MutS, a DNA Mismatch Repair Protein of E. coli

David Marcey and Eric Stoffregen
© 2021

I. Introduction
II. MutS Structure
III. MutS-DNA Interactions
IV. References
Directions

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I. Introduction

The MutS protein of Escherichia coli, shown at left in a complex with a DNA substrate containing a G-T base mismatch, is a key component of the macromolecular assemblage responsible for repairing certain types of DNA mutations. MutS is responsible for recognizing and binding to base pair mismatches, and recruits other key proteins required for repair, MutH and MutL, to the mismatch site. See Figure 1 for a schematic of the process.

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II. MutS Structure

MutS is a large protein (~1600 amino acids) with numerous alpha helices and beta sheets.

Two MutS monomers combine to form the functional MutS homodimer.

Each MutS monomer comprises six domains:

  • the helix-turn-helix (HTH) domain is involved in dimer contacts;
  • the ATPase domain is responsible for the binding and hydrolysis of ATP;
  • the mismatch domain of the mismatch binding monomer binds to DNA containing the mismatched bases;
  • the core domain has two regions that from a helical bundle, with two additional alpha helices extending as levers toward the DNA;
  • the connector domain connects the mismatch domain to the core domain
  • the clamp domain is involved in DNA binding.

The DNA double helix is clasped by the dimer between the clamp domains and the mismatch domains .

 

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III. MutS-DNA Interactions

Although the two MutS monomers are identical, they differ in their orientations relative to bound DNA. The mismatch- recognition monomer makes specific contacts to bases in the region of the mismatch DNA (see below), whereas the non-mismatch-binding monomer makes only nonspecific contacts with the DNA backbone.

Initial DNA recognition is the responsibility of the clamp domains of each monomer. These have limited, sequence-independent contacts with the DNA backbone. The clamp domain of the non-mismatch binding monomer spans the major groove of the DNA, which is unusually deep due to the kink in the DNA caused by the base mismatch (see below). The clamp domain of the mismatch-binding monomer contacts the backbone on either side of the DNA minor groove.

The clamp domains present a positively charged surface to the DNA backbone, allowing protein-phosphate electrostatic bonding (please allow time for surface view to load).

The mismatch-binding domain of the mismatch-recognition monomer contacts the minor groove of the DNA.

Three specific interactions between residues of the mismatch-binding domain and the DNA allow the recognition of the G - T base mismatch:

  • glu38 forms hydrogen bonds to the thymine of the base mismatch and to a neighboring guanine adjacent to the guanine of the mismatch;
  • asp35 forms a hydrogen bond with the guanine of the mismatch;
  • phe36 stacks with the thymine of the mismatch.

Please repeat the illustration of these interactions, noting that the minor groove of the DNA is widened by the kink caused by the base mismatch. This permits the negatively charged sidechains of glu38 and asp35 to contact bases in the minor groove without electrostatic repulsion by the negatively charged DNA backbone.

 

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IV. References

Lamers, M. H., Perrakis, A., Enzlin, J. H., Winterwerp, H. H., De Wind, N., Sixma, T. K.: The Crystal Structure of DNA Mismatch Repair Protein Muts Binding to a G x T Mismatch. Nature 407: 711-717 (2000).

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