8aj8 | pdb_00008aj8
Structure of p110 gamma bound to the p84 regulatory subunit
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 PubMedClass IB phosphoinositide 3-kinase (PI3Kgamma) is activated in immune cells and can form two distinct complexes (p110gamma-p84 and p110gamma-p101), which are differentially activated by G protein-coupled receptors (GPCRs) and Ras. Using a combination of X-ray crystallography, hydrogen deuterium exchange mass spectrometry (HDX-MS), electron microscopy, molecular modeling, single-molecule imaging, and activity assays, we identify molecular differences between p110gamma-p84 and p110gamma-p101 that explain their differential membrane recruitment and activation by Ras and GPCRs. The p110gamma-p84 complex is dynamic compared with p110gamma-p101. While p110gamma-p101 is robustly recruited by Gbetagamma subunits, p110gamma-p84 is weakly recruited to membranes by Gbetagamma subunits alone and requires recruitment by Ras to allow for Gbetagamma activation. We mapped two distinct Gbetagamma interfaces on p101 and the p110gamma helical domain, with differences in the C-terminal domain of p84 and p101 conferring sensitivity of p110gamma-p101 to Gbetagamma activation. Overall, our work provides key insight into the molecular basis for how PI3Kgamma complexes are activated. Molecular basis for differential activation of p101 and p84 complexes of PI3Kgamma by Ras and GPCRs.,Rathinaswamy MK, Jenkins ML, Duewell BR, Zhang X, Harris NJ, Evans JT, Stariha JTB, Dalwadi U, Fleming KD, Ranga-Prasad H, Yip CK, Williams RL, Hansen SD, Burke JE Cell Rep. 2023 Feb 25;42(3):112172. doi: 10.1016/j.celrep.2023.112172. PMID:36842083[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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