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The crystal structure of DNA mismatch repair protein MutS binding to a G·T mismatch

Nature volume 407, pages 711–717 (2000)Cite this article

Abstract

DNA mismatch repair ensures genomic integrity on DNA replication. Recognition of a DNA mismatch by a dimeric MutS protein initiates a cascade of reactions and results in repair of the newly synthesized strand; however, details of the molecular mechanism remain controversial. Here we present the crystal structure at 2.2 Å of MutS from Escherichia coli bound to a G·T mismatch. The two MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual base pairing and kinking of the DNA. Nonspecific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. The interleaved nucleotide-binding sites are located far from the DNA. Mutations in human MutSα (MSH2/MSH6) that lead to hereditary predisposition for cancer, such as hereditary non-polyposis colorectal cancer, can be mapped to this crystal structure.

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Figure 1: Overview of the MutS–DNA complex.
Figure 2: Mismatch-binding monomer coloured by domain.
Figure 3: Interaction of MutS with mismatched DNA.
Figure 4: ATPase domain of MutS.

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Acknowledgements

We thank M. Marinus for MutS plasmid pMQ372 and purification protocols; P. Modrich for strain RK1517; S. Cusack and H. te Riele for support and enthusiasm; J. Tainer for useful suggestions; G. Sheldrick for discussions on twinning; C. Vonrhein for assistance with SHARP; K. Culligan and J. Hays for use of their alignment; and staff at the ESRF and EMBL outstations Hamburg and Grenoble, in particular G. Leonard, for support in data collection. This work was supported by the Dutch Cancer Society and an EMBO post-doctoral fellowship to A.P., and by European Union TMR/LSF grants for data collection visits.

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Author notes

  1. Jacqueline H. Enzlin

    Present address: Institute for Medical Radiobiology, University of Zürich, Zürich, Switzerland

  2. Niels de Wind

    Present address: Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, Leiden, The Netherlands

  3. Meindert H. Lamers and Anastassis Perrakis: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Molecular Carcinogenesis Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Meindert H. Lamers, Jacqueline H. Enzlin, Herrie H. K. Winterwerp, Niels de Wind & Titia K. Sixma

  2. European Molecular Biology Laboratory (EMBL), c/o ILL, BP 156, 6 rue Jules Horowitz, Grenoble, 38043, France

    Anastassis Perrakis

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Correspondence to Titia K. Sixma.

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Lamers, M., Perrakis, A., Enzlin, J. et al. The crystal structure of DNA mismatch repair protein MutS binding to a G·T mismatch. Nature 407, 711–717 (2000). https://doi.org/10.1038/35037523

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