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Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18584-9. doi: 10.1073/pnas.1413282112. Epub 2014 Dec 15.

Allosteric activation of ADAMTS13 by von Willebrand factor.

Author information

1
Departments of Medicine.
2
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
3
Transfusion Research Center, Belgian Red Cross-Flanders, Ghent, Belgium; and.
4
Laboratory for Thrombosis Research, KU Leuven Kulak, 8500 Kortrijk, Belgium.
5
Cell Biology and Physiology.
6
Biochemistry and Molecular Biophysics, and Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, MO 63110;
7
Departments of Medicine, Biochemistry and Molecular Biophysics, and esadler@dom.wustl.edu.

Abstract

The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) within endovascular platelet aggregates, and ADAMTS13 deficiency causes fatal microvascular thrombosis. The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains of ADAMTS13 recognize a cryptic site in VWF that is exposed by tensile force. Another seven T and two complement C1r/C1s, sea urchin epidermal growth factor, and bone morphogenetic protein (CUB) domains of uncertain function are C-terminal to the MDTCS domains. We find that the distal T8-CUB2 domains markedly inhibit substrate cleavage, and binding of VWF or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. Small angle X-ray scattering data indicate that distal T-CUB domains interact with proximal MDTCS domains. Thus, ADAMTS13 is regulated by substrate-induced allosteric activation, which may optimize VWF cleavage under fluid shear stress in vivo. Distal domains of other ADAMTS proteases may have similar allosteric properties.

KEYWORDS:

allosteric regulation; hemostasis; metalloproteases

PMID:
25512528
PMCID:
PMC4284596
DOI:
10.1073/pnas.1413282112
[Indexed for MEDLINE]
Free PMC Article

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