Disulfide bond reduction and exchange in C4 domain of von Willebrand factor undermines platelet binding
Background - The von Willebrand factor (VWF) is a key player in regulating hemostasis through adhesion of platelets to sites of vascular injury. It is a large, multi-domain, mechano-sensitive protein that is stabilized by a net of disulfide bridges. Binding to platelet integrin is achieved by the VW...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
August 2023
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| In: |
Journal of thrombosis and haemostasis
Year: 2023, Volume: 21, Issue: 8, Pages: 2089-2100 |
| ISSN: | 1538-7836 |
| DOI: | 10.1016/j.jtha.2023.03.039 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.jtha.2023.03.039 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1538783623002738 
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| Author Notes: | Fabian Kutzki, Diego Butera, Angelina J. Lay, Denis Maag, Joyce Chiu, Heng-Giap Woon, Tomáš Kubař, Marcus Elstner, Camilo Aponte-Santamaría, Philip J. Hogg, Frauke Gräter |
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| 245 | 1 | 0 | |a Disulfide bond reduction and exchange in C4 domain of von Willebrand factor undermines platelet binding |c Fabian Kutzki, Diego Butera, Angelina J. Lay, Denis Maag, Joyce Chiu, Heng-Giap Woon, Tomáš Kubař, Marcus Elstner, Camilo Aponte-Santamaría, Philip J. Hogg, Frauke Gräter |
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| 520 | |a Background - The von Willebrand factor (VWF) is a key player in regulating hemostasis through adhesion of platelets to sites of vascular injury. It is a large, multi-domain, mechano-sensitive protein that is stabilized by a net of disulfide bridges. Binding to platelet integrin is achieved by the VWF-C4 domain, which exhibits a fixed fold, even under conditions of severe mechanical stress, but only if critical internal disulfide bonds are closed. - Objective - To determine the oxidation state of disulfide bridges in the C4 domain of VWF and implications for VWF’s platelet binding function. - Methods - We combined classical molecular dynamics and quantum mechanical simulations, mass spectrometry, site-directed mutagenesis, and platelet binding assays. - Results - We show that 2 disulfide bonds in the VWF-C4 domain, namely the 2 major force-bearing ones, are partially reduced in human blood. Reduction leads to pronounced conformational changes within C4 that considerably affect the accessibility of the integrin-binding motif, and thereby impair integrin-mediated platelet binding. We also reveal that reduced species in the C4 domain undergo specific thiol/disulfide exchanges with the remaining disulfide bridges, in a process in which mechanical force may increase the proximity of specific reactant cysteines, further trapping C4 in a state of low integrin-binding propensity. We identify a multitude of redox states in all 6 VWF-C domains, suggesting disulfide bond reduction and swapping to be a general theme. - Conclusions - Our data suggests a mechanism in which disulfide bonds dynamically swap cysteine partners and control the interaction of VWF with integrin and potentially other partners, thereby critically influencing its hemostatic function. | ||
| 650 | 4 | |a biomechanical phenomena | |
| 650 | 4 | |a blood platelets | |
| 650 | 4 | |a disulfides | |
| 650 | 4 | |a integrins | |
| 650 | 4 | |a protein folding | |
| 700 | 1 | |a Butera, Diego |e VerfasserIn |4 aut | |
| 700 | 1 | |a Lay, Angelina J. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Maag, Denis |e VerfasserIn |4 aut | |
| 700 | 1 | |a Chiu, Joyce |e VerfasserIn |4 aut | |
| 700 | 1 | |a Woon, Heng-Giap |e VerfasserIn |4 aut | |
| 700 | 1 | |a Kubař, Tomáš |e VerfasserIn |4 aut | |
| 700 | 1 | |a Elstner, Marcus |e VerfasserIn |4 aut | |
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| 700 | 1 | |a Hogg, Philip J. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Gräter, Frauke |e VerfasserIn |0 (DE-588)130664871 |0 (DE-627)505296764 |0 (DE-576)298331314 |4 aut | |
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