Structural insights into phosphoinositide 3-kinase catalysis and signalling

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 phospho...

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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
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description 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.
doi_str_mv 10.1038/46319
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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
title Structural insights into phosphoinositide 3-kinase catalysis and signalling
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