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arXiv · 1512.05127

Shear-induced unfolding and enzymatic cleavage of full-length VWF multimers

Svenja Lippok·Matthias Radtke·Tobias Obser·Lars Kleemeier·Reinhard Schneppenheim·Ulrich Budde·Roland R. Netz·Joachim O. Rädler
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Abstract

Proteolysis of the multimeric blood coagulation protein von Willebrand Factor (VWF) by ADAMTS13 is crucial for prevention of microvascular thrombosis. ADAMTS13 cleaves VWF within the mechanosensitive A2 domain, which is believed to open under shear flow. Here, we combine Fluorescence Correlation Spectroscopy (FCS) and a microfluidic shear cell to monitor real-time kinetics of full-length VWF proteolysis as a function of shear stress. For comparison, we also measure the Michaelis-Menten kinetics of ADAMTS13 cleavage of wild-type VWF in the absence of shear but partially denaturing conditions. Under shear, ADAMTS13 activity on full-length VWF arises without denaturing agent as evidenced by FCS and gel-based multimer analysis. In agreement with Brownian hydrodynamics simulations, we find a sigmoidal increase of the enzymatic rate as a function of shear at a threshold shear rate 5522/s. The same flow-rate dependence of ADAMTS13 activity we also observe in blood plasma, which is relevant to predict hemostatic dysfunction.

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Svenja Lippok, Matthias Radtke, Tobias Obser, Lars Kleemeier, Reinhard Schneppenheim, Ulrich Budde, Roland R. Netz, Joachim O. Rädler. 2015-12-16. Shear-induced unfolding and enzymatic cleavage of full-length VWF multimers. https://doi.org/10.1016/j.bpj.2015.12.023

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