|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of the PI3KC2alpha PX domain in space group P432== | | ==Crystal structure of the PI3KC2alpha PX domain in space group P432== |
| - | <StructureSection load='6bub' size='340' side='right' caption='[[6bub]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='6bub' size='340' side='right'caption='[[6bub]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6bub]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BUB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BUB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6bub]] 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=6BUB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BUB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]] 2.604Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6bu0|6bu0]], [[6bty|6bty]], [[6btz|6btz]], [[2iwl|2iwl]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIK3C2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6bub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bub OCA], [https://pdbe.org/6bub PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bub RCSB], [https://www.ebi.ac.uk/pdbsum/6bub PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bub ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4-phosphate_3-kinase Phosphatidylinositol-4-phosphate 3-kinase], with EC number [http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6bub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bub OCA], [http://pdbe.org/6bub PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bub RCSB], [http://www.ebi.ac.uk/pdbsum/6bub PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bub ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 6bub" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6bub" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Phosphatidylinositol-4-phosphate 3-kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Chen, K E]] | + | [[Category: Chen K-E]] |
| - | [[Category: Collins, B M]] | + | [[Category: Collins BM]] |
| - | [[Category: Lipid binding]]
| + | |
| - | [[Category: Phosphoinositide]]
| + | |
| - | [[Category: Pi3-kinase]]
| + | |
| - | [[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]
Publication Abstract from PubMed
Phosphorylation of phosphoinositides by the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2alpha is essential for many processes, including neuroexocytosis and formation of clathrin-coated vesicles. A defining feature of the class II PI3Ks is a C-terminal module composed of phox-homology (PX) and C2 membrane interacting domains; however, the mechanisms that control their specific cellular localization remain poorly understood. Here we report the crystal structure of the C2 domain of PI3K-C2alpha in complex with the phosphoinositide head-group mimic inositol hexaphosphate, revealing two distinct pockets for membrane binding. The C2 domain preferentially binds to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate, and low-resolution structures of the combined PX-C2 module by small-angle X-ray scattering reveal a compact conformation in which cooperative lipid binding by each domain binding can occur. Finally, we demonstrate an unexpected role for calcium in perturbing the membrane interactions of the PX-C2 module, which we speculate may be important for regulating the activity of PI3K-C2alpha.
Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2alpha.,Chen KE, Tillu VA, Chandra M, Collins BM Structure. 2018 Sep 19. pii: S0969-2126(18)30298-3. doi:, 10.1016/j.str.2018.08.010. PMID:30293811[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
- ↑ Chen KE, Tillu VA, Chandra M, Collins BM. Molecular Basis for Membrane Recruitment by the PX and C2 Domains of Class II Phosphoinositide 3-Kinase-C2alpha. Structure. 2018 Sep 19. pii: S0969-2126(18)30298-3. doi:, 10.1016/j.str.2018.08.010. PMID:30293811 doi:http://dx.doi.org/10.1016/j.str.2018.08.010
|
