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Research Highlights - MutS

  xtal - NKI - Research Highlights - Mismatch Repair MutS recognises and binds DNA mismatches (mispaired bases and short loops) and initiates the DNA mismatch repair cascade. DNA mismatch repair is of central importance for genome stability and mutations in the human MutS homolgs MSH2 and MSH6 predispose for cancer. To understand structural aspects of mismatch recognition, we have determined crystal structures of the E.coli MutS dimer bound to different DNA mismatches (Lamers et al, Nature 2000 & Natrajand et al, NAR 2003).

These structures reveal a common mode for mismatch recognition. We have also described structural details of the asymmetric nucleotide binding sites and their role in relaying conformational changes towards the DNA binding sites of MutS (Lamers, EMBO J. 2003 & Lamers et al., EMBO J 2004, Lamers et al.,JBC 2004).

More recently, we identified a hydrogen bond formed between one of the mismatched bases and a conserved glutamate residue in the mismatch binding domain of MutS as crucial in this intermolecular signaling. Formation of this hydrogen bond controls the ATPase activity in one of the asymmetric nucleotide binding sites of the MutS dimer and in this way correctly initiates the repair reaction (Lebbink et al., EMBO J. 2006)

 
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