von Willebrand factor (VWF) (VWF)

The von Willebrand factor (VWF) A2 domain Tyr1605-Met1606 peptide bond is a critical regulatory site within the VWF protein, serving as the primary substrate for the metalloprotease ADAMTS13 (UniProt P04275). Under physiological conditions of high fluid shear stress, the A2 domain undergoes mechanical unfolding, which exposes this specific peptide bond to enzymatic cleavage (Zhang et al., 2005, Science, PubMed: 16239310). This cleavage process is essential for maintaining hemostatic balance by reducing the size of ultra-large VWF multimers, which are otherwise highly prothrombotic and capable of causing spontaneous platelet aggregation (Levy et al., 2001, Nature, PubMed: 11593004). Clinically, the integrity and accessibility of this bond are central to the pathogenesis of several hematological disorders. Mutations that increase the susceptibility of the Tyr1605-Met1606 bond to proteolysis result in von Willebrand disease type 2A, a condition characterized by a deficiency of high-molecular-weight multimers and a subsequent bleeding tendency (Crawley et al., 2011, Blood, PubMed: 19228925). Conversely, a failure to cleave this bond due to a deficiency in ADAMTS13 leads to thrombotic thrombocytopenic purpura (TTP), where large multimers cause widespread microvascular thrombosis. Therapeutic strategies include the use of recombinant ADAMTS13 (Apadamtase alfa) to restore cleavage activity and VWF-targeting agents like Caplacizumab to prevent the downstream consequences of impaired multimer regulation (FDA, 2023, TAK-755 Approval).

Other names

von Willebrand factor A2 domainADAMTS13 cleavage siteTyr1605-Met1606 peptide bondVWF A2 domain

The Tyr1605-Met1606 peptide bond is the specific site of proteolytic cleavage by the enzyme ADAMTS13. This cleavage is shear-dependent; hydrodynamic forces unfold the A2 domain to expose the bond, allowing ADAMTS13 to reduce the size of VWF multimers and prevent excessive platelet aggregation (PubMed: 16239310).