Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 43, Pages E8977-E8986Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1705032114
Keywords
actin cytoskeleton; phosphoinositides; protein-lipid interactions; signal transduction; molecular dynamics simulations
Categories
Funding
- Academy of Finland (Center of Excellence program)
- Japan Society for the Promotion of Science
- European Research Council Advanced Grant CROWDED-PRO-LIPIDS
Ask authors/readers for more resources
The actin cytoskeleton powers membrane deformation during many cellular processes, such as migration, morphogenesis, and endocytosis. Membrane phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate [PI(4,5)P-2], regulate the activities of many actinbinding proteins (ABPs), including profilin, cofilin, Dia2, N-WASP, ezrin, and moesin, but the underlying molecular mechanisms have remained elusive. Moreover, because of a lack of available methodology, the dynamics of membrane interactions have not been experimentally determined for any ABP. Here, we applied a combination of biochemical assays, photobleaching/activation approaches, and atomistic molecular dynamics simulations to uncover the molecular principles by which ABPs interact with phosphoinositide-rich membranes. We show that, despite using different domains for lipid binding, these proteins associate with membranes through similar multivalent electrostatic interactions, without specific binding pockets or penetration into the lipid bilayer. Strikingly, our experiments reveal that these proteins display enormous differences in the dynamics of membrane interactions and in the ranges of phosphoinositide densities that they sense. Profilin and cofilin display transient, low-affinity interactions with phosphoinositide-rich membranes, whereas F-actin assembly factors Dia2 and N-WASP reside on phosphoinositide-richmembranes for longer periods to performtheir functions. Ezrin and moesin, which link the actin cytoskeleton to the plasma membrane, bindmembranes with very high affinity and slow dissociation dynamics. Unlike profilin, cofilin, Dia2, and N-WASP, they do not require high stimulus-responsive phosphoinositide density for membrane binding. Moreover, ezrin can limit the lateral diffusion of PI(4,5)P-2 along the lipid bilayer. Together, these findings demonstrate that membrane-interaction mechanisms of ABPs evolved to precisely fulfill their specific functions in cytoskeletal dynamics.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available