Studies proposed in this competing renewal application are intended to dissect how tensile mechanical force increases ability of some of the most common bacterial adhesins to bind carbohydrate ligands, i.e. mediate catch-bond mechanism of receptor-ligand interaction. Our current Bioengineering Research Partnership grant project has demonstrated that the strength of mannose-specific, FimH-mediated adhesion of Escherichia coli is dramatically enhanced by the presence of shear stress. We have shown that FimH adhesin is an allosterically regulated protein, where induced-fit mechanism of interaction of the mannose ligand with the FimH binding pocket is conformationally linked with separation between mannose-binding and fimbria-incorporating domains of FimH - the configuration favored by tensile mechanical force. In the renewal application, we propose to use, among other approaches, nuclear magnetic resonance (NMR) spectroscopy and atomic force microscopy (AFM) and molecular dynamics simulation (MD/SMD) to derive a comprehensive understanding of the conformational shift in course of FimH activation by the ligand and facilitation of this process by tensile force. We will use this knowledge for developing strategies on preventing adhesion of medically-relevant bacteria to host target cells and surfaces, for developing shear- modulated nanotechnological tools, and as a paradigm for understanding other types of shear-dependent bacterial adhesion.
| Yakovenko, Olga; Tchesnokova, Veronika; Sokurenko, Evgeni V et al. (2015) Inactive conformation enhances binding function in physiological conditions. Proc Natl Acad Sci U S A 112:9884-9 |
| Kisiela, Dagmara I; Avagyan, Hovhannes; Friend, Della et al. (2015) Inhibition and Reversal of Microbial Attachment by an Antibody with Parasteric Activity against the FimH Adhesin of Uropathogenic E. coli. PLoS Pathog 11:e1004857 |
| Whitfield, Matt J; Luo, Jonathon P; Thomas, Wendy E (2014) Yielding elastic tethers stabilize robust cell adhesion. PLoS Comput Biol 10:e1003971 |
| Rodriguez, Victoria B; Kidd, Brian A; Interlandi, Gianluca et al. (2013) Allosteric coupling in the bacterial adhesive protein FimH. J Biol Chem 288:24128-39 |
| Kisiela, Dagmara I; Rodriguez, Victoria B; Tchesnokova, Veronika et al. (2013) Conformational inactivation induces immunogenicity of the receptor-binding pocket of a bacterial adhesin. Proc Natl Acad Sci U S A 110:19089-94 |
| Liu, Yang; Esser, Lothar; Interlandi, Gianluca et al. (2013) Tight conformational coupling between the domains of the enterotoxigenic Escherichia coli fimbrial adhesin CfaE regulates binding state transition. J Biol Chem 288:9993-10001 |
| Kisiela, Dagmara I; Kramer, Jeremy J; Tchesnokova, Veronika et al. (2011) Allosteric catch bond properties of the FimH adhesin from Salmonella enterica serovar Typhimurium. J Biol Chem 286:38136-47 |
| Pereverzev, Yuriy V; Prezhdo, Eugenia; Sokurenko, Evgeni V (2011) The two-pathway model of the biological catch-bond as a limit of the allosteric model. Biophys J 101:2026-36 |
| Tchesnokova, Veronika; Aprikian, Pavel; Kisiela, Dagmara et al. (2011) Type 1 fimbrial adhesin FimH elicits an immune response that enhances cell adhesion of Escherichia coli. Infect Immun 79:3895-904 |
| Aprikian, Pavel; Interlandi, Gianluca; Kidd, Brian A et al. (2011) The bacterial fimbrial tip acts as a mechanical force sensor. PLoS Biol 9:e1000617 |
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