Controlling cytoskeleton structure by phosphoinositide–protein interactions: phosphoinositide binding protein domains and effects of lipid packing

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Abstract

Cell movement and resistance to mechanical forces are largely governed by the cytoskeleton, a three-dimensional network of protein filaments that form viscoelastic networks within the cytoplasm. The cytoskeleton underlying the plasma membrane of most cells is rich in actin filaments whose assembly and disassembly are regulated by actin binding proteins that are stimulated or inhibited by signals received and transmitted at the membrane/cytoplasm interface. Inositol phospholipids, or phosphoinositides, are potent regulators of many actin binding proteins, and changes in the phosphorylation of specific phosphoinositide species or in their spatial localization are associated with cytoskeletal remodeling in vitro. This review will focus on recent studies directed at defining the structural features of phosphoinositide binding sites in actin binding proteins and on the influence of the physical state of phosphoinositides on their ability to interact with their target proteins.

Introduction

Inositol phospholipids, also called polyphosphoinositides or PPIs, are key elements in many aspects of signal transduction. These lipids, notably phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3), bind tightly to actin regulatory proteins such as profilin, gelsolin and cofilin to regulate actin assembly and to α-actinin, talin, vinculin and other proteins at focal adhesion sites where they are thought to activate these proteins to assemble actin at the contact site (Janmey, 1994, Isenberg and Niggli, 1998). A major issue in defining how inositol lipids regulate cytoskeletal function is to determine where these lipids reside in the resting cell, where they are most actively recruited when changes to the cytoskeleton are signaled, and whether they function only in mixed bilayer membranes or also in non-bilayer assemblies or protein complexes. This review will focus on recent works that have identified phosphoinositide binding peptide sequences and the role of lipid packing on protein-phosphoinositide binding to lead to a general hypothesis whereby local accumulation of inositol lipids promotes actin polymerization and cytoskeleton-membrane linkage.

Section snippets

Cellular actin assembly and phosphoinositides

The movement of cells is largely controlled by the formation and disassembly of actin filament networks at the boundary between the cytoskeleton and the cell membrane (Condeelis, 1993). The assembly of monomeric actin into linear filaments, the linkage of these filaments to each other and to the cell membrane, as well as the fragmentation of filaments when the networks disassemble are controlled by a large array of actin binding proteins that are activated or inactivated in response to cellular

Actin binding proteins and PPIs

Inositol lipids do not appear to affect actin directly, but instead interact with a variety of actin binding protein to simulate or inhibit their effects on actin assembly. They can also promote activation of small GTPases that indirectly lead to actin assembly (Ma et al., 1998, Flanagan and Janmey, 1999). At least 30 actin binding proteins, summarized in Table 1, have been reported to bind PIP2 or other inositol lipids, and the details of these interactions are summarized in recent reviews (

Structural aspects of PIP2

Compared to studies of protein and peptide structures, the conformation of PIP2 complexed to its cytoskeletal target proteins is less well defined. Figure 2a illustrates a possible PIP2 monomer structure, drawn on the same scale as its gelsolin-derived peptide ligand (Fig. 2b), in which the glycerol backbone and acyl chain conformations are borrowed from phosphatidylcholine (PC) structures derived from molecular dynamics calculations (Heller et al., 1993). Figure 2c shows a hypothetical model

Conclusions and future directions

The wealth of data relating cytoskeletal protein function to phosphoinositide binding and the effects of some of these proteins on PPI turnover suggest an intimate link between cellular PPI signaling and cytoskeletal remodeling. The general picture emerging from both in vitro studies of individual actin binding proteins and PIP2 as well as the effects of manipulating PIP2 levels in vivo is that increasing PIP2 leads to actin assembly, and decreased PIP2 levels permit or stimulate actin

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