| Structural highlights
Function
[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.
Publication Abstract from PubMed
Phox homology (PX) domains, which have been identified in a variety of proteins involved in cell signaling and membrane trafficking, have been shown to interact with phosphoinositides (PIs) with different affinities and specificities. To elucidate the structural origin of diverse PI specificities of PX domains, we determined the crystal structure of the PX domain from phosphoinositide 3-kinase C2alpha (PI3K-C2alpha), which binds phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). To delineate the mechanism by which this PX domain interacts with membranes, we measured the membrane binding of the wild type domain and mutants by surface plasmon resonance and monolayer techniques. This PX domain contains a signature PI-binding site that is optimized for PtdIns(4,5)P(2) binding. The membrane binding of the PX domain is initiated by nonspecific electrostatic interactions followed by the membrane penetration of hydrophobic residues. Membrane penetration is specifically enhanced by PtdIns(4,5)P(2). Furthermore, the PX domain displayed significantly higher PtdIns(4,5)P(2) membrane affinity and specificity when compared with the PI3K-C2alpha C2 domain, demonstrating that high affinity PtdIns(4,5)P(2) binding was facilitated by the PX domain in full-length PI3K-C2alpha. Together, these studies provide new structural insight into the diverse PI specificities of PX domains and elucidate the mechanism by which the PI3K-C2alpha PX domain interacts with PtdIns(4,5)P(2)-containing membranes and thereby mediates the membrane recruitment of PI3K-C2alpha.
Structural and membrane binding analysis of the Phox homology domain of phosphoinositide 3-kinase-C2alpha.,Stahelin RV, Karathanassis D, Bruzik KS, Waterfield MD, Bravo J, Williams RL, Cho W J Biol Chem. 2006 Dec 22;281(51):39396-406. Epub 2006 Oct 12. PMID:17038310[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Stahelin RV, Karathanassis D, Bruzik KS, Waterfield MD, Bravo J, Williams RL, Cho W. Structural and membrane binding analysis of the Phox homology domain of phosphoinositide 3-kinase-C2alpha. J Biol Chem. 2006 Dec 22;281(51):39396-406. Epub 2006 Oct 12. PMID:17038310 doi:10.1074/jbc.M607079200
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