TY - JOUR
T1 - Allosteric activation of ADAMTS13 by von Willebrand factor
AU - Muia, Joshua
AU - Zhu, Jian
AU - Gupta, Garima
AU - Haberichter, Sandra L.
AU - Friedman, Kenneth D.
AU - Feys, Hendrik B.
AU - Deforche, Louis
AU - Vanhoorelbeke, Karen
AU - Westfield, Lisa A.
AU - Roth, Robyn
AU - Tolia, Niraj Harish
AU - Heuser, John E.
AU - Sadler, J. Evan
N1 - Publisher Copyright:
© 2014, National Academy of Sciences. All rights reserved.
PY - 2014/12/30
Y1 - 2014/12/30
N2 - 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.
AB - 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.
KW - Allosteric regulation
KW - Hemostasis
KW - Metalloproteases
UR - http://www.scopus.com/inward/record.url?scp=84924309931&partnerID=8YFLogxK
U2 - 10.1073/pnas.1413282112
DO - 10.1073/pnas.1413282112
M3 - Article
C2 - 25512528
AN - SCOPUS:84924309931
SN - 0027-8424
VL - 111
SP - 18584
EP - 18589
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
ER -