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. In this study, 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 γ˙1/2 = 5522/s. The same flow-rate dependence of ADAMTS13 activity we also observe in blood plasma, which is relevant to predict hemostatic dysfunction.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Lippok S,Radtke M,Obser T,Kleemeier L,Schneppenheim R,Budde U,Netz RR,Rädler JOdoi
10.1016/j.bpj.2015.12.023subject
Has Abstractpub_date
2016-02-02 00:00:00pages
545-554issue
3eissn
0006-3495issn
1542-0086pii
S0006-3495(15)04766-9journal_volume
110pub_type
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