1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease
Download icon

Bordetella adenylate cyclase toxin is a unique ligand of the integrin complement receptor 3

  1. Radim Osicka  Is a corresponding author
  2. Adriana Osickova
  3. Shakir Hasan
  4. Ladislav Bumba
  5. Jiri Cerny
  6. Peter Sebo
  1. Institute of Microbiology of the CAS, Czech Republic
  2. Institute of Biotechnology of the CAS, Czech Republic
Research Article
  • Cited 35
  • Views 1,736
  • Annotations
Cite this article as: eLife 2015;4:e10766 doi: 10.7554/eLife.10766
Voice your concerns about research culture and research communication: Have your say in our 7th annual survey.

Abstract

Integrins are heterodimeric cell surface adhesion and signaling receptors that are essential for metazoan existence. Some integrins contain an I-domain that is a major ligand binding site. The ligands preferentially engage the active forms of the integrins and trigger signaling cascades that alter numerous cell functions. Here we found that the adenylate cyclase toxin (CyaA), a key virulence factor of the whooping cough agent Bordetella pertussis, preferentially binds an inactive form of the integrin complement receptor 3 (CR3), using a site outside of its I-domain. CyaA binding did not trigger downstream signaling of CR3 in human monocytes and CyaA-catalyzed elevation of cAMP effectively blocked CR3 signaling initiated by a natural ligand. This unprecedented type of integrin-ligand interaction distinguishes CyaA from all other known ligands of the I-domain-containing integrins and provides a mechanistic insight into the previously observed central role of CyaA in the pathogenesis of B. pertussis.

Article and author information

Author details

  1. Radim Osicka

    Institute of Microbiology of the CAS, Prague, Czech Republic
    For correspondence
    osicka@biomed.cas.cz
    Competing interests
    The authors declare that no competing interests exist.
  2. Adriana Osickova

    Institute of Microbiology of the CAS, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  3. Shakir Hasan

    Institute of Microbiology of the CAS, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  4. Ladislav Bumba

    Institute of Microbiology of the CAS, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  5. Jiri Cerny

    Institute of Biotechnology of the CAS, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.
  6. Peter Sebo

    Institute of Microbiology of the CAS, Prague, Czech Republic
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Johanna Ivaska, University of Turku, Finland

Publication history

  1. Received: August 11, 2015
  2. Accepted: December 9, 2015
  3. Accepted Manuscript published: December 9, 2015 (version 1)
  4. Version of Record published: February 2, 2016 (version 2)

Copyright

© 2015, Osicka 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

  • 1,736
    Page views
  • 357
    Downloads
  • 35
    Citations

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

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. Biochemistry and Chemical Biology
    Hongki Song et al.
    Research Article

    Membrane fusion requires R-, Qa-, Qb-, and Qc-family SNAREs that zipper into RQaQbQc coiled coils, driven by the sequestration of apolar amino acids. Zippering has been thought to provide all the force driving fusion. Sec17/aSNAP can form an oligomeric assembly with SNAREs with the Sec17 C-terminus bound to Sec18/NSF, the central region bound to SNAREs, and a crucial apolar loop near the N-terminus poised to insert into membranes. We now report that Sec17 and Sec18 will drive robust fusion without requiring zippering completion. Zippering-driven fusion is blocked by deleting the C-terminal quarter of any Q-SNARE domain or by replacing the apolar amino acids of the Qa-SNARE which face the center of the 4-SNARE coiled coils with polar residues. These blocks, singly or combined, are bypassed by Sec17 and Sec18, and SNARE-dependent fusion is restored without help from completing zippering.

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Wan Hua Li et al.
    Research Article

    SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red-shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.