LAUSR

Significance While it has long been established that cell membranes are complex assemblies of proteins and bilayer-forming lipids, the inherent mobility and wide-ranging heterogeneity of the lipids have limited our ability to understand cell-membrane structure at a molecular level. Consequently, little is yet known about the protein-lipid and lipid-lipid interplay that exists in situ. The present study exploits the regular architecture of a cholinergic cell membrane to determine how the phospholipid and cholesterol organization is influenced by the protein surfaces and by differences in cholesterol concentration between the two leaflets. Lipids in the leaflet containing the most cholesterol form an ordered sterol-hydrocarbon “skin.” This hitherto unobserved hydrophobic-core structure has far-reaching implications in terms of how cholesterol-rich membranes are constructed and function.