Membrane bending by protein phase separation

Abstract

Membrane bending is a ubiquitous cellular process that is required for membrane traffic, cell motility, organelle biogenesis, and cell division. Proteins that bind to membranes using specific structural features, such as wedge-like amphipathic helices and crescent-shaped scaffolds, are thought to be the primary drivers of membrane bending. However, many membrane-binding proteins have substantial regions of intrinsic disorder which lack a stable three-dimensional structure. Interestingly, many of these disordered domains have recently been found to form networks stabilized by weak, multivalent contacts, leading to assembly of protein liquid phases on membrane surfaces. Here we ask how membrane-associated protein liquids impact membrane curvature. We find that protein phase separation on the surfaces of synthetic and cell-derived membrane vesicles creates a substantial compressive stress in the plane of the membrane. This stress drives the membrane to bend inward, creating protein-lined membrane tubules. A simple mechanical model of this process accurately predicts the experimentally measured relationship between the rigidity of the membrane and the diameter of the membrane tubules. Discovery of this mechanism, which may be relevant to a broad range of cellular protrusions, illustrates that membrane remodeling is not exclusive to structured scaffolds but can also be driven by the rapidly emerging class of liquid-like protein networks that assemble at membranes.

In situ imaging of bacterial membrane projections and associated protein complexes using electron cryo-tomography

“…However, one interesting observation in all the species we investigated here is that there was no clear distinctive molecular machine at the base of the membrane projections, raising the question of what drives their formation. This observation is consistent with a recent study which showed that liquid-like assemblies of proteins in membranes can lead to the formation of tubular extensions without the need for solid scaffolds [39].…”

Curvature-driven feedback on aggregation-diffusion of proteins in lipid bilayers

“…We note that for a given value ofŜ, the variance decreases with increasingL for higher values ofŜ and this decrease is more dramatic when compared to the Cahn-Hilliard model (Figure 4b). Even though the number of patches remains more or less unaltered for small values ofŜ asL increases, the number decreases with increasingL for larger values ofŜ (Figure 7e), consistent with the stability behavior noted in Equation (52). These results suggest that the landscape of protein inhomogeneity is not only governed by theÂ-Ŝ space as is the case in the Cahn-Hilliard model; rather the curvature parameters, specificallyL in this case, can have a significant impact on the protein aggregation behavior.…”

“…These observations can lead to system-specific claims of whether membrane protein interactions result in a mechanochemical feedback between curvature and aggregation. In the context of specific biological processes such as endocytosis, aggregation of domains of protein-induced curvature is often assumed a priori or curvature is proposed as an organizing factor to explain cellular observations and experiments in reconstituted systems [46][47][48][49][50][51][52]. By developing a general theoretical framework that accounts for the coupled effects of protein diffusion, aggregation, and curvature generation, we have eliminated the need for such strong assumptions and more importantly, demonstrated that the intricate interactions between these different physics can lead to different regimes of pattern formation and membrane deformations.…”

“…Surprisingly, whenŜ = 2000, we noticed that protein aggregates do not form for the value ofL = 8 × 10 −3 and the membrane remains flat. This phenomenon can be explained from the critical value of A in Equation (52). Since bothL andŜ have stabilizing effect on density fluctuations φ (Equation ( 52)), for higher value ofŜ andL, an aggregation coefficient of = 25 is not sufficient to overcome the stabilizing barrier.…”

Mechanical Principles Governing the Shapes of Dendritic Spines

“…Thin and mushroom spines, which have defined head shapes, require more mechanical features—heterogeneous force distributions, normal or axial forces, and an induced spontaneous deviatoric curvature representing the periodic protein rings or other deviatoric curvature inducing mechanics along the neck. The heterogeneous distribution of actin-mediated forces and BAR domain proteins can be related to the nanoscale organization of actin filaments and protein phase separation on the membrane surface (Nowak et al, 2021 ; Yuan et al, 2021 ).…”