Ezrin enrichment on curved membranes requires a specific conformation or interaction with a curvature-sensitive partner

One challenge in current cell biology is to decipher the biophysical mechanisms governing protein enrichment on curved membranes and the resulting membrane deformation. The ERM protein ezrin is abundant and associated with cellular membranes that are flat or with positive or negative curvatures. Using in vitro and cell biology approaches, we assess mechanisms of ezrins enrichment on curved membranes. We evidence that ezrin (ezrinWT) and its phosphomimetic mutant T567D (ezrinTD) do not deform membranes but self-assemble anti-parallelly, zipping adjacent membranes. EzrinTDs specific conformation reduces intermolecular ezrin interactions, allows binding to actin filaments, and promotes ezrin binding to positively curved membranes. While neither ezrinTD nor ezrinWT senses negative membrane curvature alone, we demonstrate that interacting with curvature sensors I-BAR-domain proteins facilitates ezrin enrichment in negatively curved membrane protrusions. Overall, our work reveals new mechanisms, specific conformation or binding to a curvature sensor partner, for targeting curvature insensitive proteins to curved membranes.