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1x86

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Revision as of 13:19, 6 January 2015

Crystal Structure of the DH/PH domains of Leukemia-associated RhoGEF in complex with RhoA

Structural highlights

1x86 is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1txd
Gene:	ARHGEF12, LARG, KIAA0382 (Homo sapiens), RHOA, ARHA, ARH12, RHO12 (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[ARHGC_HUMAN] Note=A chromosomal aberration involving ARHGEF12 may be a cause of acute leukemia. Translocation t(11;11)(q23;23) with MLL.

Function

[ARHGC_HUMAN] May play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Acts as guanine nucleotide exchange factor (GEF) for RhoA GTPase and may act as GTPase-activating protein (GAP) for GNA12 and GNA13.^[1] [RHOA_HUMAN] Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague, and Yersinia pseudotuberculosis, which causes gastrointestinal disorders. Stimulates PKN2 kinase activity. May be an activator of PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP for GTP. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9]

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

Rho guanine-nucleotide exchange factors (RhoGEFs) activate Rho GTPases, and thereby regulate cytoskeletal structure, gene transcription, and cell migration. Leukemia-associated RhoGEF (LARG) belongs to a small subfamily of RhoGEFs that are RhoA-selective and directly activated by the Galpha12/13 family of heterotrimeric G proteins. Herein we describe the atomic structures of the catalytic Dbl homology (DH) and pleckstrin homology (PH) domains of LARG alone and in complex with RhoA. These structures demonstrate that the DH/PH domains of LARG can undergo a dramatic conformational change upon binding RhoA, wherein both the DH and PH domains directly engage RhoA. Through mutational analysis we show that full nucleotide exchange activity requires a novel N-terminal extension on the DH domain that is predicted to exist in a broader family of RhoGEFs that includes p115-RhoGEF, Lbc, Lfc, Net1, and Xpln, and identify regions within the LARG PH domain that contribute to its ability to facilitate nucleotide exchange in vitro. In crystals of the DH/PH-RhoA complex, the active site of RhoA adopts two distinct GDP-excluding conformations among the four unique complexes in the asymmetric unit. Similar changes were previously observed in structures of nucleotide-free Ras and Ef-Tu. A potential protein-docking site on the LARG PH domain is also evident and appears to be conserved throughout the Lbc subfamily of RhoGEFs.

Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor.,Kristelly R, Gao G, Tesmer JJ J Biol Chem. 2004 Nov 5;279(45):47352-62. Epub 2004 Aug 25. PMID:15331592^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Fukuhara S, Chikumi H, Gutkind JS. Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G(12) family to Rho. FEBS Lett. 2000 Nov 24;485(2-3):183-8. PMID:11094164
↑ Quilliam LA, Lambert QT, Mickelson-Young LA, Westwick JK, Sparks AB, Kay BK, Jenkins NA, Gilbert DJ, Copeland NG, Der CJ. Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein and potential effector of Rho protein signaling. J Biol Chem. 1996 Nov 15;271(46):28772-6. PMID:8910519
↑ Vincent S, Settleman J. The PRK2 kinase is a potential effector target of both Rho and Rac GTPases and regulates actin cytoskeletal organization. Mol Cell Biol. 1997 Apr;17(4):2247-56. PMID:9121475
↑ Wing MR, Snyder JT, Sondek J, Harden TK. Direct activation of phospholipase C-epsilon by Rho. J Biol Chem. 2003 Oct 17;278(42):41253-8. Epub 2003 Aug 4. PMID:12900402 doi:http://dx.doi.org/10.1074/jbc.M306904200
↑ Yuce O, Piekny A, Glotzer M. An ECT2-centralspindlin complex regulates the localization and function of RhoA. J Cell Biol. 2005 Aug 15;170(4):571-82. PMID:16103226 doi:10.1083/jcb.200501097
↑ Kamijo K, Ohara N, Abe M, Uchimura T, Hosoya H, Lee JS, Miki T. Dissecting the role of Rho-mediated signaling in contractile ring formation. Mol Biol Cell. 2006 Jan;17(1):43-55. Epub 2005 Oct 19. PMID:16236794 doi:10.1091/mbc.E05-06-0569
↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
↑ Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107
↑ Wallace SW, Magalhaes A, Hall A. The Rho target PRK2 regulates apical junction formation in human bronchial epithelial cells. Mol Cell Biol. 2011 Jan;31(1):81-91. doi: 10.1128/MCB.01001-10. Epub 2010 Oct 25. PMID:20974804 doi:10.1128/MCB.01001-10
↑ Kristelly R, Gao G, Tesmer JJ. Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor. J Biol Chem. 2004 Nov 5;279(45):47352-62. Epub 2004 Aug 25. PMID:15331592 doi:http://dx.doi.org/10.1074/jbc.M406056200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1x86"

Categories: Homo sapiens | Gao, G | Kristelly, R | Tesmer, J J | Signaling protein-membrane protein complex

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1x86]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X86 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1X86 FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1txd|1txd]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1txd|1txd]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARHGEF12, LARG, KIAA0382 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), RHOA, ARHA, ARH12, RHO12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ARHGEF12, LARG, KIAA0382 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), RHOA, ARHA, ARH12, RHO12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1x86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x86 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1x86 RCSB], [http://www.ebi.ac.uk/pdbsum/1x86 PDBsum]</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=1x86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1x86 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1x86 RCSB], [http://www.ebi.ac.uk/pdbsum/1x86 PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://www.uniprot.org/uniprot/ARHGC_HUMAN ARHGC_HUMAN]] Note=A chromosomal aberration involving ARHGEF12 may be a cause of acute leukemia. Translocation t(11;11)(q23;23) with MLL.
@@ Line 35: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Gao, G.]]
+[[Category: Gao, G]]
-[[Category: Kristelly, R.]]
+[[Category: Kristelly, R]]
-[[Category: Tesmer, J J.]]
+[[Category: Tesmer, J J]]
 [[Category: Signaling protein-membrane protein complex]]

1x86

From Proteopedia

Revision as of 13:19, 6 January 2015

Crystal Structure of the DH/PH domains of Leukemia-associated RhoGEF in complex with RhoA

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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