7bi6
PI3KC2a core in complex with ATP
Structural highlights
FunctionP3C2A_MOUSE Generates phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) that act as second messengers. Has a role in several intracellular trafficking events. Functions in insulin signaling and secretion. Required for translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane and glucose uptake in response to insulin-mediated RHOQ activation. Regulates insulin secretion through two different mechanisms: involved in glucose-induced insulin secretion downstream of insulin receptor in a pathway that involves AKT1 activation and TBC1D4/AS160 phosphorylation, and participates in the late step of insulin granule exocytosis probably in insulin granule fusion. Synthesizes PtdIns3P in response to insulin signaling. Functions in clathrin-coated endocytic vesicle formation and distribution. Regulates dynamin-independent endocytosis, probably by recruiting EEA1 to internalizing vesicles. In neurosecretory cells synthesizes PtdIns3P on large dense core vesicles. Participates in calcium induced contraction of vascular smooth muscle by regulating myosin light chain (MLC) phosphorylation through a mechanism involving Rho kinase-dependent phosphorylation of the MLCP-regulatory subunit MYPT1. May play a role in the EGF signaling cascade. May be involved in mitosis and UV-induced damage response. Required for maintenance of normal renal structure and function by supporting normal podocyte function.[1] [2] [3] Publication Abstract from PubMedPhosphatidylinositol 3-kinase type 2alpha (PI3KC2alpha) is an essential member of the structurally unresolved class II PI3K family with crucial functions in lipid signaling, endocytosis, angiogenesis, viral replication, platelet formation and a role in mitosis. The molecular basis of these activities of PI3KC2alpha is poorly understood. Here, we report high-resolution crystal structures as well as a 4.4-A cryogenic-electron microscopic (cryo-EM) structure of PI3KC2alpha in active and inactive conformations. We unravel a coincident mechanism of lipid-induced activation of PI3KC2alpha at membranes that involves large-scale repositioning of its Ras-binding and lipid-binding distal Phox-homology and C-C2 domains, and can serve as a model for the entire class II PI3K family. Moreover, we describe a PI3KC2alpha-specific helical bundle domain that underlies its scaffolding function at the mitotic spindle. Our results advance our understanding of PI3K biology and pave the way for the development of specific inhibitors of class II PI3K function with wide applications in biomedicine. Structural basis of phosphatidylinositol 3-kinase C2alpha function.,Lo WT, Zhang Y, Vadas O, Roske Y, Gulluni F, De Santis MC, Zagar AV, Stephanowitz H, Hirsch E, Liu F, Daumke O, Kudryashev M, Haucke V Nat Struct Mol Biol. 2022 Mar;29(3):218-228. doi: 10.1038/s41594-022-00730-w., Epub 2022 Mar 7. PMID:35256802[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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