8soc
Phosphoinositide phosphate 3 kinase gamma bound with ADP and Gbetagamma
Structural highlights
FunctionPK3CG_PIG Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Required for B-lymphocyte development and signaling. Together with other PI3Ks are involved in the oxidative burst produced by neutrophils in response to chemotactic agents. Together with PIK3CD regulate neutrophil extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contribute to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis (By similarity). Publication Abstract from PubMedThe conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate by phosphoinositide 3-kinase gamma (PI3Kgamma) is critical for neutrophil chemotaxis and cancer metastasis. PI3Kgamma is activated by Gbetagamma heterodimers released from G protein-coupled receptors responding to extracellular signals. Here we determined cryo-electron microscopy structures of Sus scrofa PI3Kgamma-human Gbetagamma complexes in the presence of substrates/analogs, revealing two Gbetagamma binding sites: one on the p110gamma helical domain and another on the p101 C-terminal domain. Comparison with PI3Kgamma alone reveals conformational changes in the kinase domain upon Gbetagamma binding that are similar to Ras.GTP-induced changes. Assays of variants perturbing the Gbetagamma binding sites and interdomain contacts altered by Gbetagamma binding suggest that Gbetagamma recruits the enzyme to membranes and allosterically regulates activity via both sites. Studies of zebrafish neutrophil migration align with these findings, paving the way for in-depth investigation of Gbetagamma-mediated activation mechanisms in this enzyme family and drug development for PI3Kgamma. Molecular basis for Gbetagamma-mediated activation of phosphoinositide 3-kinase gamma.,Chen CL, Syahirah R, Ravala SK, Yen YC, Klose T, Deng Q, Tesmer JJG Nat Struct Mol Biol. 2024 Aug;31(8):1198-1207. doi: 10.1038/s41594-024-01265-y. , Epub 2024 Apr 2. PMID:38565696[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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