Jianchung Chen
Exploiting the kinetic interplay between GPIb -VWF binding interfaces to regulate hemostasis and thrombosis
Chen, Jianchung; Zhou, Hairu; Diacovo, Alexander; Zheng, X. Long; Emsley, Jonas; Diacovo, Thomas G.
Authors
Hairu Zhou
Alexander Diacovo
X. Long Zheng
prof JONAS EMSLEY jonas.emsley@nottingham.ac.uk
Professor of Macromolecular Crystallography
Thomas G. Diacovo
Abstract
Platelet–von Willebrand factor (VWF) interactions must be tightly regulated in order to promote effective hemostasis and prevent occlusive thrombus formation. However, it is unclear what role the inherent properties of the bond formed between the platelet receptor glycoprotein Ibα and the A1 domain of VWF play in these processes. Using VWF-A1 knock-in mice with mutations that enhance (I1309V) or disrupt (R1326H) platelet receptor glycoprotein Ibα binding, we now demonstrate that the kinetic interplay between two distinct contact surfaces influences the site and extent to which platelets bind VWF. Incorporation of R1326H mutation into the major site shortened bond lifetime, yielding defects in hemostasis and thrombosis comparable to VWF-deficient animals. Similarly, disrupting this region of contact with an allosteric inhibitor impaired human platelet accrual in damaged arterioles. In contrast, the I1309V mutation near the minor site prolonged bond lifetime, which was essential for the development of a type 2B–like VWD phenotype. However, combining the R1326H and I1309V mutations normalized both bond kinetics and the hemostatic and thrombotic properties of VWF. These findings broaden our understanding of mechanisms governing platelet–VWF interactions in health and disease, and underscore the importance of combined biophysical and genetic approaches in identifying potential therapeutic avenues for treating bleeding and thrombotic disorders.
Citation
Chen, J., Zhou, H., Diacovo, A., Zheng, X. L., Emsley, J., & Diacovo, T. G. (2014). Exploiting the kinetic interplay between GPIb -VWF binding interfaces to regulate hemostasis and thrombosis. Blood, 124(25), https://doi.org/10.1182/blood-2014-04-569392
Journal Article Type | Article |
---|---|
Acceptance Date | Sep 22, 2014 |
Publication Date | Dec 12, 2014 |
Deposit Date | Mar 16, 2018 |
Publicly Available Date | Mar 16, 2018 |
Journal | Blood |
Print ISSN | 0006-4971 |
Electronic ISSN | 1528-0020 |
Publisher | American Society of Hematology |
Peer Reviewed | Peer Reviewed |
Volume | 124 |
Issue | 25 |
DOI | https://doi.org/10.1182/blood-2014-04-569392 |
Public URL | https://nottingham-repository.worktribe.com/output/740946 |
Publisher URL | http://www.bloodjournal.org/content/124/25/3799 |
Additional Information | This research was originally published in Blood. Jianchung Chen, Hairu Zhou, Alexander Diacovo, X. Long Zheng, Jonas Emsley and Thomas G. Diacovo. Exploiting the kinetic interplay between GPIba–VWF binding interfaces to regulate hemostasis and thrombosis. Blood. 2014; 124:3799-3807; © the American Society of Hematology. |
Contract Date | Mar 16, 2018 |
Files
BLOOD-2014-569392v1-Diacovo copy.pdf
(658 Kb)
PDF
You might also like
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: discovery-access-systems@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search