Institute of Chemistry / Organic and Bioorganic Chemistry, Medical University of Graz, Graz, Austria; Diagnostic and Research Institute of Hygiene, Microbiology and Environmental Medicine, Medical University of Graz, Graz, Austria
Lukas Petrowitsch
Institute of Molecular Biosciences, University of Graz, Graz, Austria
Melissa A Gräwert
Biological Small Angle Scattering, EMBL Hamburg, Hamburg, Germany
Institute of Chemistry / Organic and Bioorganic Chemistry, Medical University of Graz, Graz, Austria
Tamara M Ismael Berger
Institute of Molecular Biosciences, University of Graz, Graz, Austria
Jan Schäfer
RedShiftBio, Boxborough, United States
Isabel Usón
Institute of Molecular Biology of Barcelona, Barcelona, Spain; ICREA, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
Joachim Reidl
Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
Pedro A Sánchez-Murcia
Laboratory of Computer-Aided Molecular Design, Division of Medicinal Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria
Klaus Zangger
Institute of Chemistry / Organic and Bioorganic Chemistry, Medical University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria
The seventh pandemic of the diarrheal cholera disease, which began in 1960, is caused by the Gram-negative bacterium Vibrio cholerae. Its environmental persistence provoking recurring sudden outbreaks is enabled by V. cholerae’s rapid adaption to changing environments involving sensory proteins like ToxR and ToxS. Located at the inner membrane, ToxR and ToxS react to environmental stimuli like bile acid, thereby inducing survival strategies for example bile resistance and virulence regulation. The presented crystal structure of the sensory domains of ToxR and ToxS in combination with multiple bile acid interaction studies, reveals that a bile binding pocket of ToxS is only properly folded upon binding to ToxR. Our data proposes an interdependent functionality between ToxR transcriptional activity and ToxS sensory function. These findings support the previously suggested link between ToxRS and VtrAC-like co-component systems. Besides VtrAC, ToxRS is now the only experimentally determined structure within this recently defined superfamily, further emphasizing its significance. In-depth analysis of the ToxRS complex reveals its remarkable conservation across various Vibrio species, underlining the significance of conserved residues in the ToxS barrel and the more diverse ToxR sensory domain. Unravelling the intricate mechanisms governing ToxRS’s environmental sensing capabilities, provides a promising tool for disruption of this vital interaction, ultimately inhibiting Vibrio’s survival and virulence. Our findings hold far-reaching implications for all Vibrio strains that rely on the ToxRS system as a shared sensory cornerstone for adapting to their surroundings.
