Crystal structure of the mammalian C2alpha-PI3 Kinase PX-domainCrystal structure of the mammalian C2alpha-PI3 Kinase PX-domain
Structural highlights
2ar5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
P3C2A_HUMAN 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][4][5][6][7]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
↑Domin J, Pages F, Volinia S, Rittenhouse SE, Zvelebil MJ, Stein RC, Waterfield MD. Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem J. 1997 Aug 15;326 ( Pt 1):139-47. PMID:9337861
↑Domin J, Gaidarov I, Smith ME, Keen JH, Waterfield MD. The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans-Golgi network and present in clathrin-coated vesicles. J Biol Chem. 2000 Apr 21;275(16):11943-50. PMID:10766823
↑Arcaro A, Zvelebil MJ, Wallasch C, Ullrich A, Waterfield MD, Domin J. Class II phosphoinositide 3-kinases are downstream targets of activated polypeptide growth factor receptors. Mol Cell Biol. 2000 Jun;20(11):3817-30. PMID:10805725
↑Gaidarov I, Smith ME, Domin J, Keen JH. The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking. Mol Cell. 2001 Feb;7(2):443-9. PMID:11239472
↑Didichenko SA, Fragoso CM, Thelen M. Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. J Biol Chem. 2003 Jul 11;278(28):26055-64. Epub 2003 Apr 28. PMID:12719431 doi:http://dx.doi.org/10.1074/jbc.M301657200
↑Gaidarov I, Zhao Y, Keen JH. Individual phosphoinositide 3-kinase C2alpha domain activities independently regulate clathrin function. J Biol Chem. 2005 Dec 9;280(49):40766-72. Epub 2005 Oct 7. PMID:16215232 doi:http://dx.doi.org/10.1074/jbc.M507731200
↑Krag C, Malmberg EK, Salcini AE. PI3KC2alpha, a class II PI3K, is required for dynamin-independent internalization pathways. J Cell Sci. 2010 Dec 15;123(Pt 24):4240-50. doi: 10.1242/jcs.071712. Epub 2010, Nov 16. PMID:21081650 doi:http://dx.doi.org/10.1242/jcs.071712
