Regulation of actin-binding proteins by PI(4,5)P2.

Abstract

The actin cytoskeleton powers membrane deformations during many cellular processes such as cell migration, morphogenesis, and endocytosis. One of the phosphoinositides phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] regulates activities of many actin-binding proteins (ABPs) including profilin, cofilin, Dia2, N-WASP, ezrin, and moesin; however, the underlying molecular mechanisms have remained elusive. Here, we applied biophysical approaches to uncover the molecular principles by which ABPs interact with phosphoinositide-containing membranes. Although ABPs bind to the membranes mainly through electrostatic interactions, we reveal that they show large differences in the affinities and dynamics of membrane interactions, and in the ranges of phosphoinositide densities that they sense. Profilin and cofilin show transient, low-affinity interactions with membranes, whereas F-actin assembly factors Dia2 and N-WASP reside on membranes for longer periods to perform their functions. Ezrin and moesin, which link the actin cytoskeleton to the plasma membrane, bind membranes with high affinities and slow dissociation dynamics. Unlike profilin, cofilin, Dia2, and N-WASP, they do not require high “stimulus-responsive” phosphoinositide density for membrane binding. Together, these findings demonstrate that membrane-interaction mechanisms of ABPs evolved to precisely perform their specific functions in cytoskeletal dynamics.