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Membranes are molecular interfaces that are involved in nearly all aspects of cellular physiology, insulate cells from external stresses, compartmentalize the cytoplasm, and control the flow of nutrients and information between the external world and intracellular environments. The functions of these membranes are determined by the composition and organization of their constituent lipids and proteins. A ubiquitous feature of eukaryotic plasma membranes (PM) is a highly disparate distribution of lipids between the two leaflets of the lipid bilayer. Recently, we characterized the biophysical asymmetries of a model mammalian PM, the human erythrocyte, showing that the outer PM leaflet is relatively tightly packed, less diffusive, and more fluid than the inner leaflet. Furthermore, using quantitative lipidomics, we found that the PM cytoplasmic leaflet has up to 2-fold more phospholipids compared the exoplasmic leaflet. This finding contradicts most existing models of biomembrane structure, which rest upon the implicit assumption that the two leaflets have similar abundances of phospholipids. Here, we show that this assumption is generally invalid and investigate the consequences of lipid abundance imbalances across mammalian plasma membrane leaflets. We show that phospholipid imbalance is enabled by an asymmetric distribution of cholesterol, which can rapidly redistribute to buffer leaflet stresses. Through a combination of computational and experimental approaches, we demonstrate how these lipid distributions impart unique functional characteristics to mammalian plasma membranes, including low permeability and resting tension in the cytoplasmic monolayer that leads to hydrophobic defects and regulation of protein binding. Our observations of these previously overlooked aspects of membrane asymmetry represent an evolution of classical models of biomembrane structure and physiology. M.D. was supported by NIH F32GM134704. E.L. was supported by R01 GM120351. J.L.S was supported by GM008280. K.R.L. and I.L. are supported by NIH (GM120351, GM134949), the Volkswagen Foundation (grant 93091), and the Human Frontiers Science Program (RGP0059/2019).
Levental et al. (Fri,) studied this question.