Lipid-mediated Association of the Slg1 Transmembrane Domains in Yeast Plasma Membranes

Abstract

Clustering of transmembrane proteins underlies a multitude of fundamental biological processes at the plasma membrane such as receptor activation, lateral domain formation and mechanotransduction. The self-association of the respective transmembrane domains (TMD) has also been suggested to be responsible for the micron-scaled patterns seen for integral membrane proteins in the budding yeast plasma membrane (PM). However, the underlying interplay between local lipid composition and TMD identity is still not mechanistically understood. In this work we have used coarse-grained molecular dynamics (MD) simulations as well as microscopy experiments (TIRFM) to analyze the behavior of a representative helical yeast TMD (Slg1) within different lipid environments. Via the simulations we evaluated the effect of acyl chain saturation and the presence of anionic lipids head groups on the association of TMDs via simulations. Our simulations revealed that weak lipid-protein interactions significantly affect the configuration of TMD dimers and the free energy of association. Increased amounts of unsaturated phospholipids strongly reduced helix-helix interaction and the presence of phosphatidylserine (PS) lipids only slightly affected the dimer. Experimentally, the network factor, characterizing the association strength on a mesoscopic level, was measured in the presence and absence of PS lipids. Consistently with the simulations, no significant effect was observed. We also found that formation of TMD dimers in turn increased the order parameter of the surrounding lipids and induced long-range perturbations in lipid organization, shedding new light on the lipid-mediated dimerization of TMDs in complex lipid mixtures.