Counterion-mediated cluster formation by polyphosphoinositides

Abstract

Polyphosphoinositides (PPI) and in particular PI(4,5)P2, are among the most highly charged molecules in cell membranes, are important in many cellular signaling pathways, and are frequently targeted by peripheral polybasic proteins for anchoring through electrostatic interactions. Such interactions between PIP2 and proteins containing polybasic stretches depend on the physical state and the lateral distribution of PIP2 within the inner leaflet of the cell's lipid bilayer. The physical and chemical properties of PIP2 such as pH-dependent changes in headgroup ionization and area per molecule as determined by experiments together with molecular simulations that predict headgroup conformations at various ionization states have revealed the electrostatic properties and phase behavior of PIP2-containing membranes. This review focuses on recent experimental and computational developments in defining the physical chemistry of PIP2 and its interactions with counterions. Ca(2+)-induced changes in PIP2 charge, conformation, and lateral structure within the membrane are documented by numerous experimental and computational studies. A simplified electrostatic model successfully predicts the Ca(2+)-driven formation of PIP2 clusters but cannot account for the different effects of Ca(2+) and Mg(2+) on PIP2-containing membranes. A more recent computational study is able to see the difference between Ca(2+) and Mg(2+) binding to PIP2 in the absence of a membrane and without cluster formation. Spectroscopic studies suggest that divalent cation- and multivalent polyamine-induced changes in the PIP2 lateral distribution in model membrane are also different, and not simply related to the net charge of the counterion. Among these differences is the capacity of Ca(2+) but not other polycations to induce nm scale clusters of PIP2 in fluid membranes. Recent super resolution optical studies show that PIP2 forms nanoclusters in the inner leaflet of a plasma membrane with a similar size distribution as those induced by Ca(2+) in model membranes. The mechanisms by which PIP2 forms nanoclusters and other structures inside a cell remain to be determined, but the unique electrostatic properties of PIP2 and its interactions with multivalent counterions might have particular physiological relevance.

Keywords: Ca(2+); Diffusivity; Electrostatic interactions; MD simulation; PIP(2); PIP(2) clustering.