ArticleMolecular biology of the cell2017
C-terminus of the P4-ATPase ATP8A2 functions in protein folding and regulation of phospholipid flippase activity.
Article in Molecular biology of the cell, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- Recent advances in understanding the regulatory mechanisms of P4-ATPase lipid flippases.Biochemical Society transactions · 2026Review
- Evolutionary Prevalence of the Electrostatic Switch Mechanism in P-type ATPases.The Journal of membrane biology · 2026Article
- Butyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi.Cell · 2026Article
- Diagnostic Yield of Genome Sequencing in an Iranian Exome-Negative Autosomal-Recessive Intellectual Disability Cohort.Human mutation · 2026Article
- TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD.bioRxiv : the preprint server for biology · 2025Article
- Butyrolactol A potentiates caspofungin efficacy against resistant fungi via phospholipid flippase inhibition.bioRxiv : the preprint server for biology · 2025Article
- Substrates, regulation, cellular functions, and disease associations of P4-ATPases.Communications biology · 2025Review
- Role of Enzymes Capable of Transporting Phosphatidylserine in Brain Development and Brain Diseases.ACS omega · 2024Review
- The lipid flippase ATP8A1 regulates the recruitment of ARF effectors to the trans-Golgi Network.Archives of biochemistry and biophysics · 2024Article
- Consensus, controversies, and conundrums of P4-ATPases: The emerging face of eukaryotic lipid flippases.The Journal of biological chemistry · 2024Review
- Reconstitution of ATP-dependent lipid transporters: gaining insight into molecular characteristics, regulation, and mechanisms.Bioscience reports · 2023Review
- Physiological and Pathological Functions of TMEM30A: An Essential Subunit of P4-ATPase Phospholipid Flippases.Journal of lipids · 2023Review
- Article
- 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 · 2022Article
- Lipid Transporters Beam Signals from Cell Membranes.Membranes · 2021Review
- Structure and transport mechanism of P5B-ATPases.Nature communications · 2021Article
- Dynamic membranes: the multiple roles of P4 and P5 ATPases.Plant physiology · 2021Article
- Transport Pathways That Contribute to the Cellular Distribution of Phosphatidylserine.Frontiers in cell and developmental biology · 2021Review
- The N- or C-terminal cytoplasmic regions of P4-ATPases determine their cellular localization.Molecular biology of the cell · 2020Article
- Proteomic Analysis and Functional Characterization of P4-ATPase Phospholipid Flippases from Murine Tissues.Scientific reports · 2018Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
ATP8A2 is a P4-ATPase that flips phosphatidylserine and phosphatidylethanolamine across cell membranes. This generates membrane phospholipid asymmetry, a property important in many cellular processes, including vesicle trafficking. ATP8A2 deficiency causes severe neurodegenerative diseases. We investigated the role of the C-terminus of ATP8A2 in its expression, subcellular localization, interaction with its subunit CDC50A, and function as a phosphatidylserine flippase. C-terminal deletion mutants exhibited a reduced tendency to solubilize in mild detergent and exit the endoplasmic reticulum. The solubilized protein, however, assembled with CDC50A and displayed phosphatidylserine flippase activity. Deletion of the C-terminal 33 residues resulted in reduced phosphatidylserine-dependent ATPase activity, phosphatidylserine flippase activity, and neurite extension in PC12 cells. These reduced activities were reversed with 60- and 80-residue C-terminal deletions. Unlike the yeast P4-ATPase Drs2, ATP8A2 is not regulated by phosphoinositides but undergoes phosphorylation on the serine residue within a CaMKII target motif. We propose a model in which the C-terminus of ATP8A2 consists of an autoinhibitor domain upstream of the C-terminal 33 residues and an anti-autoinhibitor domain at the extreme C-terminus. The latter blocks the inhibitory activity of the autoinhibitor domain. We conclude that the C-terminus plays an important role in the efficient folding and regulation of ATP8A2.
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