: The main goal of the proposal is to develop a comprehensive structural picture of how mechanical force affects the functional state of microbial adhesions. Specific adhesive proteins enable bacteria to recognize ligands leading to the adhesion and colonization of various living hosts or environmental niches, and finally infection. A growing number of experimental observations indicate that mechanical forces generated by shear-flow of body fluids are modulating the affinity and selectivity of adhesins to their ligands. In order to test the extent to which mechanical forces may alter the structure and thus the functional states of adhesins, we propose to characterize the dynamic properties of the most common type of bacterial adhesin - FimH -that is a lectin-like adhesive subunit of type 1 (mannose-sensitive) fimbria of Enterobacteria and Vibrio. In the course of our preliminary studies we have identified distinct structural variants of the Escherichia coli FimH adhesin where shear-flow can induce their preferential binding to target cells, obviously by switching their specificity between the mono-mannoside and tri-mannoside receptors. To develop structural hypotheses how mechanical forces acting on the binding site may affect the tertiary structure of FimH, we have been and will be conducting steered molecular dynamics simulations in which tension is applied between the receptor-binding residues and the C-terminal end of the FimH lectin domain. Deriving a comprehensive understanding of the structure-function relationship of adhesins under static and dynamic conditions requires that molecular biology tools are employed in concert with X-ray crystallography and novel powerful nano-analytical tools to probe, characterize and simulate non-equilibrium protein structures as they relate to function.
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| 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 |
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| 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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