Mechano-redox control of integrin de-adhesion

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


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


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

Grant support

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