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

Structural basis for the hijacking of endosomal sorting nexin proteins by Chlamydia trachomatis

  1. Blessy Paul
  2. Hyun Sung Kim
  3. Markus C Kerr
  4. Wilhelmina M Huston
  5. Rohan D Teasdale  Is a corresponding author
  6. Brett M Collins  Is a corresponding author
  1. The University of Queensland, Australia
  2. University of Technology Sydney, Australia
https://doi.org/10.7554/eLife.22311
Share this article
Cite this article
  1. Blessy Paul
  2. Hyun Sung Kim
  3. Markus C Kerr
  4. Wilhelmina M Huston
  5. Rohan D Teasdale
  6. Brett M Collins
(2017)
Structural basis for the hijacking of endosomal sorting nexin proteins by Chlamydia trachomatis
eLife 6:e22311.
https://doi.org/10.7554/eLife.22311
  2. Download BibTeX
  3. Download .RIS

Abstract

During infection chlamydial pathogens form an intracellular membrane-bound replicative niche termed the inclusion, which is enriched with bacterial transmembrane proteins called Incs. Incs bind and manipulate host cell proteins to promote inclusion expansion and provide camouflage against innate immune responses. Sorting nexin (SNX) proteins that normally function in endosomal membrane trafficking are a major class of inclusion-associated host proteins, and are recruited by IncE/CT116. Crystal structures of the SNX5 phox-homology (PX) domain in complex with IncE define the precise molecular basis for these interactions. The binding site is unique to SNX5 and related family members SNX6 and SNX32. Intriguingly the site is also conserved in SNX5 homologues throughout evolution, suggesting that IncE captures SNX5-related proteins by mimicking a native host protein interaction. These findings thus provide the first mechanistic insights both into how chlamydial Incs hijack host proteins, and how SNX5-related PX domains function as scaffolds in protein complex assembly.

Data availability

The following data sets were generated
    1. Collins B
    (2016) Structure of the SNX5 PX domain
    Publicly available at the University of Queensland eSpace (UQ: 409277).
    http://espace.library.uq.edu.au/view/UQ:409277

Article and author information

Author details

  1. Blessy Paul

    Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.

  2. Hyun Sung Kim

    Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.

  3. Markus C Kerr

    Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
    Competing interests
    The authors declare that no competing interests exist.

  4. Wilhelmina M Huston

    School of Life Sciences, University of Technology Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.

  5. Rohan D Teasdale

    Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
    For correspondence
    r.teasdale@imb.uq.edu.au
    Competing interests
    The authors declare that no competing interests exist.

  6. Brett M Collins

    Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
    For correspondence
    b.collins@imb.uq.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6070-3774

Funding

National Health and Medical Research Council (APP1058734)

  • Brett M Collins

National Health and Medical Research Council (606788)

  • Rohan D Teasdale

National Health and Medical Research Council (APP1041929)

  • Brett M Collins

National Health and Medical Research Council (APP1061574)

  • Rohan D Teasdale

Australian Research Council (DP0985029)

  • Brett M Collins

Australian Research Council (DP150100364)

  • Brett M Collins

Australian Research Council (DE120102321)

  • Markus C Kerr

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

Copyright

© 2017, Paul 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

  • 2,339
    views
  • 547
    downloads
  • 62
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Blessy Paul
  2. Hyun Sung Kim
  3. Markus C Kerr
  4. Wilhelmina M Huston
  5. Rohan D Teasdale
  6. Brett M Collins
(2017)
Structural basis for the hijacking of endosomal sorting nexin proteins by Chlamydia trachomatis
eLife 6:e22311.
https://doi.org/10.7554/eLife.22311

Share this article

https://doi.org/10.7554/eLife.22311

Categories and tags

Research organism

Further reading

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

    Chlamydia interfere with an interaction between the mannose-6-phosphate receptor and sorting nexins to counteract host restriction

    Cherilyn A Elwell, Nadine Czudnochowski ... Oren S Rosenberg
    Research Article Updated

    Chlamydia trachomatis is an obligate intracellular pathogen that resides in a membrane-bound compartment, the inclusion. The bacteria secrete a unique class of proteins, Incs, which insert into the inclusion membrane and modulate the host-bacterium interface. We previously reported that IncE binds specifically to the Sorting Nexin 5 Phox domain (SNX5-PX) and disrupts retromer trafficking. Here, we present the crystal structure of the SNX5-PX:IncE complex, showing IncE bound to a unique and highly conserved hydrophobic groove on SNX5. Mutagenesis of the SNX5-PX:IncE binding surface disrupts a previously unsuspected interaction between SNX5 and the cation-independent mannose-6-phosphate receptor (CI-MPR). Addition of IncE peptide inhibits the interaction of CI-MPR with SNX5. Finally, C. trachomatis infection interferes with the SNX5:CI-MPR interaction, suggesting that IncE and CI-MPR are dependent on the same binding surface on SNX5. Our results provide new insights into retromer assembly and underscore the power of using pathogens to discover disease-related cell biology.

    1. Computational and Systems Biology
    2. Structural Biology and Molecular Biophysics

    Discovery of a heparan sulfate binding domain in monkeypox virus H3 as an anti-poxviral drug target combining AI and MD simulations

    Bin Zheng, Meimei Duan ... Peng Zheng
    Research Article

    Viral adhesion to host cells is a critical step in infection for many viruses, including monkeypox virus (MPXV). In MPXV, the H3 protein mediates viral adhesion through its interaction with heparan sulfate (HS), yet the structural details of this interaction have remained elusive. Using AI-based structural prediction tools and molecular dynamics (MD) simulations, we identified a novel, positively charged α-helical domain in H3 that is essential for HS binding. This conserved domain, found across orthopoxviruses, was experimentally validated and shown to be critical for viral adhesion, making it an ideal target for antiviral drug development. Targeting this domain, we designed a protein inhibitor, which disrupted the H3-HS interaction, inhibited viral infection in vitro and viral replication in vivo, offering a promising antiviral candidate. Our findings reveal a novel therapeutic target of MPXV, demonstrating the potential of combination of AI-driven methods and MD simulations to accelerate antiviral drug discovery.

    1. Chromosomes and Gene Expression
    2. Structural Biology and Molecular Biophysics

    Surprising features of nuclear receptor interaction networks revealed by live-cell single-molecule imaging

    Liza Dahal, Thomas GW Graham ... Xavier Darzacq
    Research Article

    Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.