1. Microbiology and Infectious Disease
  2. Structural Biology and Molecular Biophysics
Download icon

Structure of the Helicobacter pylori Cag Type IV secretion system

  1. Jeong Min Chung
  2. Michael J Sheedlo
  3. Anne M Campbell
  4. Neha Sawhney
  5. Arwen E Frick-Cheng
  6. Dana Borden Lacy  Is a corresponding author
  7. Timothy L Cover  Is a corresponding author
  8. Melanie D Ohi  Is a corresponding author
  1. University of Michigan, United States
  2. Vanderbilt University School of Medicine, United States
Research Article
  • Cited 26
  • Views 6,173
  • Annotations
Cite this article as: eLife 2019;8:e47644 doi: 10.7554/eLife.47644

Abstract

Bacterial type IV secretion systems (T4SSs) are molecular machines that can mediate interbacterial DNA transfer through conjugation and delivery of effector molecules into host cells. The Helicobacter pylori Cag T4SS translocates CagA, a bacterial oncoprotein, into gastric cells, contributing to gastric cancer pathogenesis. We report the structure of a membrane-spanning Cag T4SS complex, which contains three sub-complexes: a 14-fold symmetric outer membrane core complex (OMCC), 17-fold symmetric periplasmic ring complex (PRC), and stalk domain. Features that differ markedly from those of prototypical T4SSs include an expanded OMCC and unexpected symmetry mismatch between the OMCC and PRC. This structure is one of the largest bacterial secretion system complexes ever reported and illustrates the remarkable structural diversity that exists among bacterial T4SSs.

Article and author information

Author details

  1. Jeong Min Chung

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4285-8764
  2. Michael J Sheedlo

    Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Anne M Campbell

    Department of Medicine, Vanderbilt University School of Medicine, Nasvhille, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Neha Sawhney

    Department of Medicine, Vanderbilt University School of Medicine, Nasvhille, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4943-1018
  5. Arwen E Frick-Cheng

    Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Dana Borden Lacy

    Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nasvhille, United States
    For correspondence
    borden.lacy@vumc.org
    Competing interests
    The authors declare that no competing interests exist.
  7. Timothy L Cover

    Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States
    For correspondence
    timothy.l.cover@vumc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8503-002X
  8. Melanie D Ohi

    Life Sciences Institute, University of Michigan, Ann Arbor, United States
    For correspondence
    mohi@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1750-4793

Funding

National Institute of Allergy and Infectious Diseases (AI118932)

  • Timothy L Cover
  • Melanie D Ohi

National Cancer Institute (CA116087)

  • Timothy L Cover

Department of Veterans' Affairs (1I01BX004447)

  • Timothy L Cover

National Institute of General Medical Sciences (GM103310)

  • Melanie D Ohi

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

Reviewing Editor

  1. Andrew P Carter, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Received: April 11, 2019
  2. Accepted: June 17, 2019
  3. Accepted Manuscript published: June 18, 2019 (version 1)
  4. Version of Record published: July 10, 2019 (version 2)

Copyright

© 2019, Chung 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.

Metrics

  • 6,173
    Page views
  • 721
    Downloads
  • 26
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Microbiology and Infectious Disease
    David Ranava et al.
    Research Article

    Integral outer membrane proteins (OMPs) are crucial for the maintenance of the proteobacterial envelope permeability barrier to some antibiotics and detergents. In Enterobacteria, envelope stress caused by unfolded OM proteins (OMPs) activates the sigmaE (σE) transcriptional response. σE upregulates OMP-biogenesis factors, including the b-barrel assembly machinery (BAM) that catalyzes OMP folding. Here we report that DolP (formerly YraP), a σE-upregulated and poorly understood OM lipoprotein, is crucial for fitness in cells that undergo envelope stress. We demonstrate that DolP interacts with the BAM complex by associating to OM-assembled BamA. We provide evidence that DolP is important for proper folding of BamA that overaccumulates in the OM, thus supporting OMP biogenesis and OM integrity. Notably, mid-cell recruitment of DolP had been linked to regulation of septal peptidoglycan remodelling by an unknown mechanism. We now reveal that, during envelope stress, DolP loses its association with the mid-cell, thereby suggesting a mechanistic link between envelope stress caused by impaired OMP biogenesis and the regulation of a late step of cell division.

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease
    Tingting Wang et al.
    Tools and Resources Updated

    A high-throughput systematic evolution of ligands by exponential enrichment assay was applied to 371 putative TFs in Pseudomonas aeruginosa, which resulted in the robust enrichment of 199 unique sequence motifs describing the binding specificities of 182 TFs. By scanning the genome, we predicted in total 33,709 significant interactions between TFs and their target loci, which were more than 11-fold enriched in the intergenic regions but depleted in the gene body regions. To further explore and delineate the physiological and pathogenic roles of TFs in P. aeruginosa, we constructed regulatory networks for nine major virulence-associated pathways and found that 51 TFs were potentially significantly associated with these virulence pathways, 32 of which had not been characterized before, and some were even involved in multiple pathways. These results will significantly facilitate future studies on transcriptional regulation in P. aeruginosa and other relevant pathogens, and accelerate to discover effective treatment and prevention strategies for the associated infectious diseases.