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Transbilayer Lipid Interactions Mediate Nanoclustering of Lipid-Anchored Proteins

2015; Cell Press; Volume: 161; Issue: 3 Linguagem: Inglês

10.1016/j.cell.2015.03.048

1097-4172

Riya Raghupathy, Anupama Ambika Anilkumar, Anirban Polley, Parvinder Pal Singh, Mahipal Yadav, Charles Johnson, Sharad Suryawanshi, Varma Saikam, Sanghapal D. Sawant, Aniruddha Panda, Zhongwu Guo, Ram A. Vishwakarma, Madan Rao, Satyajit Mayor,

Protein Structure and Dynamics

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.