Platelet clearance via shear-induced unfolding of a membrane mechanoreceptor

Wei Deng, Yan Xu, Wenchun Chen, David S. Paul, Anum K. Syed, Matthew A. Dragovich, Xin Liang, Philip Zakas, Michael C. Berndt, Jorge Di Paola, Jerry Ware, Francois Lanza, Christopher B. Doering, Wolfgang Bergmeier, X. Frank Zhang and Renhao Li ()
Additional contact information
Wei Deng: Aflac Cancer and Blood Disorders Center, Emory University School of Medicine
Yan Xu: Bioengineering Program, Lehigh University
Wenchun Chen: Aflac Cancer and Blood Disorders Center, Emory University School of Medicine
David S. Paul: McAllister Heart Institute, University of North Carolina
Anum K. Syed: Aflac Cancer and Blood Disorders Center, Emory University School of Medicine
Matthew A. Dragovich: Bioengineering Program, Lehigh University
Xin Liang: Aflac Cancer and Blood Disorders Center, Emory University School of Medicine
Philip Zakas: Aflac Cancer and Blood Disorders Center, Emory University School of Medicine
Michael C. Berndt: Faculty of Health Sciences, Curtin University
Jorge Di Paola: Genomics Program, University of Colorado School of Medicine
Jerry Ware: University of Arkansas for Medical Sciences
Francois Lanza: UMR_S949 INSERM, Université de Strasbourg, EFS-Alsace
Christopher B. Doering: Aflac Cancer and Blood Disorders Center, Emory University School of Medicine
Wolfgang Bergmeier: McAllister Heart Institute, University of North Carolina
X. Frank Zhang: Bioengineering Program, Lehigh University
Renhao Li: Aflac Cancer and Blood Disorders Center, Emory University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Mechanisms by which blood cells sense shear stress are poorly characterized. In platelets, glycoprotein (GP)Ib–IX receptor complex has been long suggested to be a shear sensor and receptor. Recently, a relatively unstable and mechanosensitive domain in the GPIbα subunit of GPIb–IX was identified. Here we show that binding of its ligand, von Willebrand factor, under physiological shear stress induces unfolding of this mechanosensory domain (MSD) on the platelet surface. The unfolded MSD, particularly the juxtamembrane ‘Trigger’ sequence therein, leads to intracellular signalling and rapid platelet clearance. These results illustrate the initial molecular event underlying platelet shear sensing and provide a mechanism linking GPIb–IX to platelet clearance. Our results have implications on the mechanism of platelet activation, and on the pathophysiology of von Willebrand disease and related thrombocytopenic disorders. The mechanosensation via receptor unfolding may be applicable for many other cell adhesion receptors.

Date: 2016
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DOI: 10.1038/ncomms12863

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