Control of Actin Assembly by Polyphosphoinositides
Polyphosphoinositides (PPIs) such as phosphatidylinositol (4,5) bisphosphate (PIP2), are phospholipids that control many cellular events and bind to dozens of intracellular proteins, including many regulators of the actin-based cytoskeleton. How phosphoinositides affect their ligands is much less understood than are the mutations that produce abnormal PPI production, but defining how these lipids exert their biological control at the membrane-cytoskeletal interface could lead to new approaches to limiting or reversing the abnormal function of these lipids in disease. The large number of proteins characterized as ligands for PPIs, usually PI(4,5)P2, suggests that specificity within the cell might be attained by changing the physical state of the lipid within the membrane, in addition to its local or global concentration. Recent experiments show that cholesterol-induced redistribution of PIP2 in the lipid bilayer strongly alters its ability to inhibit the actin severing protein gelsolin at constant total PIP2 concentrations and that nucleation of actin polymerization in brain extracts occurs preferentially from liquid disordered membrane domains and from 80 nm PIP2 clusters that form in the presence of µM Ca2+. These results suggest that PPI lateral distribution within cell membranes is structured by cholesterol and divalent or multivalent counterions and affects PPI interactions with the myriad of proteins they appear to regulate in vivo. Therefore reagents that bind PIP2 and alter its distribution the cell can have important effects on cell function and potentially practical applications.