Mechanisms of substrate recognition by a typhoid toxin secretion-associated muramidase

  1. Tobias Geiger
  2. Maria Lara-Tejero
  3. Yong Xiong
  4. Jorge E Galán  Is a corresponding author
  1. Yale University School of Medicine, United States

Abstract

Typhoid toxin is a virulence factor for the bacterial pathogen Salmonella Typhi, which causes typhoid fever in humans. After its synthesis by intracellular bacteria, typhoid toxin is secreted into the lumen of the Salmonella-containing vacuole by a secretion mechanism strictly dependent on TtsA, a specific muramidase that facilitates toxin transport through the peptidoglycan layer. Here we show that substrate recognition by TtsA depends on a discrete domain within its carboxy terminus, which targets the enzyme to the bacterial poles to recognize YcbB-edited peptidoglycan. Comparison of the atomic structures of TtsA bound to its substrate and that of a close homolog with different specificity identified specific determinants involved in substrate recognition. Combined with structure-guided mutagenesis and in vitro and in vivo crosslinking experiments, this study provides an unprecedented view of the mechanisms by which a muramidase recognizes its peptidoglycan substrate to facilitate protein secretion.

Data availability

The diffraction data have been deposited in PDB under accession code 6v40 and 6v3z. The rest of the data are included in the manuscript and associated supporting files.

The following data sets were generated

Article and author information

Author details

  1. Tobias Geiger

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Maria Lara-Tejero

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yong Xiong

    Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jorge E Galán

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    For correspondence
    jorge.galan@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6531-0355

Funding

National Institute of Allergy and Infectious Diseases (AI079022)

  • Jorge E Galán

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

Reviewing Editor

  1. Michael T Laub, Massachusetts Institute of Technology, United States

Publication history

  1. Received: November 9, 2019
  2. Accepted: January 18, 2020
  3. Accepted Manuscript published: January 20, 2020 (version 1)
  4. Version of Record published: February 3, 2020 (version 2)

Copyright

© 2020, Geiger 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. Tobias Geiger
  2. Maria Lara-Tejero
  3. Yong Xiong
  4. Jorge E Galán
(2020)
Mechanisms of substrate recognition by a typhoid toxin secretion-associated muramidase
eLife 9:e53473.
https://doi.org/10.7554/eLife.53473
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