title: MutS/MutL crystal structure reveals that the MutS sliding clamp loads MutL onto DNA.
abstract: To avoid mutations in the genome, DNA replication is generally followed by DNA mismatch repair (MMR). MMR starts when a MutS homolog recognizes a mismatch and undergoes an ATP-dependent transformation to an elusive sliding clamp state. How this transient state promotes MutL homolog recruitment and activation of repair is unclear. Here we present a crystal structure of the MutS/MutL complex using a site-specifically crosslinked complex and examine how large conformational changes lead to activation of MutL. The structure captures MutS in the sliding clamp conformation, where tilting of the MutS subunits across each other pushes DNA into a new channel, and reorientation of the connector domain creates an interface for MutL with both MutS subunits. Our work explains how the sliding clamp promotes loading of MutL onto DNA, to activate downstream effectors. We thus elucidate a crucial mechanism that ensures that MMR is initiated only after detection of a DNA mismatch.
authors.affiliation: Division of Biochemistry and CGC.nl, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Flora S
authors.initials: FS
authors.lastname: Groothuizen
authors.affiliation: Institute for Biochemistry, Justus-Liebig-University, Giessen, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Winkler
authors.affiliation: Institute for Biochemistry, Justus-Liebig-University, Giessen, Germany.
authors.forename: Michele
authors.initials: M
authors.lastname: Cristóvão
authors.affiliation: Division of Biochemistry and CGC.nl, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fish
authors.affiliation: Division of Biochemistry and CGC.nl, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Herrie H K
authors.initials: HH
authors.lastname: Winterwerp
authors.affiliation: Division of Biochemistry and CGC.nl, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Annet
authors.initials: A
authors.lastname: Reumer
authors.affiliation: Institute for Biochemistry, Justus-Liebig-University, Giessen, Germany.
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Marx
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Nicolaas
authors.initials: N
authors.lastname: Hermans
authors.affiliation: Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Nicholls
authors.affiliation: Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
authors.forename: Garib N
authors.initials: GN
authors.lastname: Murshudov
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Joyce H G
authors.initials: JH
authors.lastname: Lebbink
authors.affiliation: Institute for Biochemistry, Justus-Liebig-University, Giessen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Friedhoff
authors.affiliation: Division of Biochemistry and CGC.nl, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D029968:Escherichia coli Proteins; C074770:MutL protein, E coli; D004247:DNA; D000251:Adenosine Triphosphatases; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli
keywords: DNA mismatch repair; E. coli; Lynch syndrome; biophysics; chromosomes; genes; human; structural biology