Mechano-redox control of integrin de-adhesion
- University of New South Wales, Australia
- University of Sydney, Australia
- Tel Aviv University, Israel
- Heidelberg Institute of Theoretical Studies, Germany
- University of Los Andes, Colombia
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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Camilo Aponte-Santamaría
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.
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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Mechano-redox control of integrin de-adhesion
eLife 7:e34843.
https://doi.org/10.7554/eLife.34843
