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2rqu

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2rqu, 20 NMR models ()
Gene: APC, DP2.5 (Homo sapiens)
Related: 2rqt


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Solution structure of the complex between the DDEF1 SH3 domain and the APC SAMP1 motif

Publication Abstract from PubMed

Elucidation of the basis of interactions between biological molecules is essential for the understanding of living systems. Src-homology 3 (SH3) domains play critical roles in interaction networks of proteins by recognizing a proline-rich sequence motif, PxxP. There are, however, several SH3 domains that specifically bind to polypeptide chains without the conventional recognition sequence. The SH3 domain of DDEF1 associates with the SAMP motifs of the adenomatous polyposis coli (APC) tumor suppressor. The SAMP motifs are indispensable for the normal function of APC in tumor suppression. Here we present the structural basis of the interaction between the DDEF1-SH3 domain and the APC-SAMP motifs. We determined the solution structures of the DDEF1-SH3 domain both in a free state and in a complex with APC-SAMP. As the affinity of the interaction was not sufficiently high for the determination of the complex structure in solution by conventional methods, we utilized a fusion protein of the DDEF1-SH3 domain and APC-SAMP. The structures revealed that the SAMP motif adopts a class II polyproline type II helix even though it does not contain the PxxP motif and that a characteristically large hydrophobic pocket of the SH3 domain confers high selectivity to the interaction. Furthermore, investigation into the backbone dynamics of the free and bound systems by NMR spin relaxation experiments demonstrated that the DDEF1-SH3 domain exhibits high flexibility at the peptide recognition site in the absence of the ligand and that most residues of the APC-SAMP motif display extensive local motions even in the stable complex.

Structural basis of the recognition of the SAMP motif of adenomatous polyposis coli by the Src-homology 3 domain., Kaieda S, Matsui C, Mimori-Kiyosue Y, Ikegami T, Biochemistry. 2010 Jun 29;49(25):5143-53. PMID:20509626

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

Disease

[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.[1][2][3][4][5][6][7][8][9][10] 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.[11][12] 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).[13][14][15] 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.[16][17][18] 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.[19][20] Defects in APC are a cause of hepatocellular carcinoma (HCC) [MIM:114550]. This defect includes also the disease entity termed hepatoblastoma.[21][22]

Function

[ASAP1_HUMAN] Possesses phosphatidylinositol 4,5-bisphosphate-dependent GTPase-activating protein activity for ARF1 (ADP ribosylation factor 1) and ARF5 and a lesser activity towards ARF6. May coordinate membrane trafficking with cell growth or actin cytoskeleton remodeling by binding to both SRC and PIP2. May function as a signal transduction protein involved in the differentiation of fibroblasts into adipocytes and possibly other cell types (By similarity). Plays a role in ciliogenesis.[23] [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.[24][25][26][27][28]

About this Structure

2rqu is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA.

Reference

  • Kaieda S, Matsui C, Mimori-Kiyosue Y, Ikegami T. Structural basis of the recognition of the SAMP motif of adenomatous polyposis coli by the Src-homology 3 domain. Biochemistry. 2010 Jun 29;49(25):5143-53. PMID:20509626 doi:10.1021/bi100563z
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  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. 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
  22. 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
  23. Kim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG. Functional genomic screen for modulators of ciliogenesis and cilium length. Nature. 2010 Apr 15;464(7291):1048-51. doi: 10.1038/nature08895. PMID:20393563 doi:10.1038/nature08895
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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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