Allosteric activation of ADAMTS13 by von Willebrand factor. Proc Natl Acad Sci U S A 2014 Dec 30;111(52):18584-9
Date
12/17/2014Pubmed ID
25512528Pubmed Central ID
PMC4284596DOI
10.1073/pnas.1413282112Scopus ID
2-s2.0-84924309931 (requires institutional sign-in at Scopus site) 131 CitationsAbstract
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 List
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 JEAuthors
Kenneth D. Friedman MD Professor in the Medicine department at Medical College of WisconsinJoshua Muia PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
ADAM ProteinsADAMTS13 Protein
Allosteric Regulation
Enzyme Activation
Humans
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
von Willebrand Factor
