Enhancement of phosphoinositide 3-kinase (PI 3-kinase) activity by membrane curvature and inositol-phospholipid-binding peptides

The phosphorylation of phosphatidylinositol (PtdIns) on the 3' position of the inositol ring by phosphoinositide 3-kinase (PI 3-kinase) is shown to de pend strongly on the curvature of liposomes containing a mixture of phospha tidylcholine (PtdCho) and PtdIns. Vesicles with an average diameter of 50 n m are phosphorylated 100 times faster than chemically identical vesicles wi th an average diameter greater than 300 nm. The low reactivity of large ves icles is not due to the difference in vesicle number for large and small ve sicles at constant total lipid, nor to occlusion of lipid surfaces in multi lammelar structures, and can be reversed by addition of low (<1:100) molar ratios of either the PtdIns transfer protein sec14p or a ten-residue peptid e derived from the inositol-phospholipid-binding site of gelsolin. Similar measurements using PI 4-kinase showed a weak dependence on vesicle size. Th e strong dependence of PI 3-kinase function on membrane curvature suggests possible localization of PI 3-kinase activity at sites where clustering of receptors, for example, may locally deform the membrane, and suggests that once PI 3-kinase is localized and activated at surface sites, the reaction may become self-accelerating.