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Structural insights into phosphoinositide 3-kinase catalysis and signalling

Author

Listed:
  • 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)

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.

Suggested Citation

  • Edward H. Walker & Olga Perisic & Christian Ried & Len Stephens & Roger L. Williams, 1999. "Structural insights into phosphoinositide 3-kinase catalysis and signalling," Nature, Nature, vol. 402(6759), pages 313-320, November.
    • Handle: RePEc:nat:nature:v:402:y:1999:i:6759:d:10.1038_46319
    DOI: 10.1038/46319
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    Cited by:

    1. Jonathan M Goldberg & Gerard Manning & Allen Liu & Petra Fey & Karen E Pilcher & Yanji Xu & Janet L Smith, 2006. "The Dictyostelium Kinome—Analysis of the Protein Kinases from a Simple Model Organism," PLOS Genetics, Public Library of Science, vol. 2(3), pages 1-13, March.
    2. Meredith L. Jenkins & Harish Ranga-Prasad & Matthew A. H. Parson & Noah J. Harris & Manoj K. Rathinaswamy & John E. Burke, 2023. "Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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