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Structure of the phosphoinositide 3-kinase p110 gamma (PIK3CG) p101 (PIK3R5) complex
Structural highlights
FunctionPK3CG_HUMAN 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. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and 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. Contributes 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.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe class IB phosphoinositide 3-kinase (PI3K), PI3Kgamma, is a master regulator of immune cell function and a promising drug target for both cancer and inflammatory diseases. Critical to PI3Kgamma function is the association of the p110gamma catalytic subunit to either a p101 or p84 regulatory subunit, which mediates activation by G protein-coupled receptors. Here, we report the cryo-electron microscopy structure of a heterodimeric PI3Kgamma complex, p110gamma-p101. This structure reveals a unique assembly of catalytic and regulatory subunits that is distinct from other class I PI3K complexes. p101 mediates activation through its Gbetagamma-binding domain, recruiting the heterodimer to the membrane and allowing for engagement of a secondary Gbetagamma-binding site in p110gamma. Mutations at the p110gamma-p101 and p110gamma-adaptor binding domain interfaces enhanced Gbetagamma activation. A nanobody that specifically binds to the p101-Gbetagamma interface blocks activation, providing a novel tool to study and target p110gamma-p101-specific signaling events in vivo. Structure of the phosphoinositide 3-kinase (PI3K) p110gamma-p101 complex reveals molecular mechanism of GPCR activation.,Rathinaswamy MK, Dalwadi U, Fleming KD, Adams C, Stariha JTB, Pardon E, Baek M, Vadas O, DiMaio F, Steyaert J, Hansen SD, Yip CK, Burke JE Sci Adv. 2021 Aug 27;7(35):eabj4282. doi: 10.1126/sciadv.abj4282. Print 2021 Aug. PMID:34452907[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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