Seminars

The actin cytoskeleton provides forces for vital cellular processes involving membrane dynamics. Membrane phosphoinositides regulate many actin-binding proteins including cofilin, profilin, mDia2, N-WASP, ezrin and moesin, but the underlying mechanisms have remained elusive. By applying a combination of biochemical assays, photobleaching/activation approaches, and atomistic molecular dynamics simulations, we revealed that these proteins interact with membranes through multivalent electrostatic interactions, without specific binding pockets or penetrations into the lipid bilayers. However, their membrane-binding kinetics differ drastically. Cofilin and profilin exhibit transient, low-affinity interactions with phosphoinositide-containing membranes, whereas F-actin assembly factors mDia2 and N-WASP reside on phosphoinositide-containing membranes for longer periods to perform their functions. Ezrin and moesin, which link actin cytoskeleton to the plasma membrane, bind membranes with very high affinities and slow dissociation dynamics, and do not require high stimulus-responsive phosphoinositide density for membrane binding. Thus, membrane-interaction mechanisms of actin-binding proteins evolved to precisely fulfill their specific functions in cytoskeletal dynamics.
(Senju et al., Proc Natl Acad Sci U S A. 2017; 114(43):E8977-E8986.)