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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
hemostasis, metalloproteases, allosteric regulation, THROMBOTIC THROMBOCYTOPENIC PURPURA, FACTOR-CLEAVING PROTEASE, FACTOR A2 DOMAIN, BIOLOGICAL MACROMOLECULES, SOLUTION SCATTERING, CRYSTAL-STRUCTURES, ASSIST DEVICES, PROTEINS, BINDING, METALLOPROTEASE

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Chicago
Muia, Joshua, Jian Zhu, Garima Gupta, Sandra L Haberichter, Kenneth D Friedman, Hendrik Feys, Louis Deforche, et al. 2014. “Allosteric Activation of ADAMTS13 by Von Willebrand Factor.” Proceedings of the National Academy of Sciences of the United States of America 111 (52): 18584–18589.
APA
Muia, Joshua, Zhu, J., Gupta, G., Haberichter, S. L., Friedman, K. D., Feys, H., Deforche, L., et al. (2014). Allosteric activation of ADAMTS13 by von Willebrand factor. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(52), 18584–18589.
Vancouver
1.
Muia J, Zhu J, Gupta G, Haberichter SL, Friedman KD, Feys H, et al. Allosteric activation of ADAMTS13 by von Willebrand factor. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2014;111(52):18584–9.
MLA
Muia, Joshua, Jian Zhu, Garima Gupta, et al. “Allosteric Activation of ADAMTS13 by Von Willebrand Factor.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 111.52 (2014): 18584–18589. Print.
@article{8549087,
  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.},
  author       = {Muia, Joshua and Zhu, Jian and Gupta, Garima and Haberichter, Sandra L and Friedman, Kenneth D and Feys, Hendrik and Deforche, Louis and Vanhoorelbeke, Karen and Westfield, Lisa A and Roth, Robyn and Tolia, Niraj Harish and Heuser, John E and Sadler, J Evan},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  language     = {eng},
  number       = {52},
  pages        = {18584--18589},
  title        = {Allosteric activation of ADAMTS13 by von Willebrand factor},
  url          = {http://dx.doi.org/10.1073/pnas.1413282112},
  volume       = {111},
  year         = {2014},
}

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