Beyond Bar Domains: The Collective Behavior of Peripheral Membrane Proteins in Membrane Remodeling

No protein family is as ubiquitous in plasma membrane remodeling as the Bin/Amphiphysin/Rvs (BAR) domain. Both in vitro and in vivo work have demonstrated the dramatic tubulation activity of BAR domains alone and in concert with other peripheral proteins, and the general dependence of this effect on the presence of negatively charged lipids such as phosphatidylserine (PS) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Using atomistic and coarse-grained (CG) molecular dynamics simulation in tandem with in vitro and in vivo imaging, we investigate at the molecular level the interactions of BAR domains with other protein domains and with the underlying lipids in the membrane. To demonstrate the general principles we have learned in our work, we study three example BAR domain systems: the paradigmatic endophilin, the PX-BAR domain of sorting nexin 9 (SNX9), and the newly identified lymphocyte oriented kinase (LOK) C-terminal domain. We find that BAR domains interact synergistically with other peripheral membrane protein domains, but the collective remodelling behavior of these proteins are not mediated by direct protein/protein interactions. Rather, local non-stoichiometric protein/lipid interactions act to generate long-range clustering, particularly through modulating the lipid diffusivity. The implications of this work extend broadly from considerations in structural biology of peripheral membrane proteins to regulation of plasma membrane tension and cell motility.