Cell
Volume 161, Issue 3, 23 April 2015, Pages 581-594
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Article
Transbilayer Lipid Interactions Mediate Nanoclustering of Lipid-Anchored Proteins

https://doi.org/10.1016/j.cell.2015.03.048Get rights and content
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Highlights

  • Lipids with long saturated acyl chains are required for actin-based nanoclustering

  • Inner leaflet phosphatidylserine couples to outer leaflet lipids

  • Immobilization of long saturated acyl chain lipids promotes transbilayer coupling

  • Actin association can mediate immobilization of phosphatidylserine

Summary

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.

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