Mechano-redox control of integrin de-adhesion

Freda Passam; Joyce Chiu; Lining Ju; Aster Pijning; Zeenat Jahan; Ronit Mor-Cohen; Adva Yeheskel; Katra Kolšek; Lena Thärichen; Camilo Aponte-Santamaría; Frauke Gräter; Philip J Hogg

doi:10.7554/eLife.34843

Mechano-redox control of integrin de-adhesion

Elife. 2018 Jun 22:7:e34843. doi: 10.7554/eLife.34843.

Authors

Freda Passam^#¹, Joyce Chiu^#^{2

3}, Lining Ju⁴, Aster Pijning², Zeenat Jahan¹, Ronit Mor-Cohen⁵, Adva Yeheskel⁶, Katra Kolšek^{7

8}, Lena Thärichen^{7

8}, Camilo Aponte-Santamaría^{7

9}, Frauke Gräter^{7

8}, Philip J Hogg^{2

3}

Affiliations

¹ St George Clinical School, Kogarah, Australia.
² The Centenary Institute, Newtown, Australia.
³ National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
⁴ Heart Research Institute and Charles Perkins Centre, University of Sydney, Sydney, Australia.
⁵ 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.
⁶ The Bioinformatics Unit, George S. Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel.
⁷ Heidelberg Institute of Theoretical Studies, Heidelberg, Germany.
⁸ Interdisciplinary Center for Scientific Computing, Heidelberg University, Heidelberg, Germany.
⁹ Max Planck Tandem Group in Computational Biophysics, University of Los Andes, Bogotá, Colombia.

^# Contributed equally.

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.

Keywords: Erp5; allosteric disulfide; biochemistry; chemical biology; human; integrin; mechanical force; platelet; redox.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Binding Sites
Blood Platelets / chemistry
Blood Platelets / cytology
Blood Platelets / metabolism*
Cloning, Molecular
Crystallography, X-Ray
Escherichia coli / genetics
Escherichia coli / metabolism
Fibrinogen / chemistry*
Fibrinogen / genetics
Fibrinogen / metabolism
Gene Expression
Genetic Vectors / chemistry
Genetic Vectors / metabolism
Humans
Kinetics
Mechanotransduction, Cellular*
Molecular Dynamics Simulation
Oxidation-Reduction
Platelet Adhesiveness
Platelet Glycoprotein GPIIb-IIIa Complex / chemistry*
Platelet Glycoprotein GPIIb-IIIa Complex / genetics
Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Disulfide-Isomerases / chemistry
Protein Disulfide-Isomerases / genetics
Protein Disulfide-Isomerases / metabolism
Protein Interaction Domains and Motifs
Proteolysis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Substrate Specificity

Substances

Platelet Glycoprotein GPIIb-IIIa Complex
Recombinant Proteins
Fibrinogen
PDIA6 protein, human
Protein Disulfide-Isomerases

Grants and funding

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