Structure of the A2 domain. (A) Three-dimensional representation of the VWF A2 domain derived from PDB-deposit 3ZQK.⁵¹ The Tyr¹⁶⁰⁵-Met¹⁶⁰⁶ scissile bond is in red, the α4-less loop in violet, the unique Ca²⁺-ion is in purple, and cis-Pro¹⁶⁴⁵ is in orange. Figure was generated using PyMOL software. (B) Cartoon impression the A2 domain in its unfolded conformation. Once unfolded, the A2 domain exposes several interactive sites for ADAMTS13, allowing the Tyr¹⁶⁰⁵-Met¹⁶⁰⁶ scissile bond to be hydrolyzed by the ADAMTS13 metalloprotease domain (MP). Other interactive sites involve the α4-less loop residues Asp¹⁶¹⁴-Asp¹⁶²² interacting with the disintegrin domain (Dis), the α5-helix/β6-sheet region Ile¹⁶⁴²-Ile¹⁶⁵¹ binding to the cysteine-rich domain (Cys), and the α6-helix residues Glu¹⁶⁶⁰-Arg¹⁶⁶⁸ associating to the spacer domain of ADAMTS13. (C) Two-dimensional representation of the A2 domain including the Ca²⁺ binding site and the vicinal disulfide bridge, both being unique to the A2 domain. The Tyr¹⁶⁰⁵-Met¹⁶⁰⁶ scissile bond is located in the middle of the β4-strand. Circles indicate positions of residues where mutations have been associated with increased ADAMTS13-mediated degradation in patients with group 2 von Willebrand disease-type 2A. In contrast to the A1 and A3 domains, the A2 domain lacks a disulfide bridge that connects the N- and C-termini of this domain.