The Centenary Institute, Newtown, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
Lining Ju
Heart Research Institute and Charles Perkins Centre, University of Sydney, Sydney, Australia
Aster Pijning
The Centenary Institute, Newtown, Australia
Zeenat Jahan
St George Clinical School, Kogarah, Australia
Ronit Mor-Cohen
The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Adva Yeheskel
The Bioinformatics Unit, George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel
Katra Kolšek
Heidelberg Institute of Theoretical Studies, Heidelberg, Germany; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany
Lena Thärichen
Heidelberg Institute of Theoretical Studies, Heidelberg, Germany; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany
Heidelberg Institute of Theoretical Studies, Heidelberg, Germany; Max Planck Tandem Group in Computational Biophysics, University of Los Andes, Bogotá, Colombia
Frauke Gräter
Heidelberg Institute of Theoretical Studies, Heidelberg, Germany; Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany
The Centenary Institute, Newtown, Australia; National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia
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.
