Linear aggregation of proteins on the membrane as a prelude to membrane remodeling

Abstract

Adhesion and insertion of curvature-mediating proteins can induce dramatic structural changes in cell membranes, allowing them to participate in several key cellular tasks. The way proteins interact to generate curvature remains largely unclear, especially at early stages of membrane remodeling. Using a coarse-grained model of Bin/ amphiphysin/Rvs domain with an N-terminal helix (N-BAR) interacting with flat membranes and vesicles, we demonstrate that at low protein surface densities, binding of N-BAR domain proteins to the membrane is followed by a linear aggregation and the formation of meshes on the surface. In this process, the proteins assemble at the base of emerging membrane buds. Our work shows that beyond a more straightforward scaffolding mechanism at high bound densities, the interplay of anisotropic interactions and the local stress imposed by the N-BAR proteins results in deep invaginations and endocytic vesicular bud-like deformations, an order of magnitude larger than the size of the individual protein. Our results imply that by virtue of this mechanism, cell membranes may achieve rapid local increases in protein concentration.coarse-grained simulation | membrane stress | self-assembly | membrane curvature | Gaussian curvature L ipid membranes protect cells and their organelles and serve as mechanical support for proteins involved in signal transduction and cellular trafficking (1). Owing to the way lipids are assembled into bilayers of mesoscopic length and molecular width, membranes behave as elastic and highly dynamic molecular sheets. Their innate multiscale nature is further evident in the local interplay between proteins and lipids, which results in large-scale membrane remodeling characterized by an impressive array of morphologies (2). These properties allow biological membranes to take part in several important cellular processes, as their restructuring is key to enabling communication between cells, formation of organelles, trafficking, division, and cell migration (1).The interactions between individual proteins and lipid molecules alone are insufficient to remodel flat membrane sheets to an appreciable extent, implying that the experimentally observed membrane remodeling is a result of the concerted action of multiple proteins (3) in ways mechanistically differing from the mode of action of a single protein. Considering the multiple timescales required to capture protein dynamics as the membrane deformations are induced, as well as the difficulty in separating individual events of the remodeling process, this mechanism remains largely unclear. It previously was demonstrated that the binding of curvature-inducing nanoparticles may form tubular and vesicular structures, in which particles interact with one another solely via curvature (3-6). Furthermore, analytical theory predicts that anisotropic inclusions may induce budding on the membrane surface (7). However, the way proteins assemble on the membrane and how their oligomerization couples to both local and long-wavelength transformat...

Shape deformation of lipid membranes by banana-shaped protein rods: Comparison with isotropic inclusions and membrane rupture

“…Atomic and coarse-grained molecular simulations [40][41][42][43][44][45] have been employed to investigate molecular-scale interactions between BAR proteins and lipids. The scaffold formation [43] and linear assembly [44] of BAR domains have been demonstrated.…”

Rigidity of transmembrane proteins determines their cluster shape

“…Remodeling of the biomembrane is achievable by proteins [34] and nanoparticles [35], and it is a vital step in endocytosis and vesiculation [24]. Interestingly, in a system of spherical nano-particles on lipid membranes [35] different aggregation patterns have been induced by varying the membrane rigidity.…”

Computational ‘microscopy’ of cellular membranes

“…When sufficient chemical information is retained, coarse-grained models can discriminate between different lipids and distinguish protein residues, and thus form a useful bridge between atomistic and macroscopic data. For instance, one can now simulate the collective lipid-mediated selfassembly of membrane proteins (Benjamini and Smit, 2013;Hall et al, 2012;Johnston et al, 2012;Periole et al, 2012;van den Bogaart et al, 2011) and their sorting between different membrane domains (de Jong et al, 2013;Janosi et al, 2012;Schäfer et al, 2011), as well as large-scale protein-induced membrane remodelling -including fusion and fission events (Baoukina and Tieleman, 2010;Braun et al, 2014;Davies et al, 2012;Fuhrmans and Müller, 2015;Kawamoto et al, 2015;Pinot et al, 2014;Risselada et al, 2014;Simunovic et al, 2013).…”

“…However, when carefully parameterized from higher-resolution models, semi-quantitative predictions can be made (Dama et al, 2013). Recent examples of the supra-coarse-grained approach include simulations of large-scale membrane remodelling by Bin-amphiphysin-Rvs (BAR) domains (Cui et al, 2013;Simunovic et al, 2013;Yu and Schulten, 2013), the membrane-induced formation of peptide fibrils (Morriss-Andrews et al, 2014) and the supra-molecular organization of photosynthetic membranes (Lee et al, 2015). Furthermore, the supra-coarse-grained approach allows for a natural connection to the macroscopic scale using, for instance, field-theory-or fluid-dynamics-based descriptions of cell membranes (Ayton et al, 2009;Camley and Brown, 2014;Fedosov et al, 2014;Yolcu et al, 2014).…”