Protein crowding and lipid complexity influence the nanoscale dynamic organization of ion channels in cell membranes

Anna L Duncan,Matthieu Chavent,Philip W Fowler,Heidi Koldsø,Mark S P Sansom,Tyler Reddy,Jean Hélie

doi:10.1038/s41598-017-16865-6

Abstract

Cell membranes are crowded and complex environments. To investigate the effect of protein-lipid interactions on dynamic organization in mammalian cell membranes, we have performed coarse-grained molecular dynamics simulations containing >100 copies of an inwardly rectifying potassium (Kir) channel which forms specific interactions with the regulatory lipid phosphatidylinositol 4,5-bisphosphate (PIP2). The tendency of protein molecules to cluster has the effect of organizing the membrane into dynamic compartments. At the same time, the diversity of lipids present has a marked effect on the clustering behavior of ion channels. Sub-diffusion of proteins and lipids is observed. Protein crowding alters the sub-diffusive behavior of proteins and lipids such as PIP2 which interact tightly with Kir channels. Protein crowding also affects bilayer properties, such as membrane undulations and bending rigidity, in a PIP2-dependent manner. This interplay between the diffusion and the dynamic organization of Kir channels may have important implications for channel function.

Highlights

Cell membranes are crowded and complex environments, containing up to 50% protein by mass, which is equivalent to ca. 25% protein by cross-sectional area[1]
To explore the dynamic organization of Kir channels we simulated 144 copies of the Kir2.2 channel embedded in a plasma membrane (PM) model
The bilayer of the PM model contained the major lipid species observed in a mammalian plasma membrane[54]

Summary

Introduction

Cell membranes are crowded and complex environments, containing up to 50% protein by mass, which is equivalent to ca. 25% protein by cross-sectional area[1]. In addition to probing the nature of protein-lipid interactions, there has been much interest in how complex lipid mixtures may generate dynamic organization in lipid bilayers This has embraced e.g. lateral nanodomains of specific lipid composition[20,21], and the contribution of lipid properties to membrane curvature[22] and fluctuations[23]. Despite impressive progress[7] much remains to be understood regarding how the molecular interactions between protein and lipids, including crowding, influence higher-level membrane organization and dynamics[24]. In order to investigate the role of protein crowding and lipid complexity on the organization and dynamics of a model membrane containing a protein whose activity is regulated by interactions with lipids, we have focused www.nature.com/scientificreports/. The cytoplasmic domain of the homologous Kir2.1 channel has been shown to form clusters in the presence of channel-organising protein, PSD-95 (see below)[38]

Methods

Results

Conclusion