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| | <StructureSection load='2dx1' size='340' side='right'caption='[[2dx1]], [[Resolution|resolution]] 2.36Å' scene=''> | | <StructureSection load='2dx1' size='340' side='right'caption='[[2dx1]], [[Resolution|resolution]] 2.36Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2dx1]] 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=2DX1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2DX1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2dx1]] 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=2DX1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2DX1 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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]] 2.36Å</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=2dx1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2dx1 OCA], [http://pdbe.org/2dx1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2dx1 RCSB], [http://www.ebi.ac.uk/pdbsum/2dx1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2dx1 ProSAT], [http://www.topsan.org/Proteins/RSGI/2dx1 TOPSAN]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></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=2dx1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2dx1 OCA], [https://pdbe.org/2dx1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2dx1 RCSB], [https://www.ebi.ac.uk/pdbsum/2dx1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2dx1 ProSAT], [https://www.topsan.org/Proteins/RSGI/2dx1 TOPSAN]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ARHG4_HUMAN ARHG4_HUMAN]] Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.<ref>PMID:10947987</ref> <ref>PMID:12598901</ref> <ref>PMID:17145773</ref> <ref>PMID:17599059</ref> <ref>PMID:19893577</ref> | + | [https://www.uniprot.org/uniprot/ARHG4_HUMAN ARHG4_HUMAN] Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.<ref>PMID:10947987</ref> <ref>PMID:12598901</ref> <ref>PMID:17145773</ref> <ref>PMID:17599059</ref> <ref>PMID:19893577</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/dx/2dx1_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/dx/2dx1_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kato-Murayama, M]] | + | [[Category: Kato-Murayama M]] |
| - | [[Category: Murayama, K]] | + | [[Category: Murayama K]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Shirouzu M]] |
| - | [[Category: Shirouzu, M]] | + | [[Category: Terada T]] |
| - | [[Category: Terada, T]] | + | [[Category: Yokoyama S]] |
| - | [[Category: Yokoyama, S]] | + | |
| - | [[Category: National project on protein structural and functional analyse]]
| + | |
| - | [[Category: Nppsfa]]
| + | |
| - | [[Category: Rho-gef]]
| + | |
| - | [[Category: Rsgi]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Function
ARHG4_HUMAN Acts as guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases. Binding of APC may activate RAC1 GEF activity. The APC-ARHGEF4 complex seems to be involved in cell migration as well as in E-cadherin-mediated cell-cell adhesion. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Involved in tumor angiogenesis and may play a role in intestinal adenoma formation and tumor progression.[1] [2] [3] [4] [5]
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
The Rac-specific guanine nucleotide exchange factor (GEF) Asef is activated by binding to the tumor suppressor adenomatous polyposis coli mutant, which is found in sporadic and familial colorectal tumors. This activated Asef is involved in the migration of colorectal tumor cells. The GEFs for Rho family GTPases contain the Dbl homology (DH) domain and the pleckstrin homology (PH) domain. When Asef is in the resting state, the GEF activity of the DH-PH module is intramolecularly inhibited by an unidentified mechanism. Asef has a Src homology 3 (SH3) domain in addition to the DH-PH module. In the present study, the three-dimensional structure of Asef was solved in its autoinhibited state. The crystal structure revealed that the SH3 domain binds intramolecularly to the DH domain, thus blocking the Rac-binding site. Furthermore, the RT-loop and the C-terminal region of the SH3 domain interact with the DH domain in a manner completely different from those for the canonical binding to a polyproline-peptide motif. These results demonstrate that the blocking of the Rac-binding site by the SH3 domain is essential for Asef autoinhibition. This may be a common mechanism in other proteins that possess an SH3 domain adjacent to a DH-PH module.
Crystal structure of the rac activator, Asef, reveals its autoinhibitory mechanism.,Murayama K, Shirouzu M, Kawasaki Y, Kato-Murayama M, Hanawa-Suetsugu K, Sakamoto A, Katsura Y, Suenaga A, Toyama M, Terada T, Taiji M, Akiyama T, Yokoyama S J Biol Chem. 2007 Feb 16;282(7):4238-42. Epub 2006 Dec 26. PMID:17190834[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kawasaki Y, Senda T, Ishidate T, Koyama R, Morishita T, Iwayama Y, Higuchi O, Akiyama T. Asef, a link between the tumor suppressor APC and G-protein signaling. Science. 2000 Aug 18;289(5482):1194-7. PMID:10947987
- ↑ Kawasaki Y, Sato R, Akiyama T. Mutated APC and Asef are involved in the migration of colorectal tumour cells. Nat Cell Biol. 2003 Mar;5(3):211-5. PMID:12598901 doi:10.1038/ncb937
- ↑ Hamann MJ, Lubking CM, Luchini DN, Billadeau DD. Asef2 functions as a Cdc42 exchange factor and is stimulated by the release of an autoinhibitory module from a concealed C-terminal activation element. Mol Cell Biol. 2007 Feb;27(4):1380-93. Epub 2006 Dec 4. PMID:17145773 doi:10.1128/MCB.01608-06
- ↑ Kawasaki Y, Sagara M, Shibata Y, Shirouzu M, Yokoyama S, Akiyama T. Identification and characterization of Asef2, a guanine-nucleotide exchange factor specific for Rac1 and Cdc42. Oncogene. 2007 Dec 6;26(55):7620-267. Epub 2007 Jun 18. PMID:17599059 doi:10.1038/sj.onc.1210574
- ↑ Kawasaki Y, Tsuji S, Muroya K, Furukawa S, Shibata Y, Okuno M, Ohwada S, Akiyama T. The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in Apc(Min/+)mice. EMBO Rep. 2009 Dec;10(12):1355-62. doi: 10.1038/embor.2009.233. Epub 2009 Nov 6. PMID:19893577 doi:10.1038/embor.2009.233
- ↑ Murayama K, Shirouzu M, Kawasaki Y, Kato-Murayama M, Hanawa-Suetsugu K, Sakamoto A, Katsura Y, Suenaga A, Toyama M, Terada T, Taiji M, Akiyama T, Yokoyama S. Crystal structure of the rac activator, Asef, reveals its autoinhibitory mechanism. J Biol Chem. 2007 Feb 16;282(7):4238-42. Epub 2006 Dec 26. PMID:17190834 doi:10.1074/jbc.C600234200
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