4yk6: Difference between revisions

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<StructureSection load='4yk6' size='340' side='right'caption='[[4yk6]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
<StructureSection load='4yk6' size='340' side='right'caption='[[4yk6]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4yk6]] is a 2 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=4YK6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YK6 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4yk6]] 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=4YK6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YK6 FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yje|4yje]], [[4yjl|4yjl]]</td></tr>
</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=4yk6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yk6 OCA], [https://pdbe.org/4yk6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yk6 RCSB], [https://www.ebi.ac.uk/pdbsum/4yk6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yk6 ProSAT]</span></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4yk6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yk6 OCA], [http://pdbe.org/4yk6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yk6 RCSB], [http://www.ebi.ac.uk/pdbsum/4yk6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yk6 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/AMER1_HUMAN AMER1_HUMAN]] Osteopathia striata - cranial sclerosis. The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/APC_HUMAN APC_HUMAN]] Defects in APC are a cause of familial adenomatous polyposis (FAP) [MIM:[http://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:[http://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:[http://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:[http://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:[http://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:[http://omim.org/entry/114550 114550]]. This defect includes also the disease entity termed hepatoblastoma.<ref>PMID:8940264</ref> <ref>PMID:10782927</ref> 
[https://www.uniprot.org/uniprot/AMER1_HUMAN AMER1_HUMAN] Osteopathia striata - cranial sclerosis. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/AMER1_HUMAN AMER1_HUMAN]] Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development.<ref>PMID:17510365</ref> <ref>PMID:17925383</ref> <ref>PMID:19416806</ref> <ref>PMID:21304492</ref> <ref>PMID:21498506</ref> [[http://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> 
[https://www.uniprot.org/uniprot/AMER1_HUMAN AMER1_HUMAN] Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development.<ref>PMID:17510365</ref> <ref>PMID:17925383</ref> <ref>PMID:19416806</ref> <ref>PMID:21304492</ref> <ref>PMID:21498506</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</div>
</div>
<div class="pdbe-citations 4yk6" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 4yk6" style="background-color:#fffaf0;"></div>
==See Also==
*[[Adenomatous polyposis coli|Adenomatous polyposis coli]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Wu, G]]
[[Category: Wu G]]
[[Category: Xiao, Y]]
[[Category: Xiao Y]]
[[Category: Zhang, Z]]
[[Category: Zhang Z]]
[[Category: Armadillo-ligand complex]]
[[Category: Protein binding-cell adhesion complex]]

Revision as of 11:16, 3 May 2023

Crystal structure of APC-ARM in complexed with Amer1-A4Crystal structure of APC-ARM in complexed with Amer1-A4

Structural highlights

4yk6 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AMER1_HUMAN Osteopathia striata - cranial sclerosis. The disease is caused by mutations affecting the gene represented in this entry.

Function

AMER1_HUMAN Regulator of the canonical Wnt signaling pathway. Acts by specifically binding phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), translocating to the cell membrane and interacting with key regulators of the canonical Wnt signaling pathway, such as components of the beta-catenin destruction complex. Acts both as a positive and negative regulator of the Wnt signaling pathway, depending on the context: acts as a positive regulator by promoting LRP6 phosphorylation. Also acts as a negative regulator by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the cell membrane. Promotes CTNNB1 ubiquitination and degradation. Involved in kidney development.[1] [2] [3] [4] [5]

Publication Abstract from PubMed

The tumor suppressor APC employs its conserved armadillo repeat (ARM) domain to recognize many of its binding partners, including Amer1/WTX, which is mutated in Wilms' tumor and bone overgrowth syndrome. The APC-Amer1 complex has important roles in regulating Wnt signaling and cell adhesion. Three sites A1, A2, and A3 of Amer1 have been reported to mediate its interaction with APC-ARM. In this study, crystal structures of APC-ARM in complexes with Amer1-A1, -A2, and -A4, which is newly identified in this work, were determined. Combined with our GST pull-down, yeast two-hybrid, and isothermal titration calorimetry (ITC) assay results using mutants of APC and Amer1 interface residues, our structures demonstrate that Amer1-A1, -A2, and -A4, as well as other APC-binding proteins such as Asef and Sam68, all employ a common recognition pattern to associate with APC-ARM. In contrast, Amer1-A3 binds to the C-terminal side of APC-ARM through a bipartite interaction mode. Composite mutations on either APC or Amer1 disrupting all four interfaces abrogated their association in cultured cells and impaired the membrane recruitment of APC by Amer1. Our study thus comprehensively elucidated the recognition mechanism between APC and Amer1, and revealed a consensus recognition sequence employed by various APC-ARM binding partners.

Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners.,Zhang Z, Akyildiz S, Xiao Y, Gai Z, An Y, Behrens J, Wu G Cell Discov. 2015 Jul 14;1:15016. doi: 10.1038/celldisc.2015.16. eCollection, 2015. PMID:27462415[6]

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

See Also

References

  1. ↑ Major MB, Camp ND, Berndt JD, Yi X, Goldenberg SJ, Hubbert C, Biechele TL, Gingras AC, Zheng N, Maccoss MJ, Angers S, Moon RT. Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling. Science. 2007 May 18;316(5827):1043-6. PMID:17510365 doi:http://dx.doi.org/10.1126/science/1141515
  2. ↑ Grohmann A, Tanneberger K, Alzner A, Schneikert J, Behrens J. AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane. J Cell Sci. 2007 Nov 1;120(Pt 21):3738-47. Epub 2007 Oct 9. PMID:17925383 doi:http://dx.doi.org/10.1242/jcs.011320
  3. ↑ Rivera MN, Kim WJ, Wells J, Stone A, Burger A, Coffman EJ, Zhang J, Haber DA. The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8338-43. doi:, 10.1073/pnas.0811349106. Epub 2009 May 4. PMID:19416806 doi:10.1073/pnas.0811349106
  4. ↑ Tanneberger K, Pfister AS, Brauburger K, Schneikert J, Hadjihannas MV, Kriz V, Schulte G, Bryja V, Behrens J. Amer1/WTX couples Wnt-induced formation of PtdIns(4,5)P2 to LRP6 phosphorylation. EMBO J. 2011 Apr 20;30(8):1433-43. doi: 10.1038/emboj.2011.28. Epub 2011 Feb 8. PMID:21304492 doi:http://dx.doi.org/10.1038/emboj.2011.28
  5. ↑ Tanneberger K, Pfister AS, Kriz V, Bryja V, Schambony A, Behrens J. Structural and functional characterization of the Wnt inhibitor APC membrane recruitment 1 (Amer1). J Biol Chem. 2011 Jun 3;286(22):19204-14. doi: 10.1074/jbc.M111.224881. Epub 2011, Apr 15. PMID:21498506 doi:http://dx.doi.org/10.1074/jbc.M111.224881
  6. ↑ Zhang Z, Akyildiz S, Xiao Y, Gai Z, An Y, Behrens J, Wu G. Structures of the APC-ARM domain in complexes with discrete Amer1/WTX fragments reveal that it uses a consensus mode to recognize its binding partners. Cell Discov. 2015 Jul 14;1:15016. doi: 10.1038/celldisc.2015.16. eCollection, 2015. PMID:27462415 doi:http://dx.doi.org/10.1038/celldisc.2015.16

4yk6, resolution 1.70Å

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