1. Biochemistry and Chemical Biology
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Mechano-redox control of integrin de-adhesion

  1. Freda Passam
  2. Joyce Chiu
  3. Lining Ju
  4. Aster Pijning
  5. Zeenat Jahan
  6. Ronit Mor-Cohen
  7. Adva Yeheskel
  8. Katra Kolšek
  9. Lena Thärichen
  10. Camilo Aponte-Santamaría
  11. Frauke Gräter
  12. Philip J Hogg  Is a corresponding author
  1. University of New South Wales, Australia
  2. University of Sydney, Australia
  3. Tel Aviv University, Israel
  4. Heidelberg Institute of Theoretical Studies, Germany
  5. University of Los Andes, Colombia
Research Article
  • Cited 10
  • Views 2,124
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Cite this article as: eLife 2018;7:e34843 doi: 10.7554/eLife.34843

Abstract

How proteins harness mechanical force to control function is a significant biological question. Here we describe a human cell surface receptor that couples ligand binding and force to trigger a chemical event which controls the adhesive properties of the receptor. Our studies of the secreted platelet oxidoreductase, ERp5, have revealed that it mediates release of fibrinogen from activated platelet αIIbβ3 integrin. Protein chemical studies show that ligand binding to extended αIIbβ3 integrin renders the βI-domain Cys177-Cys184 disulfide bond cleavable by ERp5. Fluid shear and force spectroscopy assays indicate that disulfide cleavage is enhanced by mechanical force. Cell adhesion assays and molecular dynamics simulations demonstrate that cleavage of the disulfide induces long-range allosteric effects within the βI-domain, mainly affecting the metal-binding sites, that results in release of fibrinogen. This coupling of ligand binding, force and redox events to control cell adhesion may be employed to regulate other protein-protein interactions.

Article and author information

Author details

  1. Freda Passam

    St George Clinical School, University of New South Wales, Kogarah, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Joyce Chiu

    Centenary Institute, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Lining Ju

    Heart Research Institute, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Aster Pijning

    Centenary Institute, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Zeenat Jahan

    St George Clinical School, University of New South Wales, Kogarah, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Ronit Mor-Cohen

    Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Adva Yeheskel

    George S Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Katra Kolšek

    Heidelberg Institute of Theoretical Studies, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Lena Thärichen

    Heidelberg Institute of Theoretical Studies, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Camilo Aponte-Santamaría

    Max Planck Tandem Group in Computational Biophysics, University of Los Andes, Bogotá, Colombia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8427-6965
  11. Frauke Gräter

    Heidelberg Institute of Theoretical Studies, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Philip J Hogg

    Centenary Institute, University of Sydney, Sydney, Australia
    For correspondence
    phil.hogg@sydney.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6486-2863

Funding

National Health and Medical Research Council (Research Fellowship 1110219)

  • Philip J Hogg

Deutsche Forschungsgemeinschaft (Research Unit FOR 1543)

  • Katra Kolšek
  • Camilo Aponte-Santamaría
  • Frauke Gräter

National Heart Foundation of Australia (Australia Postdoctoral Fellowship 101285)

  • Lining Ju

Klaus Tschira Stiftung

  • Frauke Gräter

Diabetes Australia Research Trust (Grant G179720)

  • Lining Ju

Royal College of Pathologists of Australasia (Kanematsu/Novo Nordisk Research Award)

  • Freda Passam
  • Lining Ju

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

Ethics

Human subjects: All procedures involving collection of human blood from healthy volunteers were in accordance with the St George Hospital Human Ethics Committee (HREC 12/252), Human Research Ethics Committee (HREC) (Project number 2014/244) of the University of Sydney , and the Helsinki Declaration of 1983.

Reviewing Editor

  1. William I Weis, Stanford University Medical Center, United States

Publication history

  1. Received: January 5, 2018
  2. Accepted: June 21, 2018
  3. Accepted Manuscript published: June 22, 2018 (version 1)
  4. Version of Record published: July 20, 2018 (version 2)
  5. Version of Record updated: March 6, 2019 (version 3)
  6. Version of Record updated: March 29, 2019 (version 4)

Copyright

© 2018, Passam 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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