Mechano-redox control of integrin de-adhesion

Blood Platelets Protein Conformation, alpha-Helical 0301 basic medicine integrin QH301-705.5 Science Genetic Vectors Protein Disulfide-Isomerases Gene Expression Platelet Glycoprotein GPIIb-IIIa Complex Molecular Dynamics Simulation Crystallography, X-Ray Mechanotransduction, Cellular mechanical force 03 medical and health sciences Platelet Adhesiveness Allosteric Regulation Biochemistry and Chemical Biology Escherichia coli Humans Biology (General) Cloning, Molecular platelet 0303 health sciences Binding Sites Q R Erp5 Fibrinogen Kinetics redox Medicine Protein Conformation, beta-Strand Oxidation-Reduction allosteric disulfide Protein Binding
DOI: 10.7554/elife.34843 Publication Date: 2018-06-22T12:00:29Z
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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