Abstract

tThe MutL protein is best known for its function in DNA mismatch repair (MMR). However, there isevidence to suggest that MutL is not only the linker connecting the functions of MutS and MutH in MMR,but that it also participates in other repair systems, such as Very Short Patch (VSP), Base Excision (BER)and Nucleotide Excision Repair (NER). This study set out to identify the most highly conserved aminoacid sequence motifs in MutL proteins.We analyzed 208 MutL amino acid sequences of 199 representative prokaryotic species belonging to28 classes of bacteria and archaea. The analysis revealed 16 conserved motifs situated in the ATPaseand endonuclease domains, as well as within the disordered loop, and in the MutL regions interactingwith the clamp of DNA polymerase III. The conserved sequence motifs thus determined constitutea structural definition of MutL and they may be used in site-directed mutagenesis studies. We foundconserved residues within the potential regions where binding with MutS occurs. However, the existingdata does not provide clues as to the possible sites of MutL interactions with the proteins involved inother DNA repair systems such as NER, BER and VSP.We determined the 57 most highly conserved amino acid residues, including 43 which were identicalin all the sequences analyzed. The greater part of the most predominantly conserved amino acid residuesidentified in MutL are identical to the corresponding residues reported as mutational hot-spots in one ofits human homologues, MLH1, but not in the other, PMS2.This is the first study to present the conserved sequence motifs of MutL widespread in bacteria andarchaea and the classification of MutLs into five groups distinguished on the basis of differences in theC-terminal region. Our analysis is of use in better understanding MutL functions.

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