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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-H (02))
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Baqar, Shahida
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University of Washington
Schools of Medicine
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