Active and stochastic triggering of protein self-assembly in cells

Bending of the membrane into vesicles and viruses requires work performed by multi-protein assemblies. The ability of these protein components to nucleate and assemble on membranes can be triggered through both ATP-independent processes, and through energy-consuming reactions such as phosphorylation. Clathrin-mediated endocytosis, an essential process for internalizing transmembrane cargo across the cell membrane, provides a rich system for studying how assembly is controlled via stochastic and active forces. Using kinetic and reaction-diffusion modeling, we show how the stoichiometry of the assembly components, which can be effectively controlled via enzymatic reactions (which turn on and off interactions), can control the kinetics and success of clathrin assembly. We quantify how specific assembly components can stabilize assembly growth either through the formation of 2D interactions on the surface, or through their ability to induce or stabilize curvature and membrane bending necessary for vesicle formation. Using continuum thin-film models, we show how these proteins can create mechanical feedback that renders the membrane effectively more ‘sticky’ to subsequent protein recruitment interactions. Our models can be directly applied to studying related assembly processes such as viral budding within the cell.