title: Catch-bond mechanism of the bacterial adhesin FimH.
abstract: Ligand-receptor interactions that are reinforced by mechanical stress, so-called catch-bonds, play a major role in cell-cell adhesion. They critically contribute to widespread urinary tract infections by pathogenic Escherichia coli strains. These pathogens attach to host epithelia via the adhesin FimH, a two-domain protein at the tip of type I pili recognizing terminal mannoses on epithelial glycoproteins. Here we establish peptide-complemented FimH as a model system for fimbrial FimH function. We reveal a three-state mechanism of FimH catch-bond formation based on crystal structures of all states, kinetic analysis of ligand interaction and molecular dynamics simulations. In the absence of tensile force, the FimH pilin domain allosterically accelerates spontaneous ligand dissociation from the FimH lectin domain by 100,000-fold, resulting in weak affinity. Separation of the FimH domains under stress abolishes allosteric interplay and increases the affinity of the lectin domain. Cell tracking demonstrates that rapid ligand dissociation from FimH supports motility of piliated E. coli on mannosylated surfaces in the absence of shear force.
authors.affiliation: Institute of Molecular Biology and Biophysics, Department of Biology, ETH, Zurich, Otto-Stern-Weg 5, 8093 Zurich, Switzerland.
authors.forename: Maximilian M
authors.initials: MM
authors.lastname: Sauer
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Roman P
authors.initials: RP
authors.lastname: Jakob
authors.affiliation: Institute of Molecular Biology and Biophysics, Department of Biology, ETH, Zurich, Otto-Stern-Weg 5, 8093 Zurich, Switzerland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Eras
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.|SIB Swiss Institute of Bioinformatics, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Sefer
authors.initials: S
authors.lastname: Baday
authors.affiliation: Institute of Molecular Pharmacy, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Deniz
authors.initials: D
authors.lastname: Eriş
authors.affiliation: Institute of Molecular Pharmacy, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Giulio
authors.initials: G
authors.lastname: Navarra
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.|SIB Swiss Institute of Bioinformatics, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Bernèche
authors.affiliation: Institute of Molecular Pharmacy, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Maier
authors.affiliation: Institute of Molecular Biology and Biophysics, Department of Biology, ETH, Zurich, Otto-Stern-Weg 5, 8093 Zurich, Switzerland.
authors.forename: Rudi
authors.initials: R
authors.lastname: Glockshuber
mesh_terms: D018830:Adhesins, Escherichia coli / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001422:Bacterial Adhesion; D001696:Biomechanical Phenomena; D004926:Escherichia coli / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology*; D036781:Fimbriae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010861:Fimbriae, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008358:Mannose / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D018830:Adhesins, Escherichia coli; D008024:Ligands; C058769:fimH protein, E coli; D036781:Fimbriae Proteins; D008358:Mannose