View source for 3nmz


==Crystal structure of APC complexed with Asef==
<StructureSection load='3nmz' size='340' side='right'caption='[[3nmz]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3nmz]] is a 4 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=3NMZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NMZ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.01&#8491;</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=3nmz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nmz OCA], [https://pdbe.org/3nmz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nmz RCSB], [https://www.ebi.ac.uk/pdbsum/3nmz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nmz ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/APC_HUMAN APC_HUMAN] Defects in APC are a cause of familial adenomatous polyposis (FAP) [MIM:[https://omim.org/entry/175100 175100]; which includes also Gardner syndrome (GS). FAP and GS contribute to tumor development in patients with uninherited forms of colorectal cancer. FAP is characterized by adenomatous polyps of the colon and rectum, but also of upper gastrointestinal tract (ampullary, duodenal and gastric adenomas). This is a viciously premalignant disease with one or more polyps progressing through dysplasia to malignancy in untreated gene carriers with a median age at diagnosis of 40 years.<ref>PMID:8940264</ref> <ref>PMID:10782927</ref> <ref>PMID:1651563</ref> <ref>PMID:1338904</ref> <ref>PMID:1338691</ref> <ref>PMID:1338764</ref> <ref>PMID:7833149</ref> <ref>PMID:7833931</ref> <ref>PMID:8990002</ref> <ref>PMID:10470088</ref>   Defects in APC are a cause of hereditary desmoid disease (HDD) [MIM:[https://omim.org/entry/135290 135290]; also known as familial infiltrative fibromatosis (FIF). HDD is an autosomal dominant trait with 100% penetrance and possible variable expression among affected relatives. HDD patients show multifocal fibromatosis of the paraspinal muscles, breast, occiput, arms, lower ribs, abdominal wall, and mesentery. Desmoid tumors appears also as a complication of familial adenomatous polyposis.<ref>PMID:8940264</ref> <ref>PMID:10782927</ref>   Defects in APC are a cause of medulloblastoma (MDB) [MIM:[https://omim.org/entry/155255 155255]. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. Although the majority of medulloblastomas occur sporadically, some manifest within familial cancer syndromes such as Turcot syndrome and basal cell nevus syndrome (Gorlin syndrome).<ref>PMID:8940264</ref> <ref>PMID:10782927</ref> <ref>PMID:10666372</ref>   Defects in APC are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:[https://omim.org/entry/276300 276300]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots.<ref>PMID:8940264</ref> <ref>PMID:10782927</ref> <ref>PMID:7661930</ref>   Defects in APC are a cause of gastric cancer (GASC) [MIM:[https://omim.org/entry/613659 613659]; also called gastric cancer intestinal or stomach cancer. Gastric cancer is a malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.<ref>PMID:8940264</ref> <ref>PMID:10782927</ref>   Defects in APC are a cause of hepatocellular carcinoma (HCC) [MIM:[https://omim.org/entry/114550 114550]. This defect includes also the disease entity termed hepatoblastoma.<ref>PMID:8940264</ref> <ref>PMID:10782927</ref> 
== Function ==
[https://www.uniprot.org/uniprot/APC_HUMAN APC_HUMAN] Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. APC activity is correlated with its phosphorylation state. Activates the GEF activity of SPATA13 and ARHGEF4. Plays a role in hepatocyte growth factor (HGF)-induced cell migration. Required for MMP9 up-regulation via the JNK signaling pathway in colorectal tumor cells. Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex. It is required for the localization of MACF1 to the cell membrane and this localization of MACF1 is critical for its function in microtubule stabilization.<ref>PMID:10947987</ref> <ref>PMID:17599059</ref> <ref>PMID:19893577</ref> <ref>PMID:19151759</ref> <ref>PMID:20937854</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:21788986</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3nmz" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adenomatous polyposis coli|Adenomatous polyposis coli]]
*[[Rho guanine nucleotide exchange factor 3D structures|Rho guanine nucleotide exchange factor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen L]]
[[Category: Gao L]]
[[Category: Lin K]]
[[Category: Wu G]]
[[Category: Zhang Z]]