Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 20, Issue 4, Pages 461-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2511
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Funding
- Association pour la Recherche contre le Cancer [4995, 8006]
- Ministere de l'Education Nationale de la Recherche et de la Technologie (University Paris Sud)
- Fondation pour la Recherche Medicale
- European Commission Infrastructure Protein Production Platform (P-CUBE) project [227764]
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Mismatch-repair factors have a prominent role in surveying eukaryotic DNA-replication fidelity and in ensuring correct meiotic recombination. These functions depend on MutL-homolog heterodimers with Mlh1. In humans, MLH1 mutations underlie half of hereditary nonpolyposis colorectal cancers (HNPCCs). Here we report crystal structures of the MutL alpha (Mlh1-Pms1 heterodimer) C-terminal domain (CTD) from Saccharomyces cerevisiae, alone and in complex with fragments derived from Mlh1 partners. These structures reveal structural rearrangements and additional domains in MutL alpha as compared to the bacterial MutL counterparts and show that the strictly conserved C terminus of Mlh1 forms part of the Pms1 endonuclease site. The structures of the ternary complexes between MutL alpha(CTD) and Exo1 or Ntg2 fragments reveal the binding mode of the MIP-box motif shared by several Mlh1 partners. Finally, the structures provide a rationale for the deleterious impact of MLH1 mutations in HNPCCs.
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