Crystal structure and substrate-induced activation of ADAMTS13

Anastasis Petri, Hyo Jung Kim, Yaoxian Xu, Rens de Groot, Chan Li, Aline Vandenbulcke, Karen Vanhoorelbeke, Jonas Emsley () and James T. B. Crawley ()
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Anastasis Petri: Imperial College London
Hyo Jung Kim: University of Nottingham
Yaoxian Xu: Imperial College London
Rens de Groot: Imperial College London
Chan Li: University of Nottingham
Aline Vandenbulcke: Laboratory for Thrombosis Research
Karen Vanhoorelbeke: Laboratory for Thrombosis Research
Jonas Emsley: University of Nottingham
James T. B. Crawley: Imperial College London

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Platelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformational changes in VWF that reveal the A2 domain cleavage site. Multiple ADAMTS13 exosite interactions are involved in recognition of the unfolded A2 domain. Here we report through kinetic analyses that, in binding VWF, the ADAMTS13 cysteine-rich and spacer domain exosites bring enzyme and substrate into proximity. Thereafter, binding of the ADAMTS13 disintegrin-like domain exosite to VWF allosterically activates the adjacent metalloprotease domain to facilitate proteolysis. The crystal structure of the ADAMTS13 metalloprotease to spacer domains reveals that the metalloprotease domain exhibits a latent conformation in which the active-site cleft is occluded supporting the requirement for an allosteric change to enable accommodation of the substrate. Our data demonstrate that VWF functions as both the activating cofactor and substrate for ADAMTS13.

Date: 2019
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DOI: 10.1038/s41467-019-11474-5

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