Crystal structure and substrate-induced activation of ADAMTS13
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Author(s)
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.
(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 Issued
2019-08-22
Date Acceptance
2019-07-02
Citation
Nature Communications, 2019, 10 (1)
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/.
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
British Heart Foundation
British Heart Foundation
Medical Research Council (MRC)
Grant Number
PG/18/17/33572
FS/14/44/30962
RGS : 115324
Subjects
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
Date Publish Online
2019-08-22