A model for the role of MutL in E. coli mismatch repair. In step 1, a mismatch is recognized by MutS, and a MutS·MutL complex forms a symmetrical loop that increases in size until reaching the nearest hemimethylated d(GATC) site (step 2). After nicking by MutH (not shown) and as UvrD (helicase II) unwinds toward the mismatch, the loop structure remains intact. UvrD initiates unwinding at the nick, and UvrD molecules are loaded by MutL. As UvrD unwinds the DNA, the MutS·MutL complex remains bound at the base of the loop structure (steps 2 and 3). Consistent with this notion, it was observed that when the complete mismatch repair reaction was included in electron microscopic imaging experiments, MutS and MutL remained bound to the nicked site, and the unwound strand was visualized. One of the newly generated single strands (the nicked or nascent strand) is inserted through a groove in the MutL structure (step 3). A groove has been suggested to function in single-stranded DNA binding by MutL, and double-stranded DNA will not fit within the groove. The strand that is being pushed through the groove of MutL is then hydrolyzed by the appropriate single-strand specific exonuclease. The intact single-stranded DNA serves as a template for DNA polymerase III (step 3). As the DNA is unwound and pushed through MutL, the loop decreases in size until UvrD reaches the mismatch, providing a possible mechanism for UvrD to "know" when to terminate unwinding. Once UvrD reaches the mismatch, the loop may have decreased to a size that creates torsional strain, forcing the protein·DNA complex to dissociate. Alternatively, a physical interaction between proteins could act as a signal for dissociation. In this model, MutL remains in a constant position with respect to the advancing ssDNA/double-stranded DNA junction and acts catalytically, continually loading UvrD molecules. MutL is likely to be the master coordinator in the mismatch repair reaction. The interaction of MutL with the three mismatch repair proteins (MutS, MutH, and UvrD) and with DNA is likely to be critical for the proper three-dimensional arrangement of these proteins as well as for the appropriate sequential timing for each event in the repair reaction. Precisely how MutL accomplishes these goals remains to be elucidated.
Proteins shown in step 2 are UvrD, MutL (L), and MutS (S). After unwinding has initiated and the excision step of mismatch repair is progressing (step 3), proteins shown are UvrD, MutL, MutS, DNA polymerase III (III), and the appropriate single-stranded exonuclease (Exo).
From: L. E. Mechanic, B. A. Frankel, and S. W. Matson (2000) Escherichia coli MutL Loads DNA Helicase II onto DNA, J. Biol. Chem. 275, 38337-38346.