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Crystal structure and substrate-induced activation of ADAMTS13

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Title: Crystal structure and substrate-induced activation of ADAMTS13
Authors: Petri, A
Kim, HJ
Xu, Y
De Groot, R
Li, C
Vandenbulcke, A
Vanhoorelbeke, K
Emsley, J
Crawley, J
Item Type: Journal Article
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.
Issue Date: 22-Aug-2019
Date of Acceptance: 2-Jul-2019
URI: http://hdl.handle.net/10044/1/72217
DOI: 10.1038/s41467-019-11474-5
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Journal / Book Title: Nature Communications
Volume: 10
Issue: 1
Copyright Statement: © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Sponsor/Funder: British Heart Foundation
British Heart Foundation
Medical Research Council (MRC)
Funder's Grant Number: PG/18/17/33572
FS/14/44/30962
RGS : 115324
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
VON-WILLEBRAND-FACTOR
THROMBOTIC THROMBOCYTOPENIC PURPURA
DISINTEGRIN-LIKE DOMAIN
METALLOPROTEASE DOMAIN
SPACER DOMAIN
CONFORMATIONAL ACTIVATION
COAGULATION-FACTOR
CATALYTIC DOMAIN
SCISSILE BOND
BINDING-SITE
Publication Status: Published
Article Number: 3781
Online Publication Date: 2019-08-22
Appears in Collections:Department of Immunology and Inflammation