title: Allosteric activation of ADAMTS13 by von Willebrand factor.
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.
authors.affiliation: Departments of Medicine.
authors.forename: Joshua
authors.initials: J
authors.lastname: Muia
authors.affiliation: Departments of Medicine.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Departments of Medicine.
authors.forename: Garima
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Haberichter
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201;
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Friedman
authors.affiliation: Transfusion Research Center, Belgian Red Cross-Flanders, Ghent, Belgium; and.
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Feys
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Kulak, 8500 Kortrijk, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Deforche
authors.affiliation: Laboratory for Thrombosis Research, KU Leuven Kulak, 8500 Kortrijk, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Vanhoorelbeke
authors.affiliation: Departments of Medicine.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Westfield
authors.affiliation: Cell Biology and Physiology.
authors.forename: Robyn
authors.initials: R
authors.lastname: Roth
authors.affiliation: Biochemistry and Molecular Biophysics, and Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Niraj Harish
authors.initials: NH
authors.lastname: Tolia
authors.affiliation: Cell Biology and Physiology.
authors.forename: John E
authors.initials: JE
authors.lastname: Heuser
authors.affiliation: Departments of Medicine, Biochemistry and Molecular Biophysics, and esadler@dom.wustl.edu.
authors.forename: J Evan
authors.identifier: http://orcid.org/0000-0001-5705-469X
authors.initials: JE
authors.lastname: Sadler
mesh_terms: D051722:ADAM Proteins / Q000097:blood / Q000737:chemistry* / Q000235:genetics; D000071120:ADAMTS13 Protein; D000494:Allosteric Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D014841:von Willebrand Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: allosteric regulation; hemostasis; metalloproteases