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Conformational Switch of the Bacterial Adhesin FimH in the Absence of the Regulatory Domain: Engineering a Minimalistic Allosteric System

Rabbani, Said and Fiege, Brigitte and Eris, Deniz and Silbermann, Marleen and Jakob, Roman Peter and Navarra, Giulio and Maier, Timm and Ernst, Beat. (2018) Conformational Switch of the Bacterial Adhesin FimH in the Absence of the Regulatory Domain: Engineering a Minimalistic Allosteric System. Journal of Biological Chemistry, 293 (5). pp. 1835-1849.

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Official URL: http://edoc.unibas.ch/57369/

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Abstract

For many biological processes such as ligand binding, enzymatic catalysis, or protein folding, allosteric regulation of protein conformation and dynamics is fundamentally important. One example is the bacterial adhesin FimH, where the C-terminal pilin domain exerts negative allosteric control over binding of the N-terminal lectin domain to mannosylated ligands on host cells. When the lectin and pilin domains are separated under shear stress, the FimH-ligand interaction switches in a so-called catch-bond mechanism from low to high affinity state. So far, it has been assumed that the pilin domain is essential for the allosteric propagation within the lectin domain that would otherwise be conformationally rigid. To test this hypothesis, we generated mutants of the isolated FimH lectin domain and characterized their thermodynamic, kinetic, and structural properties using ITC, SPR, NMR and X-ray techniques. Intriguingly, some of the mutants mimicked the conformational and kinetic behaviors of the full-length protein and, even in absence of the pilin domain, conducted the crosstalk between allosteric sites and the mannoside binding pocket. Thus, these mutants represent a minimalistic allosteric system of FimH, useful for further mechanistic studies and antagonist design.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Maier, Timm and Ernst, Beat and Rabbani, Said and Navarra, Giulio and Jakob, Roman Peter and Fiege, Brigitte and Eris, Deniz and Silbermann, Marleen
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
e-ISSN:1083-351X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:18 Sep 2018 13:23
Deposited On:25 Apr 2018 15:46

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