Structural insights into phosphoinositide 3-kinase catalysis and signalling

• Published in: Nature (London) 1999-11, Vol.402 (6759), p.313-320
• Main Authors: Williams, Roger L, Walker, Edward H, Perisic, Olga, Ried, Christian, Stephens, Len
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Catalysis; Catalytic Domain; Cell Membrane - metabolism; Crystallography, X-Ray; Enzymes; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; Humans; letter; Models, Molecular; Molecular biology; Molecular Sequence Data; multidisciplinary; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Protein Binding; Protein Conformation; Protein Structure, Tertiary; rap1 GTP-Binding Proteins - metabolism; ras Proteins - metabolism; Recombinant Proteins; Science; Sequence Homology, Amino Acid; Signal Transduction; Spine; Swine; Transducers; Transferases
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/46319

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 trafficking. Here we report the 2.2  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.