Mechanoenzymatic Cleavage of the Ultralarge Vascular Protein von Willebrand Factor

Prof. Xiaohui Zhang at IBCB and collaborative research groups from Harvard University have recently found a novel mechanism to cleave ultralarge vascular protein Von Willebrand Factor. Their work was published on Science on June 5th.

 

Von Willebrand factor (VWF) is the key shear-sensing protein in haemostasis and is especially important in arterial bleeding where shear is high. It is secreted as ultralarge multimers that are cleaved in the A2 domain by the metalloprotease ADAMTS13 to give smaller multimers. Cleaved VWF is activated by hydrodynamic forces found in arteriolar bleeding to promote hemostasis, whereas uncleaved VWF is activated at lower, physiologic shear stresses and causes thrombosis. Using single-molecule experiments, the scientists demonstrated that elongational forces in the range experienced by VWF in the vasculature unfold the A2 domain, and only the unfolded A2 domain is cleaved by ADAMTS13. In shear flow, tensile force on a VWF multimer increases with the square of multimer length and is highest at the middle, providing an efficient mechanism for homeostatic regulation of VWF size distribution by force-induced A2 unfolding and cleavage by ADAMTS13, as well as providing a counterbalance for VWF-mediated platelet aggregation.

 

The results provide a new insight in understanding and diagnosis of haemostasis, thrombosis and related diseases.