Asymmetry and vulnerability on phospholipids in the plasma membrane

Abstract

In mammalian cells, the plasma membrane is composed of various lipids such as phospholipids, glycolipids, and cholesterol, with most of them being asymmetrically positioned between the lipid bilayer. Typically, phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtn) are localized in the inner leafl et, while phosphatidylcholine (PtdCho) and sphingomyelin (SM) are enriched in the outer leaflet. ATP11A and ATP11C are phospholipid flippases at the plasma membrane that specifi cally translocate PtdSer and PtdEtn from the outer to the inner leafl et, maintaining their asymmetry. Dysfunction of these fl ippases, such as impairment of the fl ippase activity and alteration of their substrate specifi city, results in improper distribution of phospholipids in the plasma membrane. As a result, mutations in ATP11A and ATP11C genes cause various diseases, such as B-cell lymphopenia, cholestasis, anemia, developmental disorder, hearing loss, and neurological deterioration in mice and humans. These fi ndings indicate that ATP11A and ATP11C are essential for maintaining the lipid organization of the plasma membrane and the homeostasis of mammals.