Line Activity of Ganglioside GM1 Regulates the Raft Size Distribution in a Cholesterol-Dependent Manner

Abstract

Liquid-ordered lipid domains, also called rafts, are assumed to be important players in different cellular processes, mainly signal transduction and membrane trafficking. They are thicker than the disordered part of the membrane and are thought to form to compensate for the hydrophobic mismatch between transmembrane proteins and the lipid environment. Despite the existence of such structures in vivo still being an open question, they are observed in model systems of multicomponent lipid bilayers. Moreover, the predictions obtained from model experiments allow the explanation of different physiological processes possibly involving rafts. Here we present the results of the study of the regulation of raft size distribution by ganglioside GM1. Combining atomic force microscopy with theoretical considerations based on the theory of membrane elasticity, we predict that this glycolipid should change the line tension of raft boundaries in two different ways, mainly depending on the cholesterol content. These results explain the shedding of gangliosides from the surface of tumor cells and the following ganglioside-induced apoptosis of T-lymphocytes in a raft-dependent manner. Moreover, the generality of the model allows the prediction of the line activity of different membrane components based on their molecular geometry.

Elastic deformations mediate interaction of the raft boundary with membrane inclusions leading to their effective lateral sorting

“…This results in a sharp decrease of the boundary elastic energy allowing us to conclude that any membrane component with a strong positive spontaneous curvature should be line-active. This conclusion is quantitatively demonstrated for ganglioside GM1 31 .…”

“…A local enrichment of the L o /L d phase boundary by lipids possessing a positive spontaneous curvature was recently indicated as a mechanism of a line activity of ganglioside GM1 31 . GM1 introduced into the membrane in small amounts (~1 mol %) induces a decreases in the average size of the L o domains, which is consistent with the drastic drop of the domain boundary energy 27,31,76 . Our elastic model describes both effects: GM1 local enrichment and drop of the boundary energy ( Fig.…”

“…Such an equilibrium shift of the domain boundaries is observed in molecular dynamics simulations 24,34,35 . The structure of deformations in this intermediate region favors the accumulation of membrane components with positive spontaneous curvature near the domain boundary 31 . This results in a sharp decrease of the boundary elastic energy allowing us to conclude that any membrane component with a strong positive spontaneous curvature should be line-active.…”

“…Recently, we have explained the molecular mechanism of the line activity, basing on a thickness mismatch concept 31 . From experiments in vitro [31][32][33] and in silico 24,34,35 we know that ordered domains are thicker than the surrounding liquid-disordered membrane. If L o and L d phases were homogeneous up to their boundary, a step in the bilayer thickness would exist.…”

BILMIX: a new approach to restore the size polydispersity and electron density profiles of lipid bilayers from liposomes using small-angle X-ray scattering data

“…4, curves 3 and 4). In addition, it should be noted that the mixtures studied here give rise to the formation of liquidordered lipid domains (or rafts) in liposomal membranes (Heberle & Feigenson, 2011;Galimzyanov et al, 2017). In addition, it should be noted that the mixtures studied here give rise to the formation of liquidordered lipid domains (or rafts) in liposomal membranes (Heberle & Feigenson, 2011;Galimzyanov et al, 2017).…”