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| - | [[Image:1emu.gif|left|200px]]<br /> | |
| - | <applet load="1emu" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1emu, resolution 1.90Å" /> | |
| - | '''STRUCTURE OF THE AXIN RGS-HOMOLOGOUS DOMAIN IN COMPLEX WITH A SAMP REPEAT FROM APC'''<br /> | |
| | | | |
| - | ==Overview== | + | ==STRUCTURE OF THE AXIN RGS-HOMOLOGOUS DOMAIN IN COMPLEX WITH A SAMP REPEAT FROM APC== |
| - | Axin and the adenomatous polyposis coli (APC) tumor suppressor protein are, components of the Wnt/Wingless growth factor signaling pathway. In the, absence of Wnt signal, Axin and APC regulate cytoplasmic levels of the, proto-oncogene beta-catenin through the formation of a large complex, containing these three proteins, glycogen synthase kinase 3beta (GSK3beta), and several other proteins. Both Axin and APC are known to be critical for, beta-catenin regulation, and truncations in APC that eliminate the, Axin-binding site result in human cancers. A protease-resistant domain of, Axin that contains the APC-binding site is a member of the regulators of, G-protein signaling (RGS) superfamily. The crystal structures of this, domain alone and in complex with an Axin-binding sequence from APC reveal, that the Axin-APC interaction occurs at a conserved groove on a face of, the protein that is distinct from the G-protein interface of classical RGS, proteins. The molecular interactions observed in the Axin-APC complex, provide a rationale for the evolutionary conservation seen in both, proteins.
| + | <StructureSection load='1emu' size='340' side='right'caption='[[1emu]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1emu]] is a 2 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=1EMU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1EMU 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]] 1.9Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=1emu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1emu OCA], [https://pdbe.org/1emu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1emu RCSB], [https://www.ebi.ac.uk/pdbsum/1emu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1emu ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/AXIN1_HUMAN AXIN1_HUMAN] Defects in AXIN1 are involved in hepatocellular carcinoma (HCC) [MIM:[https://omim.org/entry/114550 114550].<ref>PMID:10700176</ref> <ref>PMID:12101426</ref> Defects in AXIN1 are a cause of caudal duplication anomaly (CADUA) [MIM:[https://omim.org/entry/607864 607864]. Caudal duplication anomaly is characterized by the occurrence of duplications of different organs in the caudal region. Note=Caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter.<ref>PMID:10700176</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/AXIN1_HUMAN AXIN1_HUMAN] Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling. Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway. In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B. Likely to function as a tumor suppressor. Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7. Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development.<ref>PMID:12192039</ref> <ref>PMID:16601693</ref> <ref>PMID:17210684</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/em/1emu_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=1emu ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | ==Disease== | + | ==See Also== |
| - | Known diseases associated with this structure: Adenoma, periampullary OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]], Adenomatous polyposis coli OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]], Adenomatous polyposis coli, attenuated OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]], Caudal duplication anomaly OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603816 603816]], Colorectal cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]], Desmoid disease, hereditary OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]], Gardner syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]], Gastric cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603816 603816]], Turcot syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175100 175100]]
| + | *[[Axin 3D structures|Axin 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure== | + | <references/> |
| - | 1EMU is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with GOL as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EMU OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference==
| + | |
| - | Structural basis of the Axin-adenomatous polyposis coli interaction., Spink KE, Polakis P, Weis WI, EMBO J. 2000 May 15;19(10):2270-9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10811618 10811618]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Protein complex]] | + | [[Category: Large Structures]] |
| - | [[Category: Polakis, P.]] | + | [[Category: Polakis P]] |
| - | [[Category: Spink, K.E.]] | + | [[Category: Spink KE]] |
| - | [[Category: Weis, W.I.]] | + | [[Category: Weis WI]] |
| - | [[Category: GOL]]
| + | |
| - | [[Category: rgs domain]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:45:07 2007''
| + | |
| Structural highlights
Disease
AXIN1_HUMAN Defects in AXIN1 are involved in hepatocellular carcinoma (HCC) [MIM:114550.[1] [2] Defects in AXIN1 are a cause of caudal duplication anomaly (CADUA) [MIM:607864. Caudal duplication anomaly is characterized by the occurrence of duplications of different organs in the caudal region. Note=Caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter.[3]
Function
AXIN1_HUMAN Component of the beta-catenin destruction complex required for regulating CTNNB1 levels through phosphorylation and ubiquitination, and modulating Wnt-signaling. Controls dorsoventral patterning via two opposing effects; down-regulates CTNNB1 to inhibit the Wnt signaling pathway and ventralize embryos, but also dorsalizes embryos by activating a Wnt-independent JNK signaling pathway. In Wnt signaling, probably facilitates the phosphorylation of CTNNB1 and APC by GSK3B. Likely to function as a tumor suppressor. Facilitates the phosphorylation of TP53 by HIPK2 upon ultraviolet irradiation. Enhances TGF-beta signaling by recruiting the RNF111 E3 ubiquitin ligase and promoting the degradation of inhibitory SMAD7. Also component of the AXIN1-HIPK2-TP53 complex which controls cell growth, apoptosis and development.[4] [5] [6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
References
- ↑ Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000 Mar;24(3):245-50. PMID:10700176 doi:10.1038/73448
- ↑ Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002 Jul 18;21(31):4863-71. PMID:12101426 doi:10.1038/sj.onc.1205591
- ↑ Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000 Mar;24(3):245-50. PMID:10700176 doi:10.1038/73448
- ↑ Kusano S, Raab-Traub N. I-mfa domain proteins interact with Axin and affect its regulation of the Wnt and c-Jun N-terminal kinase signaling pathways. Mol Cell Biol. 2002 Sep;22(18):6393-405. PMID:12192039
- ↑ Liu W, Rui H, Wang J, Lin S, He Y, Chen M, Li Q, Ye Z, Zhang S, Chan SC, Chen YG, Han J, Lin SC. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006 Apr 19;25(8):1646-58. Epub 2006 Apr 6. PMID:16601693 doi:7601057
- ↑ Li Q, Wang X, Wu X, Rui Y, Liu W, Wang J, Wang X, Liou YC, Ye Z, Lin SC. Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. Cancer Res. 2007 Jan 1;67(1):66-74. PMID:17210684 doi:10.1158/0008-5472.CAN-06-1671
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