Stahlhut Steen G, Tchesnokova Veronika, Struve Carsten, Weissman Scott J, Chattopadhyay Sujay, Yakovenko Olga, Aprikian Pavel, Sokurenko Evgeni V, Krogfelt Karen Angeliki
Department of Bacteriology, Mycology and Parasitology, Statens Serum Institut, 2300 Copenhagen S, Denmark.
J Bacteriol. 2009 Nov;191(21):6592-601. doi: 10.1128/JB.00786-09. Epub 2009 Sep 4.
FimH, the adhesive subunit of type 1 fimbriae expressed by many enterobacteria, mediates mannose-sensitive binding to target host cells. At the same time, fine receptor-structural specificities of FimH from different species can be substantially different, affecting bacterial tissue tropism and, as a result, the role of the particular fimbriae in pathogenesis. In this study, we compared functional properties of the FimH proteins from Escherichia coli and Klebsiella pneumoniae, which are both 279 amino acids in length but differ by some approximately 15% of residues. We show that K. pneumoniae FimH is unable to mediate adhesion in a monomannose-specific manner via terminally exposed Manalpha(1-2) residues in N-linked oligosaccharides, which are the structural basis of the tropism of E. coli FimH for uroepithelial cells. However, K. pneumoniae FimH can bind to the terminally exposed Manalpha(1-3)Manbeta(1-4)GlcNAcbeta1 trisaccharide, though only in a shear-dependent manner, wherein the binding is marginal at low shear force but enhanced sevenfold under increased shear. A single mutation in the K. pneumoniae FimH, S62A, converts the mode of binding from shear dependent to shear independent. This mutation has occurred naturally in the course of endemic circulation of a nosocomial uropathogenic clone and is identical to a pathogenicity-adaptive mutation found in highly virulent uropathogenic strains of E. coli, in which it also eliminates the dependence of E. coli binding on shear. The shear-dependent binding properties of the K. pneumoniae and E. coli FimH proteins are mediated via an allosteric catch bond mechanism. Thus, despite differences in FimH structure and fine receptor specificity, the shear-dependent nature of FimH-mediated adhesion is highly conserved between bacterial species, supporting its remarkable physiological significance.
FimH是许多肠道杆菌表达的1型菌毛的黏附亚基，介导对靶宿主细胞的甘露糖敏感结合。同时，来自不同物种的FimH的精细受体结构特异性可能存在显著差异，影响细菌的组织嗜性，进而影响特定菌毛在发病机制中的作用。在本研究中，我们比较了大肠杆菌和肺炎克雷伯菌的FimH蛋白的功能特性，它们长度均为279个氨基酸，但约15%的残基有所不同。我们发现，肺炎克雷伯菌FimH无法通过N - 连接寡糖中末端暴露的Manα(1 - 2)残基以单甘露糖特异性方式介导黏附，而这些残基是大肠杆菌FimH对尿道上皮细胞嗜性的结构基础。然而，肺炎克雷伯菌FimH可以结合末端暴露的Manα(1 - 3)Manβ(1 - 4)GlcNAcβ1三糖，但仅以剪切力依赖的方式结合，即在低剪切力下结合微弱，但在增加剪切力时增强7倍。肺炎克雷伯菌FimH中的单个突变S62A将结合模式从剪切力依赖转变为剪切力不依赖。这种突变在医院内致病性克隆的地方性传播过程中自然发生，并且与在高毒力的大肠杆菌致病性菌株中发现的致病性适应性突变相同，在大肠杆菌中该突变也消除了其结合对剪切力的依赖性。肺炎克雷伯菌和大肠杆菌FimH蛋白的剪切力依赖结合特性是通过变构捕获键机制介导的。因此，尽管FimH结构和精细受体特异性存在差异，但FimH介导的黏附的剪切力依赖性质在细菌物种之间高度保守，支持了其显著的生理意义。
