title: Structure of the MutLα C-terminal domain reveals how Mlh1 contributes to Pms1 endonuclease site.
abstract: 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 MutLα (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 MutLα 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 MutLα(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.
authors: Unité Mixte de Recherche 8221, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Institut de Biologie et Technologies de Saclay, Gif-sur-Yvette, France.
authors: Emeric
authors: E
authors: Gueneau
authors: Claudine
authors: C
authors: Dherin
authors: Pierre
authors: P
authors: Legrand
authors: Carine
authors: C
authors: Tellier-Lebegue
authors: Bernard
authors: B
authors: Gilquin
authors: Pierre
authors: P
authors: Bonnesoeur
authors: Floriana
authors: F
authors: Londino
authors: Cathy
authors: C
authors: Quemener
authors: Marie-Hélene
authors: MH
authors: Le Du
authors: Josan A
authors: JA
authors: Márquez
authors: Mireille
authors: M
authors: Moutiez
authors: Muriel
authors: M
authors: Gondry
authors: Serge
authors: S
authors: Boiteux
authors: Jean-Baptiste
authors: JB
authors: Charbonnier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000378:metabolism; D004720:Endonucleases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; C500929:MutLalpha protein, human; D009687:Nuclear Proteins; D004720:Endonucleases; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D045643:DNA Repair Enzymes