Abstract

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 e.g. 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.

Data availability

- Diffraction data have been deposited in PDB under the accession code 8ALO-SAXS data have been deposited:ToxR - SASDR25https://www.sasbdb.org/data/SASDR25/x14svn58xr/ToxS - SASDR35https://www.sasbdb.org/data/SASDR35/ti6yxfu94f/ToxR:ToxS -SASDR45https://www.sasbdb.org/data/SASDR45/8t9oq6fvvj/ToxR:ToxS:bile - SASDR55https://www.sasbdb.org/data/SASDR55/1f1om17ki6/- All data generated or analysed during this study are included in the manuscript and supporting files

The following data sets were generated

Article and author information

Author details

  1. Nina Gubensäk

    Institute of Molecular Biosciences, University of Graz, Graz, Austria
    For correspondence
    nina.gubensaek@uni-graz.at
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0415-4299
  2. Theo Sagmeister

    Institute of Molecular Biosciences, University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  3. Christoph Buhlheller

    Institute of Molecular Biosciences, University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  4. Bruno Di Geronimo

    Laboratory of Computer-Aided Molecular Design, Medical University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  5. Gabriel E Wagner

    Institute of Chemistry, Medical University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5704-3955
  6. Lukas Petrowitsch

    Institute of Molecular Biosciences, University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  7. Melissa A Gräwert

    Biological Small Angle Scattering, EMBL Hamburg, Hamburg, Germany
    Competing interests
    No competing interests declared.
  8. Markus Rotzinger

    Institute of Chemistry, University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0411-3403
  9. Tamara M Ismael Berger

    Institute of Molecular Biosciences, University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  10. Jan Schäfer

    RedShiftBio, Boxborough, United States
    Competing interests
    Jan Schäfer, is affiliated with Redshift BioAnalytics, Inc. which distributes the AQS3pro. Access to the AQS3pro instrument was provided to Nina Gubensäk as part of the RedShiftBio demo lab..
  11. Isabel Usón

    Crystallographic Methods, Institute of Molecular Biology, Barcelona, Spain
    Competing interests
    No competing interests declared.
  12. Joachim Reidl

    Institute of Molecular Biosciences, University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  13. Pedro A Sánchez-Murcia

    Laboratory of Computer-Aided Molecular Design, Medical University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  14. Klaus Zangger

    Institute of Chemistry, University of Graz, Graz, Austria
    Competing interests
    No competing interests declared.
  15. Tea Pavkov-Keller

    Institute of Chemistry, University of Graz, Graz, Austria
    For correspondence
    tea.pavkov@uni-graz.at
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7871-6680

Funding

Austrian Science Fund (FWF T-1239)

  • Nina Gubensäk

Austrian Science Fund (FWF DK W09)

  • Klaus Zangger

Austrian Science Fund (FWF P 29405)

  • Joachim Reidl

Land Steiermark (1109)

  • Klaus Zangger

Spanish MICINN/AEI/FEDER/UE (PID2021-128751NB-I00)

  • Isabel Usón

Austrian Science Fund (Biomolecular Structures and Interactions DOC 130)

  • Tea Pavkov-Keller

Austrian Science Fund (Molecular Metabolism DOC 50)

  • Theo Sagmeister

Fundación Martínez Escudero

  • Bruno Di Geronimo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Hannes Neuweiler, University of Würzburg, Germany

Version history

  1. Received: April 20, 2023
  2. Preprint posted: May 4, 2023 (view preprint)
  3. Accepted: September 27, 2023
  4. Accepted Manuscript published: September 28, 2023 (version 1)
  5. Version of Record published: November 3, 2023 (version 2)

Copyright

© 2023, Gubensäk et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nina Gubensäk
  2. Theo Sagmeister
  3. Christoph Buhlheller
  4. Bruno Di Geronimo
  5. Gabriel E Wagner
  6. Lukas Petrowitsch
  7. Melissa A Gräwert
  8. Markus Rotzinger
  9. Tamara M Ismael Berger
  10. Jan Schäfer
  11. Isabel Usón
  12. Joachim Reidl
  13. Pedro A Sánchez-Murcia
  14. Klaus Zangger
  15. Tea Pavkov-Keller
(2023)
Vibrio cholerae's ToxRS bile sensing system
eLife 12:e88721.
https://doi.org/10.7554/eLife.88721

Share this article

https://doi.org/10.7554/eLife.88721

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