Protein–lipid architecture of a cholinergic postsynaptic membrane

Abstract

The cholinergic postsynaptic membrane is an acetylcholine receptor-rich membrane mediating fast chemical communication at the nerve–muscle synapse. Here, cryo-EM is used to examine the protein–lipid architecture of this membrane in tubular vesicles obtained from the (muscle-derived) electric organ of theTorpedoray. As reported earlier, the helical arrangement of the protein component of the vesicles facilitates image averaging and enables us to determine how cholesterol and phospholipid molecules are distributed in the surrounding matrix, using headgroup size as a means to discriminate between the two kinds of lipid. It is shown that cholesterol segregates preferentially around the receptors in both leaflets of the lipid bilayer, interacting robustly with specific transmembrane sites and creating a network of bridging microdomains. Cholesterol interactions with the receptor are apparently essential for stabilizing and maintaining its physiological architecture, since the transmembrane structure contracts, involving displacements of the helices at the outer membrane surface by ∼2 Å (1–3 Å), when this lipid is extracted. The microdomains may promote cooperativity between neighbouring receptors, leading to an enhanced postsynaptic response.