Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides

Research output: Contribution to journalArticleScientificpeer-review

Researchers

  • Yosuke Senju
  • Maria Kalimeri
  • Essi V. Koskela
  • Pentti Somerharju
  • Hongxia Zhao
  • Ilpo Vattulainen
  • Pekka Lappalainen

Research units

  • University of Helsinki
  • Tampere University of Technology

Abstract

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)P2], 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)P2 along the lipid bilayer. Together, these findings demonstrate that membrane-interaction mechanisms of ABPs evolved to precisely fulfill their specific functions in cytoskeletal dynamics.

Details

Original languageEnglish
Pages (from-to)E8977-E8986
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number43
Publication statusPublished - 24 Oct 2017
MoE publication typeA1 Journal article-refereed

    Research areas

  • Actin cytoskeleton, Molecular dynamics simulations, Phosphoinositides, Protein-lipid interaction, Signal transduction

ID: 16230401