1luj: Difference between revisions

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OCA

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-[[Image:1luj.gif|left|200px]]<br />
-<applet load="1luj" size="450" color="white" frame="true" align="right" spinBox="true"
-caption="1luj, resolution 2.50&Aring;" />
-'''Crystal Structure of the Beta-catenin/ICAT Complex'''<br />
-==Overview==
+==Crystal Structure of the Beta-catenin/ICAT Complex==
-Beta-catenin is a multifunctional protein involved in both cell adhesion, and transcriptional activation. Transcription mediated by the, beta-catenin/Tcf complex is involved in embryological development and is, upregulated in various cancers. We have determined the crystal structure, at 2.5 A resolution of a complex between beta-catenin and ICAT, a protein, that prevents the interaction between beta-catenin and Tcf/Lef family, transcription factors. ICAT contains a 3-helix bundle that binds armadillo, repeats 10-12 and a C-terminal tail that, similar to Tcf and E-cadherin, binds in the groove formed by armadillo repeats 5-9 of beta-catenin. We, show that ICAT selectively inhibits beta-catenin/Tcf binding in vivo, without disrupting beta-catenin/cadherin interactions. Thus, it should be, possible to design cancer therapeutics that inhibit beta-catenin-mediated, transcriptional activation without interfering with cell adhesion.
+<StructureSection load='1luj' size='340' side='right'caption='[[1luj]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1luj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1LUJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1LUJ 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]] 2.5&#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=1luj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1luj OCA], [https://pdbe.org/1luj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1luj RCSB], [https://www.ebi.ac.uk/pdbsum/1luj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1luj ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN] Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].  Note=Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life.  Defects in CTNNB1 are a cause of pilomatrixoma (PTR) [MIM:[https://omim.org/entry/132600 132600]; a common benign skin tumor.<ref>PMID:11703283</ref> <ref>PMID:12027456</ref> <ref>PMID:10192393</ref>   Defects in CTNNB1 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.<ref>PMID:12027456</ref> <ref>PMID:10666372</ref>   Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM:[https://omim.org/entry/167000 167000]. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease.  Note=A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1.  Defects in CTNNB1 may be a cause of mesothelioma malignant (MESOM) [MIM:[https://omim.org/entry/156240 156240]. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.<ref>PMID:11464291</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/CTNB1_HUMAN CTNB1_HUMAN] Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.<ref>PMID:17524503</ref> <ref>PMID:18086858</ref> <ref>PMID:18957423</ref> <ref>PMID:21262353</ref>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/lu/1luj_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1luj ConSurf].
+<div style="clear:both"></div>
-==Disease==
+==See Also==
-Known diseases associated with this structure: Colorectal cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=116806 116806]], Hepatoblastoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=116806 116806]], Hepatocellular carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=116806 116806]], Ovarian carcinoma, endometrioid type OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=116806 116806]], Pilomatricoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=116806 116806]]
+*[[Catenin 3D structures|Catenin 3D structures]]
+== References ==
-==About this Structure==
+<references/>
-LUJ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1LUJ OCA].
+__TOC__
+</StructureSection>
-==Reference==
-The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT., Graham TA, Clements WK, Kimelman D, Xu W, Mol Cell. 2002 Sep;10(3):563-71. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12408824 12408824]
 [[Category: Homo sapiens]]
-[[Category: Protein complex]]
+[[Category: Large Structures]]
-[[Category: Clements, W.K.]]
+[[Category: Mus musculus]]
-[[Category: Graham, T.A.]]
+[[Category: Clements WK]]
-[[Category: Kimelman, D.]]
+[[Category: Graham TA]]
-[[Category: Xu, W.]]
+[[Category: Kimelman D]]
-[[Category: beta-catenin]]
+[[Category: Xu W]]
-[[Category: icat]]
-[[Category: inhibitor]]
-[[Category: wnt pathway]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:04:16 2007''