About this item:

311 Views | 391 Downloads

Author Notes:

Email: renhao.li@emory.edu

W.D. designed and performed the experiments, analysed the data, prepared the figures and wrote the manuscript; Y.X. and M.A.D. performed single-molecule force measurements; W.C. and D.S.P. performed platelet clearance studies; A.K.S. assisted in the uniform shear assay; X.L. purified botrocetin and assisted in the botrocetin-binding assay; P.Z. and C.B.D. helped with inducible expression of GPIb–IX in CHO cells, and edited the manuscript; M.C.B., J.W., J.D.P. and F.L. provided critical reagents and discussed the results; W.B. and X.F.Z. analysed the data, prepared the figures and edited the manuscript; R.L. designed the study, analysed the data, prepared the figures and wrote the manuscript.

This paper is dedicated to a type 2B VWD patient who generously donated plasma for the study but passed away recently due to illness.

We thank the Emory Children's Pediatric Research Center Flow Cytometry Core and Emory Integrated Cellular Imaging Core for technical support.

Subjects:

Research Funding:

This work was supported in part by National Institutes of Health grants HL082808 and HL123984 (R.L.), a Bridge Grant from the American Society of Hematology (R.L.) and a Faculty Research Grant from Lehigh University (X.F.Z.).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • VON-WILLEBRAND-FACTOR
  • IB-IX COMPLEX
  • VONWILLEBRAND-FACTOR BINDING
  • BERNARD-SOULIER-SYNDROME
  • NECROSIS-FACTOR-ALPHA
  • GLYCOPROTEIN-IB
  • HEMOSTATIC FUNCTION
  • GPIB-BETA
  • MONOCLONAL-ANTIBODY
  • NONHUMAN-PRIMATES

Platelet clearance via shear-induced unfolding of a membrane mechanoreceptor

Show all authors Show less authors

Tools:

Journal Title:

Nature Communications

Volume:

Volume 7

Publisher:

, Pages 12863-12863

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author(s) 2016

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote