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1th1

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1th1, resolution 2.50Å ()
Non-Standard Residues: ,
Gene: CTNNB1, CTNNB (Homo sapiens), APC, DP2.5 (Homo sapiens)
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Beta-catenin in complex with a phosphorylated APC 20aa repeat fragment

Publication Abstract from PubMed

The tumor suppressor adenomatous polyposis coli (APC) plays a critical role in the turnover of cytosolic beta-catenin, the key effector of the canonical Wnt signaling pathway. APC contains seven 20 amino acid (20 aa) beta-catenin binding repeats that are required for beta-catenin turnover. We have determined the crystal structure of beta-catenin in complex with a phosphorylated APC fragment containing two 20 aa repeats. Surprisingly, one single phosphorylated 20 aa repeat, together with its flanking regions, covers the entire structural groove of beta-catenin and may thus compete for beta-catenin binding with all other beta-catenin armadillo repeat partners. Our biochemical studies show that phosphorylation of the APC 20 aa repeats increases the affinity of the repeats for beta-catenin by 300- to 500-fold and the phosphorylated 20 aa repeats prevent beta-catenin binding to Tcf. Our work suggests that the phosphorylation of the APC 20 aa repeats could be a critical switch for APC function.

Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function., Xing Y, Clements WK, Le Trong I, Hinds TR, Stenkamp R, Kimelman D, Xu W, Mol Cell. 2004 Aug 27;15(4):523-33. PMID:15327769

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

Disease

[CTNB1_HUMAN] Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM: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:132600]; a common benign skin tumor.[1][2][3] Defects in CTNNB1 are a cause of medulloblastoma (MDB) [MIM:155255]. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.[4][5] Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM: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: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.[6] [APC_HUMAN] Defects in APC are a cause of familial adenomatous polyposis (FAP) [MIM: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.[7][8][9][10][11][12][13][14][15][16] Defects in APC are a cause of hereditary desmoid disease (HDD) [MIM: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.[17][18] Defects in APC are a cause of medulloblastoma (MDB) [MIM: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).[19][20][21] Defects in APC are a cause of mismatch repair cancer syndrome (MMRCS) [MIM: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.[22][23][24] Defects in APC are a cause of gastric cancer (GASC) [MIM: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.[25][26] Defects in APC are a cause of hepatocellular carcinoma (HCC) [MIM:114550]. This defect includes also the disease entity termed hepatoblastoma.[27][28]

Function

[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.[29][30][31][32] [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.[33][34][35][36][37]

About this Structure

1th1 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Xing Y, Clements WK, Le Trong I, Hinds TR, Stenkamp R, Kimelman D, Xu W. Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function. Mol Cell. 2004 Aug 27;15(4):523-33. PMID:15327769 doi:10.1016/j.molcel.2004.08.001
  1. Moreno-Bueno G, Gamallo C, Perez-Gallego L, Contreras F, Palacios J. beta-catenin expression in pilomatrixomas. Relationship with beta-catenin gene mutations and comparison with beta-catenin expression in normal hair follicles. Br J Dermatol. 2001 Oct;145(4):576-81. PMID:11703283
  2. van Noort M, van de Wetering M, Clevers H. Identification of two novel regulated serines in the N terminus of beta-catenin. Exp Cell Res. 2002 Jun 10;276(2):264-72. PMID:12027456 doi:10.1006/excr.2002.5520
  3. Chan EF, Gat U, McNiff JM, Fuchs E. A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet. 1999 Apr;21(4):410-3. PMID:10192393 doi:10.1038/7747
  4. van Noort M, van de Wetering M, Clevers H. Identification of two novel regulated serines in the N terminus of beta-catenin. Exp Cell Res. 2002 Jun 10;276(2):264-72. PMID:12027456 doi:10.1006/excr.2002.5520
  5. Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H. APC mutations in sporadic medulloblastomas. Am J Pathol. 2000 Feb;156(2):433-7. PMID:10666372
  6. Shigemitsu K, Sekido Y, Usami N, Mori S, Sato M, Horio Y, Hasegawa Y, Bader SA, Gazdar AF, Minna JD, Hida T, Yoshioka H, Imaizumi M, Ueda Y, Takahashi M, Shimokata K. Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene. 2001 Jul 12;20(31):4249-57. PMID:11464291 doi:10.1038/sj.onc.1204557
  7. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
  8. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
  9. Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991 Aug 9;253(5020):665-9. PMID:1651563
  10. Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T, Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992 Jul;1(4):229-33. PMID:1338904
  11. Nakatsuru S, Yanagisawa A, Ichii S, Tahara E, Kato Y, Nakamura Y, Horii A. Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Hum Mol Genet. 1992 Nov;1(8):559-63. PMID:1338691
  12. Nagase H, Miyoshi Y, Horii A, Aoki T, Petersen GM, Vogelstein B, Maher E, Ogawa M, Maruyama M, Utsunomiya J, et al.. Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients. Hum Mutat. 1992;1(6):467-73. PMID:1338764 doi:http://dx.doi.org/10.1002/humu.1380010603
  13. Dobbie Z, Spycher M, Hurliman R, Ammann R, Ammann T, Roth J, Muller A, Muller H, Scott RJ. Mutational analysis of the first 14 exons of the adenomatous polyposis coli (APC) gene. Eur J Cancer. 1994;30A(11):1709-13. PMID:7833149
  14. Stella A, Montera M, Resta N, Marchese C, Susca F, Gentile M, Romio L, Pilia S, Prete F, Mareni C, et al.. Four novel mutations of the APC (adenomatous polyposis coli) gene in FAP patients. Hum Mol Genet. 1994 Sep;3(9):1687-8. PMID:7833931
  15. van der Luijt RB, Khan PM, Vasen HF, Tops CM, van Leeuwen-Cornelisse IS, Wijnen JT, van der Klift HM, Plug RJ, Griffioen G, Fodde R. Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. Hum Mutat. 1997;9(1):7-16. PMID:8990002 doi:<7::AID-HUMU2>3.0.CO;2-8 10.1002/(SICI)1098-1004(1997)9:1<7::AID-HUMU2>3.0.CO;2-8
  16. Lamlum H, Ilyas M, Rowan A, Clark S, Johnson V, Bell J, Frayling I, Efstathiou J, Pack K, Payne S, Roylance R, Gorman P, Sheer D, Neale K, Phillips R, Talbot I, Bodmer W, Tomlinson I. The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis. Nat Med. 1999 Sep;5(9):1071-5. PMID:10470088 doi:10.1038/12511
  17. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
  18. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
  19. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
  20. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
  21. Huang H, Mahler-Araujo BM, Sankila A, Chimelli L, Yonekawa Y, Kleihues P, Ohgaki H. APC mutations in sporadic medulloblastomas. Am J Pathol. 2000 Feb;156(2):433-7. PMID:10666372
  22. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
  23. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
  24. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, et al.. The molecular basis of Turcot's syndrome. N Engl J Med. 1995 Mar 30;332(13):839-47. PMID:7661930
  25. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
  26. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
  27. Eccles DM, van der Luijt R, Breukel C, Bullman H, Bunyan D, Fisher A, Barber J, du Boulay C, Primrose J, Burn J, Fodde R. Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet. 1996 Dec;59(6):1193-201. PMID:8940264
  28. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, Fodde R, Alman B, Bapat B. A germline mutation at the extreme 3' end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet. 2000 Mar;57(3):205-12. PMID:10782927
  29. Lillehoj EP, Lu W, Kiser T, Goldblum SE, Kim KC. MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. Biochim Biophys Acta. 2007 Jul;1773(7):1028-38. Epub 2007 Apr 22. PMID:17524503 doi:S0167-4889(07)00092-4
  30. Bahmanyar S, Kaplan DD, Deluca JG, Giddings TH Jr, O'Toole ET, Winey M, Salmon ED, Casey PJ, Nelson WJ, Barth AI. beta-Catenin is a Nek2 substrate involved in centrosome separation. Genes Dev. 2008 Jan 1;22(1):91-105. Epub 2007 Dec 17. PMID:18086858 doi:10.1101/gad.1596308
  31. Li H, Ray G, Yoo BH, Erdogan M, Rosen KV. Down-regulation of death-associated protein kinase-2 is required for beta-catenin-induced anoikis resistance of malignant epithelial cells. J Biol Chem. 2009 Jan 23;284(4):2012-22. doi: 10.1074/jbc.M805612200. Epub 2008, Oct 27. PMID:18957423 doi:10.1074/jbc.M805612200
  32. Fiset A, Xu E, Bergeron S, Marette A, Pelletier G, Siminovitch KA, Olivier M, Beauchemin N, Faure RL. Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and regulates insulin internalization. Cell Signal. 2011 May;23(5):911-9. doi: 10.1016/j.cellsig.2011.01.019. Epub 2011 , Jan 22. PMID:21262353 doi:10.1016/j.cellsig.2011.01.019
  33. 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
  34. 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
  35. 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
  36. Sagara M, Kawasaki Y, Iemura SI, Natsume T, Takai Y, Akiyama T. Asef2 and Neurabin2 cooperatively regulate actin cytoskeletal organization and are involved in HGF-induced cell migration. Oncogene. 2009 Mar 12;28(10):1357-65. doi: 10.1038/onc.2008.478. Epub 2009 Jan, 19. PMID:19151759 doi:10.1038/onc.2008.478
  37. Zaoui K, Benseddik K, Daou P, Salaun D, Badache A. ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18517-22. doi:, 10.1073/pnas.1000975107. Epub 2010 Oct 11. PMID:20937854 doi:10.1073/pnas.1000975107

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