Speaker
Description
The actin cytoskeleton drives membrane deformation during many cellular processes, such as migration, morphogenesis, and endocytosis. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], one of the phosphoinositides, regulates the activities of many actin-binding proteins (ABPs), including profilin, cofilin, Dia2, N-WASP, ezrin, and moesin; however, the underlying molecular mechanisms remain elusive. Here, we applied a combination of biophysical assays and atomistic molecular dynamics simulations to uncover the molecular principles underlying ABP interactions with phosphoinositide-containing membranes. Our results reveal that these proteins show significant differences in membrane interaction dynamics and in the ranges of phosphoinositide densities they can sense. Profilin and cofilin show transient, low-affinity interactions with membranes, whereas F-actin assembly factors Dia2 and N-WASP stay on membranes longer to perform their functions. Ezrin and moesin, which link the actin cytoskeleton to the plasma membrane, bind to membranes with high affinity and slow dissociation kinetics, regulating PI(4,5)P2 lateral diffusion. Unlike profilin, cofilin, Dia2, and N-WASP, they do not require a high ‘stimulus-responsive’ phosphoinositide density for membrane binding. Together, these findings demonstrate that the membrane-interaction mechanisms of ABPs have evolved to precisely fulfill their specific cellular functions in cytoskeletal dynamics.
