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 crescentshaped 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, multi-valent contacts, leading to assembly of protein liquid phases on membrane surfaces. Here we ask how membrane-associated protein liquids impact membrane curvature. Using synthetic and cell-derived membrane vesicles, we find that liquid-liquid phase separation of membrane-associated disordered proteins creates a substantial compressive stress in the plane of the membrane. This stress drives the membrane to bend away from the protein layer, 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 membrane 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.

Local sensitivity analysis of the “membrane shape equation” derived from the Helfrich energy

“…Note that W is a scalar multiple of the total elastic bending energy of the membrane and h ( α ) is a scalar multiple of the mean curvature at the corresponding points on the membrane. The boundary conditions used for the original unknowns are: The boundary conditions for the corresponding sensitivities are all set to be zero. Our choices for the input parameters are given in Table 4. This particular choice of parameters is in agreement with [24].…”

“…Our choices for the input parameters are given in Table 4. This particular choice of parameters is in agreement with [24].…”

Surfing on Membrane Waves: Microvilli, Curved Membranes, and Immune Signaling

“…Polymerization of actin filaments drives membrane protrusion; in parallel, membrane-associated proteins can also induce membrane curvature by the insertion of conical transmembrane proteins or hydrophobic protein domains into the membrane ( 66 , 67 ). Intriguingly, intrinsically disordered domains, when attached to membranes, can drive membrane protrusion either with a positive or negative curvature ( 68 – 70 ).…”

Surface Densities Prewet a Near-Critical Membrane

“…Many examples in biology display some of the phenomena we investigate here but with additional subtleties and complications. Recent studies have shown that condensates can induce membrane deformations in clathrin-mediated endocytosis (42) and in synthetic systems (43). While we expect that surface densities can substantially deform the membrane, and that deformations may influence the interactions between membrane and bulk, we don’t allow this in our model and so cannot explore it’s consequences here.…”