Fig. 9
From: Crystal structure and substrate-induced activation of ADAMTS13
Mode of action of ADAMTS13. a Under normal circumstances, multimeric Von Willebrand factor (VWF) circulates in the plasma in a globular conformation, in which its A1 domains are concealed, and so does not interact with platelets. ADAMTS13 circulates in a “closed” conformation stabilized through the interaction of the C-terminal CUB domains with the central Spacer domain. The MP domain of ADAMTS13 also has a latent conformation in which the active-site cleft is occluded by the Ca2+-binding loop. This prevents ADAMTS13 from proteolyzing off-target substrates and confers resistance to plasma inhibitors. b Following vessel damage, the endothelium (EC) is disrupted to reveal subendothelial collagen. Globular VWF binds to this surface via its A3 domain and unravels into an elongated conformation in response to the shear forces exerted by the flowing blood. This reveals the A1 domain that can then capture platelets via the GPIbα receptor on the platelet surface. Unravelling of VWF also unravels the VWF A2 domain into a linear polypeptide conformation that reveals the binding sites for ADAMTS13 and the Tyr1605-Met1606 cleavage site, making it susceptible to proteolysis by ADAMTS13. c ADAMTS13 recognizes unfolded VWF through multiple interactions. (1) The CUB domains bind the VWF D4-CK domains, which (2) induces their dissociation from the Spacer domain. (3) The Spacer and (4) cysteine (Cys)-rich domain exosites recognize the C-terminal region of the unfolded A2 domain to bring the enzyme and substrate into proximity. d Once bound, (5) the disintegrin-like (Dis) domain exosite engages VWF residues Asp1614-Asp1622. This interaction (6) induces an allosteric change in the MP domain. This causes a conformational change, disrupting the “gatekeeper triad” that otherwise occludes the active-site cleft, to reveal the S1′ pocket. Once allosterically activated, (7) the MP domain proteolyzes the scissile bond
