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| | <StructureSection load='2rea' size='340' side='right'caption='[[2rea]], [[Resolution|resolution]] 2.50Å' scene=''> | | <StructureSection load='2rea' size='340' side='right'caption='[[2rea]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2rea]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2REA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2REA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2rea]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2REA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2REA FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2ar5|2ar5]], [[2red|2red]]</div></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIK3C2A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Phosphatidylinositol-4-phosphate_3-kinase Phosphatidylinositol-4-phosphate 3-kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.154 2.7.1.154] </span></td></tr>
| + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2rea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rea OCA], [https://pdbe.org/2rea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2rea RCSB], [https://www.ebi.ac.uk/pdbsum/2rea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2rea ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2rea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rea OCA], [https://pdbe.org/2rea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2rea RCSB], [https://www.ebi.ac.uk/pdbsum/2rea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2rea ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/P3C2A_HUMAN 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.<ref>PMID:9337861</ref> <ref>PMID:10766823</ref> <ref>PMID:10805725</ref> <ref>PMID:11239472</ref> <ref>PMID:12719431</ref> <ref>PMID:16215232</ref> <ref>PMID:21081650</ref>
| + | [https://www.uniprot.org/uniprot/P3C2A_HUMAN 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.<ref>PMID:9337861</ref> <ref>PMID:10766823</ref> <ref>PMID:10805725</ref> <ref>PMID:11239472</ref> <ref>PMID:12719431</ref> <ref>PMID:16215232</ref> <ref>PMID:21081650</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Phosphatidylinositol-4-phosphate 3-kinase]]
| + | [[Category: Djordjevic S]] |
| - | [[Category: Djordjevic, S]] | + | [[Category: Driscoll PC]] |
| - | [[Category: Driscoll, P C]] | + | [[Category: Parkinson GN]] |
| - | [[Category: Parkinson, G N]] | + | [[Category: Vines D]] |
| - | [[Category: Vines, D]] | + | |
| - | [[Category: Cytoplasm]]
| + | |
| - | [[Category: Cytoplasmic vesicle]]
| + | |
| - | [[Category: Golgi apparatus]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Nuclear protein]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Phosphoinositide]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Pi3k]]
| + | |
| - | [[Category: Polymorphism]]
| + | |
| - | [[Category: Px domain]]
| + | |
| - | [[Category: Transferase]]
| + | |
| 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
BACKGROUND: PX domains have specialized protein structures involved in binding of phosphoinositides (PIs). Through binding to the various PIs PX domains provide site-specific membrane signals to modulate the intracellular localisation and biological activity of effector proteins. Several crystal structures of these domains are now available from a variety of proteins. All PX domains contain a canonical core structure with main differences exhibited within the loop regions forming the phosphoinositide binding pockets. It is within these areas that the molecular basis for ligand specificity originates. RESULTS: We now report two new structures of PI3K-C2alpha PX domain that crystallised in a P3121 space group. The two structures, refined to 2.1 A and 2.5 A, exhibit significantly different conformations of the phosphoinositide-binding loops. Unexpectedly, in one of the structures, we have detected a putative-ligand trapped in the binding site during the process of protein purification and crystallisation. CONCLUSION: The two structures reported here provide a more complete description of the phosphoinositide binding region compared to the previously reported 2.6 A crystal structure of human PI3K-C2alpha PX where this region was highly disordered. The structures enabled us to further analyse PI specificity and to postulate that the observed conformational change could be related to ligand-binding.
Crystal structures of PI3K-C2alpha PX domain indicate conformational change associated with ligand binding.,Parkinson GN, Vines D, Driscoll PC, Djordjevic S BMC Struct Biol. 2008 Feb 29;8:13. PMID:18312637[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
- ↑ Parkinson GN, Vines D, Driscoll PC, Djordjevic S. Crystal structures of PI3K-C2alpha PX domain indicate conformational change associated with ligand binding. BMC Struct Biol. 2008 Feb 29;8:13. PMID:18312637 doi:http://dx.doi.org/10.1186/1472-6807-8-13
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