The effects of shear stress on the interaction between ADAMTS13 and VWF

Abstract

<p indent="0mm">Both ADAMTS13 (a disintegrin and metalloprotease with a thrombosspondin type-1 motif, member 13) and VWF (von Willebrand factor) are critical in the regulation of platelet adhesion in hemostasis and thrombosis. Dysregulation of their functions is associated with thrombotic thrombocytopenic purpura (TTP) and von Willebrand disease (VWD). VWF is a multimeric glycoprotein discovered by Erik A. von Willebrand in 1926. It can bind and stabilize coagulation factor VIII. In addition, it can mediate platelet adhesion by binding to the components of the blood vessel wall and the glycoprotein Ib (GPIb) on the platelet membrane. Under physiology, VWF is synthesized as a disulfide-linked dimer in the endoplasmic reticulum and transported into the Golgi apparatus for further processing. In the Golgi, the intra- and inter-VWF disulfide bonds are reorganized so that VWF can polymerize into macro-molecular helices and be packed into Weibel-Palade Bodies in a tubular form. Upon stimulation by blood vessel injury, packed VWF can be rapidly unwound and released into the blood vessels, forming millimeter-long protein fibers. Under the stretch of increased shear force at the injury site, the cryptic platelet binding site on the A1 domain of VWF will be exposed, enabling the recruitment and aggregation of platelets on VWF fibers for hemostasis. However, the accumulation of ultra-long VWF in the blood would lead to the formation of microthrombi, blocking blood vessels and capillaries and causing the failure of multiple organs. To prevent thrombosis, multimeric VWF is cleaved by ADAMTS13 into short fragments to reduce platelet binding and aggregation. As such, the length and distribution of VWF multimers, which ADAMTS13 regulates, are essential for the precise balance between hemostasis and thrombosis. Unlike other proteases, which are secreted in an inactive state and activated proteolytically, ADAMTS13 is secreted in an active form and circulates in the blood as an active enzyme. Its activity is regulated by VWF binding and shear stress. Under resting state, the head and the tail of ADAMTS13 interact with each other to mask the exosites of ADAMTS13 on its DTCS domains. VWF binding induces conformational changes of ADAMTS13 to expose its exosites. On the other hand, shear stress not only causes the conformational changes of VWF to expose its ADAMTS13 cleavage site on the VWF A2 domain, but also regulates the interactions between VWF and ADAMTS13. Studies have shown that, under shear stress, VWF and ADAMTS13 need to be properly aligned so that the VWF A2 domain can be positioned in the vicinity of the ADATS13 M domain for cleavage. In this article, we summarize recent progress in the structural and functional studies of VWF and ADAMTS13. Primarily, we focus on how the conformations and interactions between VWF and ADAMTS13 are regulated under static and shear force conditions. The collected information will be helpful for better understanding the regulation of ADAMTS13 and VWF activities under physiological and pathological conditions. Such understanding could facilitate the screening and development of novel therapeutics in the treatment of TTP and VWD.