"Turning multi-protein self-assembly by membrane localization"

Abstract

Clathrin-mediated endocytosis (CME) is an essential pathway used by all eukaryotes for transport across the plasma membrane; it is one of many diverse cellular pathways that require cytosolic proteins to localize and self-assemble on the membrane. A wealth of biochemical, structural, and in vivo imaging data has provided deep insight into the dynamics of endocytosis. Yet because of the complexity of the pathway, it is still remarkably difficult to predict how the stoichiometry of components, membrane bending, or coupling to ATP-driven reactions impacts cargo uptake, and this is where computational modeling can provide important insights. We recently developed novel reaction-diffusion algorithms and software that enable detailed computer simulations of nonequilibrium self-assembly over long time-scales. We have shown through theory and simulation how localization of protein binding partners to the membrane can dramatically enhance binding through dimensionality reduction, providing a trigger for assembly. As a result, we show how tuning the localization strength of proteins to the membrane, via either protein or lipid binding partners, can drive assembly and disassembly of clathrin-coated structures. This will help us to predict how the transition from early clathrin coated structures to productive vesicles is controlled in the cell. Lastly, our generalized computational methods can directly simulate a broad range of assembly processes at the cell-scale, providing a natural companion to quantitative cell biology.