Crystal Structure and Substrate-induced Activation of ADAMTS13

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Aug 24

PMID 31439947

Citations 31

Authors

Anastasis Petri

Hyo Jung Kim

Yaoxian Xu

Rens de Groot

Chan Li

Aline Vandenbulcke

Karen Vanhoorelbeke

Jonas Emsley

James T B Crawley

Affiliations

Soon will be listed here.

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.

Citing Articles

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