Figure 7.

Mode of action of ADAMTS13. (A) Under normal circumstances, ADAMTS13 circulates in a closed conformation stabilized by the interaction of the C-terminal CUB domains with the central Spacer domain. The MP domain of ADAMTS13 naturally favors a latent conformation in which the active site cleft is occluded, preventing off-target proteolysis and conferring resistance to inhibition. (B) When ADAMTS13 is bound by activating mAbs that recognize either the Spacer domain (1a) or CUB domains (1b), or when it binds to VWF via the D4-CK domains of VWF (1c), the CUB-Spacer interaction is disrupted (2) causing ADAMTS13 to adopt an open conformation. This opening of ADAMTS13 induces a structural shift in the MP domain into a preactivated state (3) that, ultimately, enhances the proteolytic function of the enzyme. (C) ADAMTS13 recognizes unfolded VWF A2 domain through multiple interactions. The Spacer (4) and (5) Cys-rich domain exosites recognize the C-terminal region of the unfolded VWF A2 domain bringing enzyme and substrate into close proximity. Thereafter, the Dis domain exosite engages VWF (6), which induces a further allosteric change in the MP domain (7). This conformational change opens the active site cleft to enable accommodation and proteolysis of the cleavage site (8). The preactivation of ADAMTS13 augments this final activation step by ∼twofold.