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ECB-ART-43771
Proc Natl Acad Sci U S A 2014 Dec 30;11152:18584-9. doi: 10.1073/pnas.1413282112.
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Allosteric activation of ADAMTS13 by von Willebrand factor.

Muia J , Zhu J , Gupta G , Haberichter SL , Friedman KD , Feys HB , Deforche L , Vanhoorelbeke K , Westfield LA , Roth R , Tolia NH , Heuser JE , Sadler JE .


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.

PubMed ID: 25512528
PMC ID: PMC4284596
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Genes referenced: LOC100887844 LOC100893812 LOC582189 LOC582915 LOC591618

References [+] :
Akiyama, Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor. 2009, Pubmed