Catch-bond mechanism of the bacterial adhesin FimH.

Maximilian M Sauer,Deniz Eriş,Jonathan Eras,Timm Maier,Beat Ernst,Sefer Baday,Simon Bernèche,Giulio Navarra,Roman P Jakob,Rudi Glockshuber

doi:10.1038/ncomms10738

Maximilian M Sauer, Deniz Eriş + Show 8 more

Open Access

https://doi.org/10.1038/ncomms10738

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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.

Highlights

Ligand–receptor interactions that are reinforced by mechanical stress, so-called catch-bonds, play a major role in cell–cell adhesion
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 antigenpresenting cells[6,7]
Catch-bonds 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]

Summary

Results

FimHF18 Á DsG comprises the jellyroll fold FimHL and the immunoglobulin-like FimHP domain complemented with the FimG donor strand (Fig. 1b and Supplementary Fig. 1b) It closely resembles unliganded FimH in the fimbrial tip complex (Fig. 1c)[17], with a root-mean-square deviation of Ca positions (Ca r.m.s.d.) of 1.1 Å. All contacts in the FimHL–FimHP interdomain region (Supplementary Fig. 1c,d)[17] as well as the conformation of the empty ligand-binding pocket observed in FimH in the fimbrial tip are preserved in FimHF18 Á DsG. FimHL and FimHP other than the direct covalent linkage are detected, equivalent to a breakdown of the total 500 Å2 interdomain interface of the Abound state (Fig. 3) This molecule represents a third state, the domain-Separated, ligandbound state of FimH, Sbound. Despite the virtually identical conformations of the entire ligand-binding site depicted by X-ray crystallography (Fig. 2b), the clamp loop, which exhibits the most significant conformational changes between the open and closed

11 Å Model

60 Start End

Discussion

Methods