N-RAS Lipid Anchor Adsorption to Membranes as a Function of Lipid Composition and Curvature

Abstract

Protein recruitment to biological membranes is motivated by either highly selective recognition of specific target membrane components or non-specific attraction to general physical properties of the membrane, such as charge, lipid heterogeneity, and curvature. Here we discuss the interaction between lipid-anchored proteins and lipid membranes from a comprehensive examination of how features of the membrane and its lipid constituents, including lipid head-group size, composition, heterogeneity, membrane thickness, degree of unsaturation, and membrane geometry, effect the adsorption ability of the proteins. Of key importance is the strong interconnection among these compositional and morphological elements in mediating the binding of peripheral membrane proteins. As a model protein, we use the dual lipidated (palmitoyl and farnesyl) anchoring motif of the signaling GTPase N-Ras (tN-Ras). We find marked augmentation in tN-Ras adsorption with increasing degree of membrane curvature—a trend that is tightly regulated by the bilayer characteristics mentioned above. Experimental results are fully reproduced by a molecular level theoretical model of the systems under study. Of note, the theory suggests an explicit dependence on the lateral pressure profile of the membrane's hydrophobic region to be the mechanism and cause of variation in protein density with membrane curvature and composition. Relief in the lateral pressure of the bilayer's outer leaf, upon its expansion induced by increasing curvature, reduces the work requirement for lipid-anchor insertion into the membrane. Furthermore, the inherent pressure profile of the hydrophobic channel, at a given curvature, is unique with regard to membrane composition, which allows for fine-tuning of lipidated-protein density.