We have been studying the vascular protein von Willebrand factor (VWF) and the regulation of blood clotting in collaboration with Timothy A. Springer’s group. The A2 domain of VWF is the key to this largely mechanical molecular feedback loop. Using optical tweezers, we have characterized the unfolding and refolding kinetics of the A2 domain, and have shown that force acts as an “cofactor”, enabling the cleavage of A2 by the ADAMTS13 enzyme. Furthermore, the hydrodynamic tensile forces encountered by VWF in the circulation are sufficient to enable cleavage, which in turn down regulates the body’s hemostatic potential. Here is the abstract of work that has recently been published in Science Magazine [link]:

Von Willebrand factor (VWF) 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. Single-molecule experiments demonstrate 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, 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.