Sauer Maximilian M, Jakob Roman P, Eras Jonathan, Baday Sefer, Eriş Deniz, Navarra Giulio, Bernèche Simon, Ernst Beat, Maier Timm, Glockshuber Rudi
Institute of Molecular Biology and Biophysics, Department of Biology, ETH, Zurich, Otto-Stern-Weg 5, 8093 Zurich, Switzerland.
Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
Nat Commun. 2016 Mar 7;7:10738. doi: 10.1038/ncomms10738.
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.
由机械应力增强的配体-受体相互作用，即所谓的捕捉键，在细胞间黏附中起主要作用。它们对致病性大肠杆菌菌株引起的广泛尿路感染起着关键作用。这些病原体通过黏附素FimH附着于宿主上皮细胞，FimH是I型菌毛尖端的一种双结构域蛋白，可识别上皮糖蛋白上的末端甘露糖。在此，我们建立了肽互补FimH作为菌毛FimH功能研究的模型系统。基于所有状态的晶体结构、配体相互作用的动力学分析以及分子动力学模拟，我们揭示了FimH捕捉键形成的三态机制。在没有拉力的情况下，FimH菌毛蛋白结构域通过变构作用使配体从FimH凝集素结构域自发解离的速度加快100,000倍，导致亲和力较弱。在应力作用下FimH结构域的分离消除了变构相互作用，并增加了凝集素结构域的亲和力。细胞追踪表明，在没有剪切力的情况下，配体从FimH的快速解离有助于有菌毛的大肠杆菌在甘露糖基化表面上运动。
