Mechanochemistry of von Willebrand factor.

Stefano Lancellotti,Raimondo De Cristofaro,Maria Basso,Monica Sacco

doi:10.1515/bmc-2019-0022

Abstract

Von Willebrand factor (VWF), a blood multimeric protein with a very high molecular weight, plays a crucial role in the primary haemostasis, the physiological process characterized by the adhesion of blood platelets to the injured vessel wall. Hydrodynamic forces are responsible for extensive conformational transitions in the VWF multimers that change their structure from a globular form to a stretched linear conformation. This feature makes this protein particularly prone to be investigated by mechanochemistry, the branch of the biophysical chemistry devoted to investigating the effects of shear forces on protein conformation. This review describes the structural elements of the VWF molecule involved in the biochemical response to shear forces. The stretched VWF conformation favors the interaction with the platelet GpIb and at the same time with ADAMTS-13, the zinc-protease that cleaves VWF in the A2 domain, limiting its prothrombotic capacity. The shear-induced conformational transitions favor also a process of self-aggregation, responsible for the formation of a spider-web like network, particularly efficient in the trapping process of flowing platelets. The investigation of the biophysical effects of shear forces on VWF conformation contributes to unraveling the molecular mechanisms of many types of thrombotic and haemorrhagic syndromes.

Highlights

Von Willebrand factor (VWF), a blood multimeric protein with a very high molecular weight, plays a crucial role in the primary haemostasis, the physiological process characterized by the adhesion of blood platelets to the injured vessel wall
We have described how the high sensitivity of VWF multimers to mechanical forces, which is centered in the A2 domain, plays a pivotal role in the pathophysiology of this haemostatic protein
The shear-induced conformational transitions of VWF play a fundamental role in haemorrhagic and thrombotic diseases. It was shown how the phenotypes of some forms of type 2 von Willebrand disease stem from altered structural responses of VWF to external shear forces

Summary

Introduction

Abstract: Von Willebrand factor (VWF), a blood multimeric protein with a very high molecular weight, plays a crucial role in the primary haemostasis, the physiological process characterized by the adhesion of blood platelets to the injured vessel wall. Hydrodynamic forces are responsible for extensive conformational transitions in the VWF multimers that change their structure from a globular form to a stretched linear conformation. This feature makes this protein prone to be investigated by mechanochemistry, the branch of the biophysical chemistry devoted to investigating the effects of shear forces on protein conformation. Vascular damage is rapidly followed by adhesion and firm attachment of blood platelets at the site of endothelial injury This process is mediated by von Willebrand factor (VWF), a multimeric protein of variable molecular weight ranging from about 0.5 to about 20 megadalton, which acts as a bridge between the subendothelial collagen and platelets, a process referred to as primary haemostasis [1, 2].

B2 B3 C1 C2

Conclusions