Platelet clearance via shear-induced unfolding of a membrane mechanoreceptor.
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.
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Wei
W
Deng
Department of Mechanical Engineering and Mechanics, Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
Yan
Y
Xu
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Wenchun
W
Chen
McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27516, USA.
David S
DS
Paul
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Anum K
AK
Syed
Department of Mechanical Engineering and Mechanics, Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
Matthew A
MA
Dragovich
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Xin
X
Liang
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Philip
http://orcid.org/0000-0002-4919-5182
P
Zakas
Faculty of Health Sciences, Curtin University, Perth, Western Australia 6845, Australia.
Michael C
MC
Berndt
Department of Pediatrics and Human Genetics, Genomics Program, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Jorge
J
Di Paola
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Jerry
J
Ware
UMR_S949 INSERM, Université de Strasbourg, EFS-Alsace, Strasbourg 67065, France.
Francois
F
Lanza
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Christopher B
CB
Doering
McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina 27516, USA.|Department of Biochemistry/Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Wolfgang
W
Bergmeier
Department of Mechanical Engineering and Mechanics, Bioengineering Program, Lehigh University, Bethlehem, Pennsylvania 18015, USA.
X Frank
XF
Zhang
Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Renhao
R
Li
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