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Crystal structure and substrate-induced activation of ADAMTS13

DOI: 10.1038/s41467-019-11474-5 DOI Help

Authors: 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 (KU Leuven) , Karen Vanhoorelbeke (KU Leuven) , Jonas Emsley (University of Nottingham) , James T. B. Crawley (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 19880

Open Access Open Access

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.

Journal Keywords: Biochemistry; Proteases; Proteolysis; Thrombosis; X-ray crystallography

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I24-Microfocus Macromolecular Crystallography