Structural insights into phosphoinositide 3-kinase catalysis and signalling

Nature. 1999 Nov 18;402(6759):313-20. doi: 10.1038/46319.

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 trafficking. Here we report the 2.2 A X-ray crystallographic structure of the catalytic subunit of PI3Kgamma, the class I enzyme that is activated by heterotrimeric G-protein betagamma subunits and Ras. PI3Kgamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Catalysis
  • Catalytic Domain
  • Cell Membrane / metabolism
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases / chemistry*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Proteins
  • Sequence Homology, Amino Acid
  • Signal Transduction*
  • Swine
  • rap1 GTP-Binding Proteins / metabolism
  • ras Proteins / metabolism

Substances

  • Recombinant Proteins
  • Phosphatidylinositol 3-Kinases
  • rap1 GTP-Binding Proteins
  • ras Proteins

Associated data

  • PDB/1QMM