7m60

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Structure of Mouse Importin alpha MLH1-S467A NLS Peptide Complex

Structural highlights

7m60 is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MLH1_HUMAN Muir-Torre syndrome;Hereditary nonpolyposis colon cancer. Defects in MLH1 are the cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2) [MIM:609310. 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, and accounts for 15% of all colon cancers. 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.[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] [52] [53] [54] [55] [56] [57] [58] Defects in MLH1 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.[59] [60] [61] Defects in MLH1 are a cause of Muir-Torre syndrome (MRTES) [MIM:158320. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.[62] Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.[63] Defects in MLH1 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089. Note=Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.

Function

MLH1_HUMAN Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.[64] [65]

Publication Abstract from PubMed

The classical nuclear import pathway is mediated by importin (Impalpha and Impbeta), which recognizes the cargo protein by its nuclear localization sequence (NLS). NLSs have been extensively studied resulting in different proposed consensus; however, recent studies showed that exceptions may occur. This mechanism may be also dependent on specific characteristics of different Impalpha. Aiming to better understand the importance of specific residues from consensus and adjacent regions of NLSs, we studied different mutations of a high-affinity NLS complexed to Impalpha by crystallography and calorimetry. We showed that although the consensus sequence allows Lys or Arg residues at the second residue of a monopartite sequence, the presence of Arg is very important to its binding in major and minor sites of Impalpha. Mutations in the N or C-terminus (position P1 or P6) of the NLS drastically reduces their affinity to the receptor, which is corroborated by the loss of hydrogen bonds and hydrophobic interactions. Surprisingly, a mutation in the far N-terminus of the NLS led to an increase in the affinity for both binding sites, corroborated by the structure with an additional hydrogen bond. The binding of NLSs to the human variant Impalpha1 revealed that these are similar to those found in structures presented here. For human variant Impalpha3, the bindings are only relevant for the major site. This study increases understanding of specific issues sparsely addressed in previous studies that are important to the task of predicting NLSs, which will be relevant in the eventual design of synthetic NLSs.

Structural and calorimetric studies reveal specific determinants for the binding of a high-affinity NLS to mammalian importin-alpha.,de Oliveira HC, da Silva TD, Salvador GHM, Moraes IR, Fukuda CA, de Barros AC, Fontes MRM Biochem J. 2021 Jul 16;478(13):2715-2732. doi: 10.1042/BCJ20210401. PMID:34195786[66]

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

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See Also

References

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  55. ↑ 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
  56. ↑ Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner RD, Ishioka C. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007 May 15;67(10):4595-604. PMID:17510385 doi:67/10/4595
  57. ↑ Hitchins MP, Wong JJ, Suthers G, Suter CM, Martin DI, Hawkins NJ, Ward RL. Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med. 2007 Feb 15;356(7):697-705. PMID:17301300 doi:10.1056/NEJMoa064522
  58. ↑ 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
  59. ↑ Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R. The interaction of DNA mismatch repair proteins with human exonuclease I. J Biol Chem. 2001 Aug 31;276(35):33011-8. Epub 2001 Jun 26. PMID:11427529 doi:10.1074/jbc.M102670200
  60. ↑ 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
  61. ↑ Poley JW, Wagner A, Hoogmans MM, Menko FH, Tops C, Kros JM, Reddingius RE, Meijers-Heijboer H, Kuipers EJ, Dinjens WN. Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Cancer. 2007 Jun 1;109(11):2349-56. PMID:17440981 doi:10.1002/cncr.22697
  62. ↑ Bapat B, Xia L, Madlensky L, Mitri A, Tonin P, Narod SA, Gallinger S. The genetic basis of Muir-Torre syndrome includes the hMLH1 locus. Am J Hum Genet. 1996 Sep;59(3):736-9. PMID:8751876
  63. ↑ Stone JG, Coleman G, Gusterson B, Marossy A, Lakhani SR, Ward A, Nash A, McKinna A, A'Hern R, Stratton MR, Houlston RS. Contribution of germline MLH1 and MSH2 mutations to lobular carcinoma in situ of the breast. Cancer Lett. 2001 Jun 26;167(2):171-4. PMID:11369138
  64. ↑ Kadyrov FA, Dzantiev L, Constantin N, Modrich P. Endonucleolytic function of MutLalpha in human mismatch repair. Cell. 2006 Jul 28;126(2):297-308. PMID:16873062 doi:S0092-8674(06)00812-9
  65. ↑ Sacho EJ, Kadyrov FA, Modrich P, Kunkel TA, Erie DA. Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha. Mol Cell. 2008 Jan 18;29(1):112-21. PMID:18206974 doi:S1097-2765(07)00817-9
  66. ↑ de Oliveira HC, da Silva TD, Salvador GHM, Moraes IR, Fukuda CA, de Barros AC, Fontes MRM. Structural and calorimetric studies reveal specific determinants for the binding of a high-affinity NLS to mammalian importin-alpha. Biochem J. 2021 Jul 16;478(13):2715-2732. PMID:34195786 doi:10.1042/BCJ20210401

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PDB ID 7m60

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