Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome
Abstract
Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in theMLH1gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. Lastly, the structure shares a high degree of similarity with previously determined prokaryoticMLH1homologs; however, this structure affords a more accurate platform for the classification ofMLH1variants.
- Authors:
-
- Univ. of Toronto, ON (Canada)
- Myriad Genetic Laboratories Inc., Salt Lake City, UT (United States)
- Univ. of Toronto, ON (Canada). Dept. of Physiology
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1208676
- Grant/Contract Number:
- AC02- 06CH1135
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Acta Crystallographica. Section F, Structural Biology Communications
- Additional Journal Information:
- Journal Volume: 71; Journal Issue: 8; Journal ID: ISSN 2053-230X
- Publisher:
- International Union of Crystallography
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY
Citation Formats
Wu, Hong, Zeng, Hong, Lam, Robert, Tempel, Wolfram, Kerr, Iain D., and Min, Jinrong. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. United States: N. p., 2015.
Web. doi:10.1107/S2053230X15010183.
Wu, Hong, Zeng, Hong, Lam, Robert, Tempel, Wolfram, Kerr, Iain D., & Min, Jinrong. Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. United States. https://doi.org/10.1107/S2053230X15010183
Wu, Hong, Zeng, Hong, Lam, Robert, Tempel, Wolfram, Kerr, Iain D., and Min, Jinrong. Sat .
"Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome". United States. https://doi.org/10.1107/S2053230X15010183. https://www.osti.gov/servlets/purl/1208676.
@article{osti_1208676,
title = {Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome},
author = {Wu, Hong and Zeng, Hong and Lam, Robert and Tempel, Wolfram and Kerr, Iain D. and Min, Jinrong},
abstractNote = {Mismatch repair prevents the accumulation of erroneous insertions/deletions and non-Watson–Crick base pairs in the genome. Pathogenic mutations in theMLH1gene are associated with a predisposition to Lynch and Turcot's syndromes. Although genetic testing for these mutations is available, robust classification of variants requires strong clinical and functional support. Here, the first structure of the N-terminus of human MLH1, determined by X-ray crystallography, is described. Lastly, the structure shares a high degree of similarity with previously determined prokaryoticMLH1homologs; however, this structure affords a more accurate platform for the classification ofMLH1variants.},
doi = {10.1107/S2053230X15010183},
journal = {Acta Crystallographica. Section F, Structural Biology Communications},
number = 8,
volume = 71,
place = {United States},
year = {Sat Aug 01 00:00:00 EDT 2015},
month = {Sat Aug 01 00:00:00 EDT 2015}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 15 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Incidence of Hereditary Nonpolyposis Colorectal Cancer and the Feasibility of Molecular Screening for the Disease
journal, May 1998
- Aaltonen, Lauri A.; Salovaara, Reijo; Kristo, Paula
- New England Journal of Medicine, Vol. 338, Issue 21
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
phenix.model_vs_data : a high-level tool for the calculation of crystallographic model and data statistics
journal, May 2010
- Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Chen, Vincent B.
- Journal of Applied Crystallography, Vol. 43, Issue 4
Transformation of MutL by ATP Binding and Hydrolysis
journal, April 1999
- Ban, Changill; Junop, Murray; Yang, Wei
- Cell, Vol. 97, Issue 1
Crystal Structure and ATPase Activity of MutL
journal, November 1998
- Ban, Changill; Yang, Wei
- Cell, Vol. 95, Issue 4
An atypical topoisomerase II from archaea with implications for meiotic recombination
journal, March 1997
- Bergerat, Agnès; de Massy, Bernard; Gadelle, Danielle
- Nature, Vol. 386, Issue 6623
Refinement of severely incomplete structures with maximum likelihood in BUSTER–TNT
journal, November 2004
- Blanc, E.; Roversi, P.; Vonrhein, C.
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer
journal, March 1994
- Bronner, C. Eric; Baker, Sean M.; Morrison, Paul T.
- Nature, Vol. 368, Issue 6468
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187
journal, September 2003
- Classen, S.; Olland, S.; Berger, J. M.
- Proceedings of the National Academy of Sciences, Vol. 100, Issue 19
Alpha helical crossovers favor right-handed supersecondary structures by kinetic trapping: The phone cord effect in protein folding
journal, August 2009
- Cole, Benjamin J.; Bystroff, Christopher
- Protein Science, Vol. 18, Issue 8
Structure of the topoisomerase VI-B subunit: implications for type II topoisomerase mechanism and evolution
journal, January 2003
- Corbett, K. D.
- The EMBO Journal, Vol. 22, Issue 1
Structural Dissection of ATP Turnover in the Prototypical GHL ATPase TopoVI
journal, June 2005
- Corbett, Kevin D.; Berger, James M.
- Structure, Vol. 13, Issue 6
GHKL, an emergent ATPase/kinase superfamily
journal, January 2000
- Dutta, R.; Inouye, M.
- Trends in Biochemical Sciences, Vol. 25, Issue 1
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
How good are my data and what is the resolution?
journal, June 2013
- Evans, Philip R.; Murshudov, Garib N.
- Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7
The Interaction of the Human MutL Homologues in Hereditary Nonpolyposis Colon Cancer
journal, March 1999
- Guerrette, Shawn; Acharya, Samir; Fishel, Richard
- Journal of Biological Chemistry, Vol. 274, Issue 10
Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer
journal, December 2008
- Hampel, Heather; Frankel, Wendy L.; Martin, Edward
- Journal of Clinical Oncology, Vol. 26, Issue 35
Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
journal, May 2005
- Hampel, Heather; Frankel, Wendy L.; Martin, Edward
- New England Journal of Medicine, Vol. 352, Issue 18
Evidence for a direct association of hMRE11 with the human mismatch repair protein hMLH1
journal, September 2002
- Her, C.
- DNA Repair, Vol. 1, Issue 9
The α-helix dipole and the properties of proteins
journal, June 1978
- Hol, W. G. J.; van Duijnen, P. T.; Berendsen, H. J. C.
- Nature, Vol. 273, Issue 5662
Dali server: conservation mapping in 3D
journal, May 2010
- Holm, Liisa; Rosenstr�m, P�ivi
- Nucleic Acids Research, Vol. 38, Issue suppl_2
A New Scoring Function and Associated Statistical Significance for Structure Alignment by CE
journal, October 2004
- Jia, Yuting; Gregory Dewey, T.; Shindyalov, Ilya N.
- Journal of Computational Biology, Vol. 11, Issue 5
Conservation of functional asymmetry in the mammalian MutLα ATPase
journal, November 2010
- Johnson, Jennifer R.; Erdeniz, Naz; Nguyen, Megan
- DNA Repair, Vol. 9, Issue 11
NCBI BLAST: a better web interface
journal, May 2008
- Johnson, M.; Zaretskaya, I.; Raytselis, Y.
- Nucleic Acids Research, Vol. 36, Issue Web Server
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Endonucleolytic Function of MutLα in Human Mismatch Repair
journal, July 2006
- Kadyrov, Farid A.; Dzantiev, Leonid; Constantin, Nicoleta
- Cell, Vol. 126, Issue 2
Saccharomyces cerevisiae MutLα Is a Mismatch Repair Endonuclease
journal, October 2007
- Kadyrov, Farid A.; Holmes, Shannon F.; Arana, Mercedes E.
- Journal of Biological Chemistry, Vol. 282, Issue 51
Inference of Macromolecular Assemblies from Crystalline State
journal, September 2007
- Krissinel, Evgeny; Henrick, Kim
- Journal of Molecular Biology, Vol. 372, Issue 3
The origins and early evolution of DNA mismatch repair genes—multiple horizontal gene transfers and co-evolution
journal, October 2007
- Lin, Zhenguo; Nei, Masatoshi; Ma, Hong
- Nucleic Acids Research, Vol. 35, Issue 22
Interactions of Human Mismatch Repair Proteins MutSα and MutLα with Proteins of the ATR-Chk1 Pathway
journal, December 2009
- Liu, Yiyong; Fang, Yanan; Shao, Hongbing
- Journal of Biological Chemistry, Vol. 285, Issue 8
Hereditary Colorectal Cancer
journal, March 2003
- Lynch, Henry T.; de la Chapelle, Albert
- New England Journal of Medicine, Vol. 348, Issue 10
The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome
journal, April 2013
- Martín-López, Juana V.; Fishel, Richard
- Familial Cancer, Vol. 12, Issue 2
Novel genomic insertion-deletion in MLH1: possible mechanistic role for non-homologous end-joining DNA repair: Novel genomic insertion-deletion in MLH1
journal, July 2005
- McVety, S.; Younan, R.; Li, L.
- Clinical Genetics, Vol. 68, Issue 3
HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes
journal, July 2006
- Minor, Wladek; Cymborowski, Marcin; Otwinowski, Zbyszek
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 8
REFMAC 5 for the refinement of macromolecular crystal structures
journal, March 2011
- Murshudov, Garib N.; Skubák, Pavol; Lebedev, Andrey A.
- Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
Positionally cloned human disease genes: Patterns of evolutionary conservation and functional motifs
journal, May 1997
- Mushegian, A. R.; Bassett, D. E.; Boguski, M. S.
- Proceedings of the National Academy of Sciences, Vol. 94, Issue 11
The Transducer Domain Is Important for Clamp Operation in Human DNA Topoisomerase IIα
journal, October 2003
- Oestergaard, Vibe H.; Bjergbaek, Lotte; Skouboe, Camilla
- Journal of Biological Chemistry, Vol. 279, Issue 3
Mutation of a mutL homolog in hereditary colon cancer
journal, March 1994
- Papadopoulos, N.; Nicolaides, N.; Wei, Y.
- Science, Vol. 263, Issue 5153
Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1
journal, November 2001
- Pedrazzi, G.
- Nucleic Acids Research, Vol. 29, Issue 21
N-terminus of hMLH1 confers interaction of hMutL and hMutL with hMutS
journal, June 2003
- Plotz, G.
- Nucleic Acids Research, Vol. 31, Issue 12
A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone
journal, June 1997
- Prodromou, Chrisostomos; Roe, S. Mark; Piper, Peter W.
- Nature Structural Biology, Vol. 4, Issue 6
Handedness of crossover connections in beta sheets.
journal, August 1976
- Richardson, J. S.
- Proceedings of the National Academy of Sciences, Vol. 73, Issue 8
Direct Visualization of Asymmetric Adenine Nucleotide-Induced Conformational Changes in MutLα
journal, January 2008
- Sacho, Elizabeth J.; Kadyrov, Farid A.; Modrich, Paul
- Molecular Cell, Vol. 29, Issue 1
The P-loop — a common motif in ATP- and GTP-binding proteins
journal, November 1990
- Saraste, Matti; Sibbald, Peter R.; Wittinghofer, Alfred
- Trends in Biochemical Sciences, Vol. 15, Issue 11
Identification and analysis of biomarkers for mismatch repair proteins: A bioinformatic approach
journal, January 2012
- Singh, TirathaRaj; Sehgal, Manika
- Journal of Natural Science, Biology and Medicine, Vol. 3, Issue 2
Protein structure alignment by incremental combinatorial extension (CE) of the optimal path
journal, September 1998
- Shindyalov, I. N.; Bourne, P. E.
- Protein Engineering Design and Selection, Vol. 11, Issue 9
Structure of the N-Terminal Gyrase B Fragment in Complex with ADP⋅Pi Reveals Rigid-Body Motion Induced by ATP Hydrolysis
journal, September 2014
- Stanger, Frédéric V.; Dehio, Christoph; Schirmer, Tilman
- PLoS ONE, Vol. 9, Issue 9
Structure of Pyruvate Dehydrogenase Kinase: NOVEL FOLDING PATTERN FOR A SERINE PROTEIN KINASE
journal, August 2001
- Steussy, C. Nicklaus; Popov, Kirill M.; Bowker-Kinley, Melissa M.
- Journal of Biological Chemistry, Vol. 276, Issue 40
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
journal, December 2013
- Thompson, Bryony A.; Spurdle, Amanda B.; Plazzer, John-Paul
- Nature Genetics, Vol. 46, Issue 2
Contribution of Human Mlh1 and Pms2 ATPase Activities to DNA Mismatch Repair
journal, March 2002
- Tomer, Guy; Buermeyer, Andrew B.; Nguyen, Megan M.
- Journal of Biological Chemistry, Vol. 277, Issue 24
Molecular replacement with MOLREP
journal, December 2009
- Vagin, Alexei; Teplyakov, Alexei
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Are buried salt bridges important for protein stability and conformational specificity?
journal, February 1995
- Waldburger, Carey D.; Schildbach, Joel F.; Sauer, Robert T.
- Nature Structural & Molecular Biology, Vol. 2, Issue 2
Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.
journal, August 1982
- Walker, J. E.; Saraste, M.; Runswick, M. J.
- The EMBO Journal, Vol. 1, Issue 8
Nucleotide-dependent Domain Movement in the ATPase Domain of a Human Type IIA DNA Topoisomerase
journal, August 2005
- Wei, Hua; Ruthenburg, Alexander J.; Bechis, Seth K.
- Journal of Biological Chemistry, Vol. 280, Issue 44
Interaction of pyrophosphate moieties with .alpha.-helixes in dinucleotide-binding proteins
journal, March 1985
- Wierenga, Rik K.; De Maeyer, Marc C. H.; Hol, Wim G. J.
- Biochemistry, Vol. 24, Issue 6
Crystal structure of an N-terminal fragment of the DNA gyrase B protein
journal, June 1991
- Wigley, Dale B.; Davies, Gideon J.; Dodson, Eleanor J.
- Nature, Vol. 351, Issue 6328
Direct measurement of salt-bridge solvation energies using a peptide model system: implications for protein stability.
journal, April 1996
- Wimley, W. C.; Gawrisch, K.; Creamer, T. P.
- Proceedings of the National Academy of Sciences, Vol. 93, Issue 7
Use of TLS parameters to model anisotropic displacements in macromolecular refinement
journal, January 2001
- Winn, M. D.; Isupov, M. N.; Murshudov, G. N.
- Acta Crystallographica Section D Biological Crystallography, Vol. 57, Issue 1
Automated and accurate deposition of structures solved by X-ray diffraction to the Protein Data Bank
journal, September 2004
- Yang, Huanwang; Guranovic, Vladimir; Dutta, Shuchismita
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 10
Works referencing / citing this record:
Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods
journal, May 2017
- Arora, Sanjeevani; Huwe, Peter J.; Sikder, Rahmat
- Cancer Biology & Therapy, Vol. 18, Issue 7
Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome
posted_content, October 2019
- Abildgaard, Amanda B.; Stein, Amelie; Nielsen, Sofie V.
- bioRxiv
Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome
journal, November 2019
- Abildgaard, Amanda B.; Stein, Amelie; Nielsen, Sofie V.
- eLife, Vol. 8