Notably, isolated FimH L was reported to show a ligand-binding affinity about two orders of magnitude higher than that of full-length FimH in the tip fibrillum 17, 25. This extended form of FimH L is characterized by a closed ligand-binding pocket and rearranged swing, linker and insertion loops. In contrast, an ‘extended’ FimH L conformation was observed in crystal structures of the isolated, ligand-bound FimH L domain 18, 19, 20, 21, 22, 23 and in the complex between FimH and the pilus assembly chaperone FimC, where FimC prevents the interactions between FimH L and FimH P (ref. A ‘compressed’ FimH L conformation was observed in the crystal structure of FimH in the context of the type 1 pilus tip fibrillum in the absence of ligands, with an open binding site and interactions to FimH P mediated via three loop segments: the swing (amino acids (aa.) 27–33), linker (aa. The two-domain architecture of FimH is a prerequisite for catch-bond formation because the interactions between FimH L and FimH P determine the conformational state and ligand-binding properties of FimH L (refs 12, 16, 17). FimH P possesses an incomplete immunoglobulin-like fold that is completed by insertion of an N-terminal donor strand of FimG, the subsequent subunit in pilus assembly 11. Owing to its important role in establishing infection, FimH is an attractive target for the development of anti-adhesive drugs for UTI treatment 14, 15.įimH is a two-domain protein, composed of an N-terminal, mannoside-binding lectin domain (FimH L) and a C-terminal pilin domain (FimH P). The adhesin FimH at the fimbrial tip specifically binds in a catch-bond mode 12 to terminal α- D-linked mannoses of N-linked glycans of the receptor uroplakin 1a on urinary epithelial cells 13. Type 1 pili are composed of up to 3,000 copies of the subunit FimA building the pilus rod, as well as the subunits FimF, FimG and FimH forming the distal tip fibrillum 11. A first critical step in the establishment of infection is bacterial adhesion to urothelial cells under flow conditions, which is mediated by 0.1−2 μm long, proteinaceous filaments on the bacterial surface termed type 1 pili 9, 10. Catch-bonds also play a major role in bacterial adhesion and infection by uropathogenic Escherichia coli strains, which are responsible for the vast majority of urinary tract infections (UTIs) in humans 8. Catch-bond interactions are prominent in vascular systems and are formed, for example, by selectins for leukocyte recruitment 1, 2, by cadherins controlling tissue integrity 3, 4 in the epithelial adhesion of cancer cells 5 and by the interactions between T-cell receptors (TCRs) and peptide-bound major histocompatibility complexes (MHC) on antigen-presenting cells 6, 7. In many cell–cell adhesion systems, the lifetime of adhesin–receptor complexes is increased under tensile mechanical force via ‘catch-bonds’, which permit capture or retention of cells under flow conditions while still allowing for release under reduced mechanical force. coli on mannosylated surfaces in the absence of shear force.Ĭell–cell adhesion often occurs under dynamically varying conditions and mechanical stress. Cell tracking demonstrates that rapid ligand dissociation from FimH supports motility of piliated E. Separation of the FimH domains under stress abolishes allosteric interplay and increases the affinity of the lectin domain. 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. 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. Here we establish peptide-complemented FimH as a model system for fimbrial FimH function. 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.
They critically contribute to widespread urinary tract infections by pathogenic Escherichia coli strains.
Ligand–receptor interactions that are reinforced by mechanical stress, so-called catch-bonds, play a major role in cell–cell adhesion.
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