Unfolding/refolding model of the VWF A2 domain and proteolysis by ADAMTS13. (A) Cartoon of the VWF A2 domain in its native folded state. (B) The first step of unfolding occurs from the C-terminal end of the VWF A2 domain, influenced by the presence of the vicinal disulphide bond (cysteines depicted by C). Initial unfolding occurs up to, or including, the central β4 sheet in which the scissile bond (YM) is contained. This unfolding intermediate step exposes the high-affinity ADAMTS13 spacer-binding site. (C) Once the stabilizing effect of the CBS is overcome this results in the complete unfolding of the VWF A2 domain and the positioning of the ADAMTS13 active site for nucleophilic attack of the Y1605-M1606 scissile bond.