Structure of the endonuclease domain of MutL: unlicensed to cut.
DNA mismatch repair corrects errors that have escaped polymerase proofreading, increasing replication fidelity 100- to 1000-fold in organisms ranging from bacteria to humans. The MutL protein plays a central role in mismatch repair by coordinating multiple protein-protein interactions that signal strand removal upon mismatch recognition by MutS. Here we report the crystal structure of the endonuclease domain of Bacillus subtilis MutL. The structure is organized in dimerization and regulatory subdomains connected by a helical lever spanning the conserved endonuclease motif. Additional conserved motifs cluster around the lever and define a Zn(2+)-binding site that is critical for MutL function in vivo. The structure unveils a powerful inhibitory mechanism to prevent undesired nicking of newly replicated DNA and allows us to propose a model describing how the interaction with MutS and the processivity clamp could license the endonuclease activity of MutL. The structure also provides a molecular framework to propose and test additional roles of MutL in mismatch repair.
Pillon
Monica C
MC
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Lorenowicz
Jessica J
JJ
Uckelmann
Michael
M
Klocko
Andrew D
AD
Mitchell
Ryan R
RR
Chung
Yu Seon
YS
Modrich
Paul
P
Walker
Graham C
GC
Simmons
Lyle A
LA
Friedhoff
Peter
P
Guarné
Alba
A
D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001412:Bacillus subtilis / Q000201:enzymology*; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D053843:DNA Mismatch Repair; D004720:Endonucleases / Q000737:chemistry; D004789:Enzyme Activation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000378:metabolism
D004720:Endonucleases; D000251:Adenosine Triphosphatases; D015032:Zinc