2gfu

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2gfu, 20 NMR models ()
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

NMR solution structure of the PWWP domain of Mismatch repair protein hMSH6

Disease

[MSH6_HUMAN] Defects in MSH6 are the cause of hereditary non-polyposis colorectal cancer type 5 (HNPCC5) [MIM:614350]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. MSH6 mutations appear to be associated with atypical HNPCC and in particular with development of endometrial carcinoma or atypical endometrial hyperplasia, the presumed precursor of endometrial cancer. Defects in MSH6 are also found in familial colorectal cancers (suspected or incomplete HNPCC) that do not fulfill the Amsterdam criteria for HNPCC.[1][2][3][4][5][6][7][8] Defects in MSH6 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089]. Defects in MSH6 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.[9]

Function

[MSH6_HUMAN] Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair.[10][11][12][13][14][15]

About this Structure

2gfu is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA.

Reference

  1. Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997 Nov;17(3):271-2. PMID:9354786 doi:10.1038/ng1197-271
  2. Wu Y, Berends MJ, Mensink RG, Kempinga C, Sijmons RH, van Der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999 Nov;65(5):1291-8. PMID:10521294 doi:S0002-9297(07)62135-1
  3. Wang Q, Lasset C, Desseigne F, Saurin JC, Maugard C, Navarro C, Ruano E, Descos L, Trillet-Lenoir V, Bosset JF, Puisieux A. Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Hum Genet. 1999 Jul-Aug;105(1-2):79-85. PMID:10480359
  4. Wu Y, Berends MJ, Sijmons RH, Mensink RG, Verlind E, Kooi KA, van der Sluis T, Kempinga C, van dDer Zee AG, Hollema H, Buys CH, Kleibeuker JH, Hofstra RM. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat Genet. 2001 Oct;29(2):137-8. PMID:11586295 doi:10.1038/ng1001-137
  5. Wagner A, Barrows A, Wijnen JT, van der Klift H, Franken PF, Verkuijlen P, Nakagawa H, Geugien M, Jaghmohan-Changur S, Breukel C, Meijers-Heijboer H, Morreau H, van Puijenbroek M, Burn J, Coronel S, Kinarski Y, Okimoto R, Watson P, Lynch JF, de la Chapelle A, Lynch HT, Fodde R. Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet. 2003 May;72(5):1088-100. Epub 2003 Mar 25. PMID:12658575 doi:10.1086/373963
  6. Plaschke J, Kruger S, Dietmaier W, Gebert J, Sutter C, Mangold E, Pagenstecher C, Holinski-Feder E, Schulmann K, Moslein G, Ruschoff J, Engel C, Evans G, Schackert HK. Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. Hum Mutat. 2004 Mar;23(3):285. PMID:14974087 doi:10.1002/humu.9217
  7. Shin YK, Heo SC, Shin JH, Hong SH, Ku JL, Yoo BC, Kim IJ, Park JG. Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. Hum Mutat. 2004 Oct;24(4):351. PMID:15365995 doi:10.1002/humu.9277
  8. Drost M, Zonneveld JB, van Hees S, Rasmussen LJ, Hofstra RM, de Wind N. A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. Hum Mutat. 2012 Mar;33(3):488-94. doi: 10.1002/humu.22000. Epub 2011 Dec 29. PMID:22102614 doi:10.1002/humu.22000
  9. Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, Pinson S, Xu XL, Montmain G, Ruano E, Navarro C, Puisieux A, Wang Q. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat. 2007 Nov;28(11):1084-90. PMID:17557300 doi:10.1002/humu.20569
  10. Blackwell LJ, Martik D, Bjornson KP, Bjornson ES, Modrich P. Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism. J Biol Chem. 1998 Nov 27;273(48):32055-62. PMID:9822680
  11. Blackwell LJ, Bjornson KP, Modrich P. DNA-dependent activation of the hMutSalpha ATPase. J Biol Chem. 1998 Nov 27;273(48):32049-54. PMID:9822679
  12. Iaccarino I, Marra G, Palombo F, Jiricny J. hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha. EMBO J. 1998 May 1;17(9):2677-86. PMID:9564049 doi:10.1093/emboj/17.9.2677
  13. Gradia S, Subramanian D, Wilson T, Acharya S, Makhov A, Griffith J, Fishel R. hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Mol Cell. 1999 Feb;3(2):255-61. PMID:10078208
  14. Gradia S, Acharya S, Fishel R. The role of mismatched nucleotides in activating the hMSH2-hMSH6 molecular switch. J Biol Chem. 2000 Feb 11;275(6):3922-30. PMID:10660545
  15. Yang Q, Zhang R, Wang XW, Linke SP, Sengupta S, Hickson ID, Pedrazzi G, Perrera C, Stagljar I, Littman SJ, Modrich P, Harris CC. The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase. Oncogene. 2004 May 6;23(21):3749-56. PMID:15064730 doi:10.1038/sj.onc.1207462

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