| Structural highlights
3thy is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 3thw, 3thx, 3thz |
| Gene: | MSH2 (HUMAN), DUC1, DUG, MSH3 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[MSH2_HUMAN] Defects in MSH2 are the cause of hereditary non-polyposis colorectal cancer type 1 (HNPCC1) [MIM:120435]. 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. The term "suspected HNPCC" or "incomplete HNPCC" can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. MSH2 mutations may predispose to hematological malignancies and multiple cafe-au-lait spots.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] Defects in MSH2 are a cause of Muir-Torre syndrome (MRTES) [MIM:158320]. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.[52] Defects in MSH2 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089].
Function
[MSH2_HUMAN] Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long. After mismatch binding, MutS alpha or beta 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. In melanocytes may modulate both UV-B-induced cell cycle regulation and apoptosis.[53] [54] [55] [56] [57] [58] [59]
Publication Abstract from PubMed
DNA mismatch repair corrects replication errors, thus reducing mutation rates and microsatellite instability. Genetic defects in this pathway cause Lynch syndrome and various cancers in humans. Binding of a mispaired or unpaired base by bacterial MutS and eukaryotic MutSalpha is well characterized. We report here crystal structures of human MutSbeta in complex with DNA containing insertion-deletion loops (IDL) of two, three, four or six unpaired nucleotides. In contrast to eukaryotic MutSalpha and bacterial MutS, which bind the base of a mismatched nucleotide, MutSbeta binds three phosphates in an IDL. DNA is severely bent at the IDL; unpaired bases are flipped out into the major groove and partially exposed to solvent. A normal downstream base pair can become unpaired; a single unpaired base can thereby be converted to an IDL of two nucleotides and recognized by MutSbeta. The C-terminal dimerization domains form an integral part of the MutS structure and coordinate asymmetrical ATP hydrolysis by Msh2 and Msh3 with mismatch binding to signal for repair.
Mechanism of mismatch recognition revealed by human MutSbeta bound to unpaired DNA loops.,Gupta S, Gellert M, Yang W Nat Struct Mol Biol. 2011 Dec 18;19(1):72-8. doi: 10.1038/nsmb.2175. PMID:22179786[60]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Mary JL, Bishop T, Kolodner R, Lipford JR, Kane M, Weber W, Torhorst J, Muller H, Spycher M, Scott RJ. Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development. Hum Mol Genet. 1994 Nov;3(11):2067-9. PMID:7874129
- ↑ Moslein G, Tester DJ, Lindor NM, Honchel R, Cunningham JM, French AJ, Halling KC, Schwab M, Goretzki P, Thibodeau SN. Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. Hum Mol Genet. 1996 Sep;5(9):1245-52. PMID:8872463
- ↑ Bubb VJ, Curtis LJ, Cunningham C, Dunlop MG, Carothers AD, Morris RG, White S, Bird CC, Wyllie AH. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. 1996 Jun 20;12(12):2641-9. PMID:8700523
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- ↑ Wehner M, Buschhausen L, Lamberti C, Kruse R, Caspari R, Propping P, Friedl W. Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes. Hum Mutat. 1997;10(3):241-4. PMID:9298827 doi:<241::AID-HUMU12>3.0.CO;2-# 10.1002/(SICI)1098-1004(1997)10:3<241::AID-HUMU12>3.0.CO;2-#
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- ↑ Yuan Y, Han HJ, Zheng S, Park JG. Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer. Dis Colon Rectum. 1998 Apr;41(4):434-40. PMID:9559627
- ↑ Heinimann K, Scott RJ, Buerstedde JM, Weber W, Siebold K, Attenhofer M, Muller H, Dobbie Z. Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer. Cancer. 1999 Jun 15;85(12):2512-8. PMID:10375096
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- ↑ Nomura S, Sugano K, Kashiwabara H, Taniguchi T, Fukayama N, Fujita S, Akasu T, Moriya Y, Ohhigashi S, Kakizoe T, Sekiya T. Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds. Biochem Biophys Res Commun. 2000 Apr 29;271(1):120-9. PMID:10777691 doi:10.1006/bbrc.2000.2547
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- ↑ Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M, Harkonen N, Julkunen R, Kangas E, Ojala S, Tulikoura J, Valkamo E, Jarvinen H, Mecklin JP, Aaltonen LA, de la Chapelle A. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2000 Jun;18(11):2193-200. PMID:10829038
- ↑ Kim JC, Kim HC, Roh SA, Koo KH, Lee DH, Yu CS, Lee JH, Kim TW, Lee HL, Beck NE, Bodmer WF. hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer. Cancer Detect Prev. 2001;25(6):503-10. PMID:12132870
- ↑ Muller-Koch Y, Kopp R, Lohse P, Baretton G, Stoetzer A, Aust D, Daum J, Kerker B, Gross M, Dietmeier W, Holinski-Feder E. Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal cancer) patients: mutations or polymorphisms? Eur J Med Res. 2001 Nov 20;6(11):473-82. PMID:11726306
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- ↑ Scartozzi M, Bianchi F, Rosati S, Galizia E, Antolini A, Loretelli C, Piga A, Bearzi I, Cellerino R, Porfiri E. Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol. 2002 Mar 1;20(5):1203-8. PMID:11870161
- ↑ Kurzawski G, Suchy J, Kladny J, Safranow K, Jakubowska A, Elsakov P, Kucinskas V, Gardovski J, Irmejs A, Sibul H, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Clark J, Gozdz S, Niepsuj S, Slomski R, Plawski A, Lacka-Wojciechowska A, Rozmiarek A, Fiszer-Maliszewska L, Bebenek M, Sorokin D, Stawicka M, Godlewski D, Richter P, Brozek I, Wysocka B, Jawien A, Banaszkiewicz Z, Kowalczyk J, Czudowska D, Goretzki PE, Moeslein G, Lubinski J. Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States. J Med Genet. 2002 Oct;39(10):E65. PMID:12362047
- ↑ 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
- ↑ Chen-Shtoyerman R, Theodor L, Harmati E, Friedman E, Dacka S, Kopelman Y, Sternberg A, Zarivach R, Bar-Meir S, Fireman Z. Genetic analysis of familial colorectal cancer in Israeli Arabs. Hum Mutat. 2003 Apr;21(4):446-7. PMID:12655564 doi:10.1002/humu.9123
- ↑ Bartosova Z, Fridrichova I, Bujalkova M, Wolf B, Ilencikova D, Krizan P, Hlavcak P, Palaj J, Lukac L, Lukacova M, Boor A, Haider R, Jiricny J, Nystrom-Lahti M, Marra G. Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia. Hum Mutat. 2003 Apr;21(4):449. PMID:12655568 doi:10.1002/humu.9127
- ↑ Taylor CF, Charlton RS, Burn J, Sheridan E, Taylor GR. Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPA. Hum Mutat. 2003 Dec;22(6):428-33. PMID:14635101 doi:10.1002/humu.10291
- ↑ Sun MH, Cai Q, Fu G, Ren S, Mo S, Xu Y, Ding C, Zhang T, Zhu X, Xu X, Min D, Cai S, Luo D, Shi Y, Shi D. Gene symbol: hMSH2. Disease: Hereditary nonpolyposis colorectal cancer. Hum Genet. 2004 Mar;114(4):409. PMID:15046096
- ↑ Sharp A, Pichert G, Lucassen A, Eccles D. RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1. Hum Mutat. 2004 Sep;24(3):272. PMID:15300854 doi:10.1002/humu.9267
- ↑ 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
- ↑ Yuan Y, Huang YQ, Cai SR, Song YM, Zheng S, Zhang SZ. Genetic characterization of Chinese hereditary non-polyposis colorectal cancer by DHPLC and multiplex PCR. Jpn J Clin Oncol. 2004 Nov;34(11):660-6. PMID:15613555 doi:10.1093/jjco/hyh121
- ↑ Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, Westra J, Frebourg T, Espin E, Armengol M, Hamelin R, Yamamoto H, Hofstra RM, Seruca R, Lindblom A, Peltomaki P, Thibodeau SN, Aaltonen LA, Schwartz S Jr. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet. 2004 Sep;41(9):664-8. PMID:15342696 doi:10.1136/jmg.2004.020651
- ↑ Baudi F, Fersini G, Lavecchia A, Terracciano R, Leone F, Quaresima B, Faniello MC, De Paola L, Doldo P, Cuda G, Costanzo F, Venuta S. A novel missense germline mutation in exon 2 of the hMSH2 gene in a HNPCC family from Southern Italy. Cancer Lett. 2005 Jun 8;223(2):285-91. Epub 2004 Nov 25. PMID:15896463 doi:10.1016/j.canlet.2004.09.051
- ↑ Lee SC, Guo JY, Lim R, Soo R, Koay E, Salto-Tellez M, Leong A, Goh BC. Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. Clin Genet. 2005 Aug;68(2):137-45. PMID:15996210 doi:10.1111/j.1399-0004.2005.00469.x
- ↑ Wehner M, Mangold E, Sengteller M, Friedrichs N, Aretz S, Friedl W, Propping P, Pagenstecher C. Hereditary nonpolyposis colorectal cancer: pitfalls in deletion screening in MSH2 and MLH1 genes. Eur J Hum Genet. 2005 Aug;13(8):983-6. PMID:15870828 doi:10.1038/sj.ejhg.5201421
- ↑ Otway R, Tetlow N, Hornby J, Doe WF, Kohonen-Coriah MR. Gene symbol: MSH2. Disease: Hereditary nonpolyposis colorectal cancer. Hum Genet. 2005 May;116(6):539. PMID:15991316
- ↑ Kurzawski G, Suchy J, Lener M, Klujszo-Grabowska E, Kladny J, Safranow K, Jakubowska K, Jakubowska A, Huzarski T, Byrski T, Debniak T, Cybulski C, Gronwald J, Oszurek O, Oszutowska D, Kowalska E, Gozdz S, Niepsuj S, Slomski R, Plawski A, Lacka-Wojciechowska A, Rozmiarek A, Fiszer-Maliszewska L, Bebenek M, Sorokin D, Sasiadek MM, Stembalska A, Grzebieniak Z, Kilar E, Stawicka M, Godlewski D, Richter P, Brozek I, Wysocka B, Limon J, Jawien A, Banaszkiewicz Z, Janiszewska H, Kowalczyk J, Czudowska D, Scott RJ, Lubinski J. Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study). Clin Genet. 2006 Jan;69(1):40-7. PMID:16451135 doi:CGE550
- ↑ Ollila S, Sarantaus L, Kariola R, Chan P, Hampel H, Holinski-Feder E, Macrae F, Kohonen-Corish M, Gerdes AM, Peltomaki P, Mangold E, de la Chapelle A, Greenblatt M, Nystrom M. Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. Gastroenterology. 2006 Nov;131(5):1408-17. Epub 2006 Aug 22. PMID:17101317 doi:10.1053/j.gastro.2006.08.044
- ↑ Leonardis D. Gene symbol: msh2. Disease: hereditary nonpolyposis colorectal cancer. Hum Genet. 2006 Jul;119(6):675. PMID:17128465
- ↑ Ramsoekh D, Wagner A, van Leerdam ME, Dinjens WN, Steyerberg EW, Halley DJ, Kuipers EJ, Dooijes D. A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut. 2008 Nov;57(11):1539-44. doi: 10.1136/gut.2008.156695. Epub 2008 Jul 14. PMID:18625694 doi:10.1136/gut.2008.156695
- ↑ Ollila S, Dermadi Bebek D, Jiricny J, Nystrom M. Mechanisms of pathogenicity in human MSH2 missense mutants. Hum Mutat. 2008 Nov;29(11):1355-63. PMID:18951462 doi:10.1002/humu.20893
- ↑ Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frebourg T, Tosi M. A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum Mutat. 2008 Dec;29(12):1412-24. PMID:18561205 doi:10.1002/humu.20796
- ↑ Belvederesi L, Bianchi F, Galizia E, Loretelli C, Bracci R, Catalani R, Amati M, Cellerino R. MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system. Hum Mutat. 2008 Nov;29(11):E296-309. PMID:18781619 doi:10.1002/humu.20875
- ↑ Lutzen A, de Wind N, Georgijevic D, Nielsen FC, Rasmussen LJ. Functional analysis of HNPCC-related missense mutations in MSH2. Mutat Res. 2008 Oct 14;645(1-2):44-55. doi: 10.1016/j.mrfmmm.2008.08.015. Epub, 2008 Sep 4. PMID:18822302 doi:10.1016/j.mrfmmm.2008.08.015
- ↑ 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
- ↑ Zahary MN, Kaur G, Abu Hassan MR, Singh H, Naik VR, Ankathil R. Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients. World J Gastroenterol. 2012 Feb 28;18(8):814-20. doi: 10.3748/wjg.v18.i8.814. PMID:22371642 doi:10.3748/wjg.v18.i8.814
- ↑ Kolodner RD, Hall NR, Lipford J, Kane MF, Rao MR, Morrison P, Wirth L, Finan PJ, Burn J, Chapman P. Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics. 1994 Dec;24(3):516-26. PMID:7713503
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Seifert M, Scherer SJ, Edelmann W, Bohm M, Meineke V, Lobrich M, Tilgen W, Reichrath J. The DNA-mismatch repair enzyme hMSH2 modulates UV-B-induced cell cycle arrest and apoptosis in melanoma cells. J Invest Dermatol. 2008 Jan;128(1):203-13. Epub 2007 Jul 5. PMID:17611581 doi:10.1038/sj.jid.5700941
- ↑ Gupta S, Gellert M, Yang W. Mechanism of mismatch recognition revealed by human MutSbeta bound to unpaired DNA loops. Nat Struct Mol Biol. 2011 Dec 18;19(1):72-8. doi: 10.1038/nsmb.2175. PMID:22179786 doi:10.1038/nsmb.2175
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