期刊
THROMBOSIS RESEARCH
卷 136, 期 3, 页码 606-612出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.thromres.2015.06.019
关键词
Platelets; von Willebrand factor; Single bond; Glycoprotein Ib alpha; Microfluidics
资金
- National Institute of Health [HL091020, HL072886, AI088023]
Circulating von Willebrand factor (VWF) adopts a closed conformation that shields the platelet glycoprotein Ib alpha (GPIb alpha) binding site in the VWF-A1 domain. Immobilized at sites of vascular injury, VWF is activated by its interaction with collagen and the exertion of increased hemodynamic forces. Studies on native VWF strings and isolated A1 domains suggest the existence of multiple A1 binding states in different biophysical contexts. In this single-molecule study, we have used a biomembrane force probe (BFP) and a flow chamber to identify and characterize a collagen binding induced conformation with a higher affinity to platelet GPIb alpha. As force increases, our results show that collagen binding increases the stability of GPIb alpha bond with both VWF and isolated A1 domain. However, the collagen 2D binding affinity for VWF-A3 domain is 10 times of that for A1 domain, suggesting the initial VWF capture is mediated by A3-collagen interaction while A1-collagen regulates the subsequent VWF activation. Our results reveal the molecular mechanism of collagen-regulated, A1-mediated platelet adhesion enhancement. Characterization of different A1 states provides insights into binding heterogeneity of VWF in different scenarios of inflammation and thrombosis. (C) 2015 Elsevier Ltd. All rights reserved.
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