Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides

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Senju , Y , Kalimeri , M , Koskela , E V , Somerharju , P , Zhao , H , Vattulainen , I & Lappalainen , P 2017 , ' Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides ' , Proceedings of the National Academy of Sciences of the United States of America , vol. 114 , no. 43 , pp. E8977-E8986 . https://doi.org/10.1073/pnas.1705032114

Title: Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides
Author: Senju, Yosuke; Kalimeri, Maria; Koskela, Essi V.; Somerharju, Pentti; Zhao, Hongxia; Vattulainen, Ilpo; Lappalainen, Pekka
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Faculty of Medicine
University of Helsinki, Institute of Biotechnology
University of Helsinki, Department of Physics
University of Helsinki, Institute of Biotechnology
Date: 2017-10-24
Language: eng
Number of pages: 10
Belongs to series: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
URI: http://hdl.handle.net/10138/228444
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)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.
Subject: actin cytoskeleton
phosphoinositides
protein-lipid interactions
signal transduction
molecular dynamics simulations
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE
N-WASP
MOLECULAR-DYNAMICS
STRUCTURAL BASIS
CAPPING PROTEIN
CELL MOTILITY
MEDIATED ENDOCYTOSIS
ARP2/3 COMPLEX
LIPID-BINDING
FORCE-FIELD
1182 Biochemistry, cell and molecular biology
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