von Willebrand factor A2 domain (VWF A2 domain) (VWF A2)

The ADAMTS13 protease interface on the von Willebrand factor (VWF) A2 domain is a critical regulatory site in human hemostasis (UniProt P04275). Under high fluid shear stress, the VWF A2 domain undergoes mechanical unfolding, exposing a specific peptide bond (Tyr1605-Met1606) that is recognized and cleaved by the metalloprotease ADAMTS13 (PubMed: 22123954). This cleavage is essential for reducing the size of ultra-large VWF multimers, which are otherwise highly prothrombotic and can cause microvascular occlusion if left unregulated (NIH, 2023). Dysregulation of this interface is central to the pathogenesis of Thrombotic Thrombocytopenic Purpura (TTP), where a deficiency in ADAMTS13 activity leads to systemic microthrombi. Conversely, mutations in the A2 domain that increase its susceptibility to proteolysis result in von Willebrand Disease (VWD) Type 2A, a condition characterized by a lack of high-molecular-weight multimers and subsequent bleeding (PubMed: 11485153). The primary therapeutic interacting with this interface is recombinant ADAMTS13 (Adzynma), which was recently approved to provide exogenous enzyme activity for patients with congenital TTP (FDA, 2023).

Other names

VWF-A2ADAMTS13-VWF interaction siteTyr1605-Met1606 cleavage sitevon Willebrand factor domain A2

Proteolytic cleavage of von Willebrand factor (VWF) at the Tyr1605-Met1606 bond within the A2 domain, which reduces the size of VWF multimers and decreases their affinity for platelets (PubMed: 19264965).