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Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape

The manuscript "Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape" (https://www.nature.com/articles/s41589-020-0529-6) integrates lipidomic, biophysical, and bioinformatic approaches to comprehensively describe the compositional and structural asymmetry of the mammalian plasma membrane. The authors conclude that the unique lipid compositions of the two leaflets of the plasma membrane bilayer impart distinct physical properties that affect the structure of protein transmembrane domains. Although it has been known for decades that lipids are non-randomly distributed in many living membranes, the precise lipid compositions and physical properties of the two plasma membrane leaflets remain open questions. Combining mass spectrometric lipidomics and classical enzymatic approaches, the authors define the comprehensive, quantitative compositions of the two leaflets of human red blood cell membranes. These compositions are intended to ground accurate and realistic models of both surfaces of the plasma membrane. While generally consistent with classical measurements, these measurements also reveal a robust asymmetry in lipid acyl chains, with inner leaflet lipids being much more unsaturated than outer. A combination of computational simulations and cellular experiments then showed that two leaflets of live cell plasma membranes have quantitatively different lipid packing and diffusivity. This structural asymmetry persists long after membrane internalization, suggesting asymmetry in endocytic membranes. Finally, these biophysical asymmetries appear to be reflected in structural asymmetries of protein transmembrane domains, whose physical characteristics reflect the biophysical profile of their membrane matrix. These protein asymmetries are observed only for residents of plasma membranes and endosomes, but not of biosynthetic organelles (i.e. ER and Golgi). Remarkably, protein transmembrane domains are asymmetric throughout Eukarya, implying that the lipidomic and biophysical asymmetries that experimentally detailed in this work may be conserved throughout the eukaryotic domain of life.

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2021