Catch-bond mechanism of the bacterial adhesin FimH.
Catch-bond mechanism of the bacterial adhesin FimH.
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DOI：
10.1038/ncomms10738
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发表时间：
2016-03-07
影响因子：
16.6
通讯作者：
Glockshuber R
中科院分区：
文献类型：
--
作者：
Sauer MM;Jakob RP;Eras J;Baday S;Eriş D;Navarra G;Bernèche S;Ernst B;Maier T;Glockshuber R
机械应力增强的配体-受体相互作用，即所谓的捕获键，在细胞与细胞粘附中发挥着重要作用。它们对致病性大肠杆菌菌株引起的广泛尿路感染起着至关重要的作用。这些病原体通过粘附素 FimH 附着在宿主上皮细胞上，粘附素 FimH 是一种位于 I 型菌毛尖端的双结构域蛋白，可识别上皮糖蛋白上的末端甘露糖。在这里，我们建立了肽互补的 FimH 作为菌毛 FimH 功能的模型系统。我们基于所有状态的晶体结构、配体相互作用的动力学分析和分子动力学模拟，揭示了FimH捕获键形成的三态机制。在没有张力的情况下，FimH 菌毛蛋白结构域变构地加速配体自发地从 FimH 凝集素结构域解离 100,000 倍，导致亲和力较弱。 FimH 结构域在压力下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 上的快速解离支持了毛状大肠杆菌在甘露糖化表面上的运动。 捕获键在细菌粘附和尿路致病性大肠杆菌感染中发挥作用。在这里，作者报告了晶体结构、分子动力学模拟、配体结合分析和细胞追踪，以表征粘附素 FimH 和碳水化合物受体之间的捕获键相互作用。
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. Catch bonds have a role in bacterial adhesion and infection by uropathogenic E. coli. Here, the authors report crystal structures, molecular dynamics simulations, ligand binding analysis and cell tracking to characterise the catch bond interaction between the adhesin FimH and carbohydrate receptors.