Cell. 2015 Apr 23;161(3):581-94. doi: 10.1016/j.cell.2015.03.048.
Transbilayer lipid interactions mediate nanoclustering of lipid-anchored proteins.
Raghupathy R1, Anilkumar AA1, Polley A2, Singh PP3, Yadav M3, Johnson C4, Suryawanshi S4, Saikam V3, Sawant SD3, Panda A5, Guo Z4, Vishwakarma RA3, Rao M6, Mayor S7.
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Abstract

Understanding how functional lipid domains in live cell membranes are generated has posed a challenge. Here, we show that transbilayer interactions are necessary for the generation of cholesterol-dependent nanoclusters of GPI-anchored proteins mediated by membrane-adjacent dynamic actin filaments. We find that long saturated acyl-chains are required for forming GPI-anchor nanoclusters. Simultaneously, at the inner leaflet, long acyl-chain-containing phosphatidylserine (PS) is necessary for transbilayer coupling. All-atom molecular dynamics simulations of asymmetric multicomponent-membrane bilayers in a mixed phase provide evidence that immobilization of long saturated acyl-chain lipids at either leaflet stabilizes cholesterol-dependent transbilayer interactions forming local domains with characteristics similar to a liquid-ordered (lo) phase. This is verified by experiments wherein immobilization of long acyl-chain lipids at one leaflet effects transbilayer interactions of corresponding lipids at the opposite leaflet. This suggests a general mechanism for the generation and stabilization of nanoscale cholesterol-dependent and actin-mediated lipid clusters in live cell membranes.