Allosteric activation of ADAMTS13 by von Willebrand factor

Joshua Muia, Jian Zhu, Garima Gupta, Sandra L. Haberichter, Kenneth D. Friedman, Hendrik B. Feys, Louis Deforche, Karen Vanhoorelbeke, Lisa A. Westfield, Robyn Roth, Niraj Harish Tolia, John E. Heuser, J. Evan Sadler

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


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.

Original languageEnglish
Pages (from-to)18584-18589
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
StatePublished - Dec 30 2014


  • Allosteric regulation
  • Hemostasis
  • Metalloproteases


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