Structural insights into phosphoinositide 3-kinase catalysis and signalling

Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that functi on both as signal transducers downstream of cell-surface receptors and in c onstitutive intracellular membrane and protein trafficking pathways. All PI 3Ks are dual-specificity enzymes with a lipid kinase activity which phospho rylates phosphoinositides at the 3-hydroxyl, and a protein kinase activity. The products of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisp hosphate (PtdIns(3,4,5)P-3), PtdIns(3,4)P-2 and PtdIns(3)P, are second mess engers in a variety of signal transduction pathways, including those essent ial to cell proliferation, adhesion, survival, cytoskeletal rearrangement a nd vesicle trafficking(1.2). Here we report the 2.2 Angstrom X-ray crystall ographic structure of the catalytic subunit of PI3K gamma, the class I enzy me that is activated by heterotrimeric G-protein beta gamma subunits and pa s. PI3K gamma has a modular organization centred around a helical-domain sp ine, with C2 and catalytic domains positioned to interact with phospholipid membranes,:md a Ras-binding domain placed against the catalytic domain whe re if could drive allosteric activation of the enzyme.