Structural insights into phosphoinositide 3-kinase catalysis and signalling

Edward H. Walker, Olga Perisic, Christian Ried, Len Stephens and Roger L. Williams ()
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Edward H. Walker: MRC Laboratory of Molecular Biology, MRC Centre
Olga Perisic: MRC Laboratory of Molecular Biology, MRC Centre
Christian Ried: MRC Laboratory of Molecular Biology, MRC Centre
Len Stephens: The Babraham Institute
Roger L. Williams: MRC Laboratory of Molecular Biology, MRC Centre

Nature, 1999, vol. 402, issue 6759, 313-320

Abstract: Abstract Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PI3Ks are dual-specificity enzymes with a lipid kinase activity which phosphorylates phosphoinositides at the 3-hydroxyl, and a protein kinase activity. The products of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P, are second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking1,2. Here we report the 2.2 Å X-ray crystallographic structure of the catalytic subunit of PI3Kγ, the class I enzyme that is activated by heterotrimeric G-protein βγ subunits and Ras. PI3Kγ has a modular organization centred around a helical-domain spine, with C2 and catalytic domains positioned to interact with phospholipid membranes, and a Ras-binding domain placed against the catalytic domain where it could drive allosteric activation of the enzyme.

Date: 1999
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DOI: 10.1038/46319

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