Structure and dynamics of FCHo2 docking on membranes

Clathrin-mediated endocytosis is a paradigm of a cellular processes that is orchestrated by phosphoinositides, where the plasma membrane phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an instrumental role in the formation of clathrin-coated structures. Among the early endocytic proteins that reach at the plasma membrane, the F-BAR domain only protein 1 and 2 complex (FCHo1/2) is thought to orchestrate the early stages but, the exact mechanism triggering its nucleation on membranes is not well understood. By combining bottom-up synthetic approaches on in vitro and cellular membranes, we show the molecular dynamics of FCHo2 self-assembly on membranes. Our results indicate that PI(4,5)P2 guide the recruitment of FCHo2 at specific regions of the membrane, where it self-assembles into ring-like shape protein patches flanked by membrane invaginations. Importantly, we show that binding of FCHo2 on cellular membranes promotes the enrichment of PI(4,5)P2 at the boundary of specific cargo receptors, such as the epidermal growth factor receptor (EGFR). Thus, our results provide a mechanistic framework that could explain the orchestration of early PI(4,5)P2-interacting proteins recruitment at endocytic sites.