Counterion-mediated cluster formation by polyphosphoinositides

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 PIP ₂ and its interactions with counterions. Ca²⁺-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 Ca²⁺ and Mg²⁺ on PIP ₂-containing membranes. A more recent computational study is able to see the difference between Ca²⁺ and Mg²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.