATPases, revealed by de novo point mutations in neurological disorders.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes.Neurogenetics · 2024Article
- Consensus, controversies, and conundrums of P4-ATPases: The emerging face of eukaryotic lipid flippases.The Journal of biological chemistry · 2024Review
- Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.Disease models & mechanisms · 2024Article
- A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability ofmedRxiv : the preprint server for health sciences · 2024Article
- Flipping the script: Advances in understanding how and why P4-ATPases flip lipid across membranes.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Article
- Activation and substrate specificity of the human P4-ATPase ATP8B1.Nature communications · 2023Article
- Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases.Nature reviews. Molecular cell biology · 2023Review
- Transcriptional Modulation Reveals Physiological Responses to Temperature Adaptation inInternational journal of molecular sciences · 2023Article
- Exploring the Phospholipid Transport Mechanism of ATP8A1-CDC50.Biomedicines · 2023Article
- Lipid Transport byInfection and immunity · 2022Article
- The lipid flippase Drs2 regulates anterograde transport of Atg9 during autophagy.Autophagy reports · 2022Article
- Application of Coarse-Grained (CG) Models to Explore Conformational Pathway of Large-Scale Protein Machines.Entropy (Basel, Switzerland) · 2022Article
- Article
- Energetics of lipid transport by the ABC transporter MsbA is lipid dependent.Communications biology · 2021Article
- Arabidopsis P4 ATPase-mediated cell detoxification confers resistance to Fusarium graminearum and Verticillium dahliae.Nature communications · 2021Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
P4-ATPases (flippases) translocate specific phospholipids such as phosphatidylserine from the exoplasmic leaflet of the cell membrane to the cytosolic leaflet, upholding an essential membrane asymmetry. The mechanism of flipping this giant substrate has remained an enigma. We have investigated the importance of amino acid residues in transmembrane segment M4 of mammalian P4-ATPase ATP8A2 by mutagenesis. In the related ion pumps Na(+),K(+)-ATPase and Ca(2+)-ATPase, M4 moves during the enzyme cycle, carrying along the ion bound to a glutamate. In ATP8A2, the corresponding residue is an isoleucine, which recently was found mutated in patients with cerebellar ataxia, mental retardation, and dysequilibrium syndrome. Our analyses of the lipid substrate concentration dependence of the overall and partial reactions of the enzyme cycle in mutants indicate that, during the transport across the membrane, the phosphatidylserine head group passes near isoleucine-364 (I364) and that I364 is critical to the release of the transported lipid into the cytosolic leaflet. Another M4 residue, N359, is involved in recognition of the lipid substrate on the exoplasmic side. Our functional studies are supported by structural homology modeling and molecular dynamics simulations, suggesting that I364 and adjacent hydrophobic residues function as a hydrophobic gate that separates the entry and exit sites of the lipid and directs sequential formation and annihilation of water-filled cavities, thereby enabling transport of the hydrophilic phospholipid head group in a groove outlined by the transmembrane segments M1, M2, M4, and M6, with the hydrocarbon chains following passively, still in the membrane lipid phase.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.