Abstract
We have refined a series of isomorphous crystal structures of the Escherichia coli DNA mismatch repair enzyme MutS in complex with G:T, A:A, C:A and G:G mismatches and also with a single unpaired thymidine. In all these structures, the DNA is kinked by approximately 60 degrees upon protein binding. Two residues widely conserved in the MutS family are involved in mismatch recognition. The phenylalanine, Phe 36, is seen stacking on one of the mismatched bases. The same base is also seen forming a hydrogen bond to the glutamate Glu 38. This hydrogen bond involves the N7 if the base stacking on Phe 36 is a purine and the N3 if it is a pyrimidine (thymine). Thus, MutS uses a common binding mode to recognize a wide range of mismatches.
Highlights
Genomic integrity in organisms is maintained by a number of important DNA repair pathways
We have shown that MutS binds to A:A, C:A and G:G mismatches by stacking Phe 36 over the purine and either keeping it or bringing it into the syn orientation to expose the N7 to Glu 38 for hydrogen bonding
In the G:T and unpaired T, MutS binds in such a way that the N3 of the thymidine forms this hydrogen bond
Summary
Genomic integrity in organisms is maintained by a number of important DNA repair pathways. The DNA mismatch repair (MMR) pathway repairs mismatches and short insertion or deletion loops (IDLs). In E.coli, MMR is initiated when the enzyme MutS recognizes and binds to mismatches or IDLs. In E.coli, MMR is initiated when the enzyme MutS recognizes and binds to mismatches or IDLs This is followed by the uptake of ATP by MutS and the formation of a complex between MutS and the enzyme MutL. This complex initiates a number of events, leading to the recognition of the daughter strand, followed by its removal and resynthesis. The role of MutS is played by its homologs, the heterodimers MSH2/MSH6, which binds mismatches and IDLs, and MSH2/ MSH3, which binds longer loops [1,2]. Mutations in the genes that encode MMR proteins lead to mutator phenotypes in bacteria and cause a predisposition to cancer, called hereditary non-polyposis colorectal carcinomas (HNPCC) in humans [4]
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