The VWF-ADAMTS13 Interaction: Structural Insights into the Unique Relationship of a Protease and its Substrate
Thompson, Spencer E.
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Of the many protease-substrate pairs involved in blood clotting, the Von Willebrand Factor-ADAMTS13 interaction is one of the most unique from a structural and regulatory perspective. As the primary mediator of platelet adhesion, Von Willebrand Factor (VWF) is a key component in thrombogenesis, the formation of blood clots. ADAMTS13 prevents excessive coagulation by cleaving VWF into smaller multimers and breaking up platelet aggregates. In this investigation, electron microscopy is used to visualize the binding and conformation of VWF and ADAMTS13 both in complex with one another and in isolation. Two VWF fragments are engineered to maximize binding affinity to ADAMTS13 while minimizing protein size to afford the clearest possible image of the protease-substrate interaction. Images of ADAMTS13 alone suggest an auto-inhibitory function of the C-terminus previously hypothesized but never before visually corroborated. Efforts to document an image of VWF constructs complexed with ADAMTS13 were less revealing, but results suggest electron microscopy as a promising tool for furthering understanding of blood clotting and bleeding disorders on a molecular level.