3nmx

From Proteopedia

(Difference between revisions)

Revision as of 07:06, 12 May 2022

Crystal structure of APC complexed with Asef

Structural highlights

3nmx is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	3nmw, 3nmz
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Adenomatous polyposis coli (APC) regulates cell-cell adhesion and cell migration through activating the APC-stimulated guanine nucleotide-exchange factor (GEF; Asef), which is usually autoinhibited through the binding between its Src homology 3 (SH3) and Dbl homology (DH) domains. The APC-activated Asef stimulates the small GTPase Cdc42, which leads to decreased cell-cell adherence and enhanced cell migration. In colorectal cancers, truncated APC constitutively activates Asef and promotes cancer cell migration and angiogenesis. Here, we report crystal structures of the human APC/Asef complex. We find that the armadillo repeat domain of APC uses a highly conserved surface groove to recognize the APC-binding region (ABR) of Asef, conformation of which changes dramatically upon binding to APC. Key residues on APC and Asef for the complex formation were mutated and their importance was demonstrated by binding and activity assays. Structural superimposition of the APC/Asef complex with autoinhibited Asef suggests that the binding between APC and Asef might create a steric clash between Asef-DH domain and APC, which possibly leads to a conformational change in Asef that stimulates its GEF activity. Our structures thus elucidate the molecular mechanism of Asef recognition by APC, as well as provide a potential target for pharmaceutical intervention against cancers.

Structural basis for the recognition of Asef by adenomatous polyposis coli.,Zhang Z, Chen L, Gao L, Lin K, Zhu L, Lu Y, Shi X, Gao Y, Zhou J, Xu P, Zhang J, Wu G Cell Res. 2012 Feb;22(2):372-86. doi: 10.1038/cr.2011.119. Epub 2011 Jul 26. PMID:21788986^[6]

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

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
↑ Zhang Z, Chen L, Gao L, Lin K, Zhu L, Lu Y, Shi X, Gao Y, Zhou J, Xu P, Zhang J, Wu G. Structural basis for the recognition of Asef by adenomatous polyposis coli. Cell Res. 2012 Feb;22(2):372-86. doi: 10.1038/cr.2011.119. Epub 2011 Jul 26. PMID:21788986 doi:http://dx.doi.org/10.1038/cr.2011.119

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3nmx"

@@ Line 3: / Line 3: @@
 <StructureSection load='3nmx' size='340' side='right'caption='[[3nmx]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3nmx]] is a 6 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=3NMX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NMX FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3nmx]] is a 6 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=3NMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NMX FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3nmw|3nmw]], [[3nmz|3nmz]]</td></tr>
+</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3nmw|3nmw]], [[3nmz|3nmz]]</div></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=3nmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nmx OCA], [http://pdbe.org/3nmx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3nmx RCSB], [http://www.ebi.ac.uk/pdbsum/3nmx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3nmx 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=3nmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nmx OCA], [https://pdbe.org/3nmx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nmx RCSB], [https://www.ebi.ac.uk/pdbsum/3nmx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nmx ProSAT]</span></td></tr>
 </table>
 == 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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 18: @@
 </div>
 <div class="pdbe-citations 3nmx" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Rho guanine nucleotide exchange factor 3D structures|Rho guanine nucleotide exchange factor 3D structures]]
 == References ==
 <references/>

3nmx

From Proteopedia

Revision as of 07:06, 12 May 2022

Crystal structure of APC complexed with Asef

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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