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Crystal structure and substrate-induced activation of ADAMTS13.

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Petri A, Kim HJ, Xu Y, de Groot R, Li C, Vandenbulcke A, Vanhoorelbeke K, Emsley J, Crawley JTB
OpenAccess logo Nat Commun 10 3781 (2019)
Cited: 36 times
EuropePMC logo PMID: 31439947

Abstract

Platelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformational changes in VWF that reveal the A2 domain cleavage site. Multiple ADAMTS13 exosite interactions are involved in recognition of the unfolded A2 domain. Here we report through kinetic analyses that, in binding VWF, the ADAMTS13 cysteine-rich and spacer domain exosites bring enzyme and substrate into proximity. Thereafter, binding of the ADAMTS13 disintegrin-like domain exosite to VWF allosterically activates the adjacent metalloprotease domain to facilitate proteolysis. The crystal structure of the ADAMTS13 metalloprotease to spacer domains reveals that the metalloprotease domain exhibits a latent conformation in which the active-site cleft is occluded supporting the requirement for an allosteric change to enable accommodation of the substrate. Our data demonstrate that VWF functions as both the activating cofactor and substrate for ADAMTS13.

Reviews - 6qig mentioned but not cited (4)

  1. Mechanisms of ADAMTS13 regulation. DeYoung V, Singh K, Kretz CA. J Thromb Haemost 20 2722-2732 (2022)
  2. Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition. Cuffaro D, Ciccone L, Rossello A, Nuti E, Santamaria S. J Med Chem 65 13505-13532 (2022)
  3. ADAMTS13 conformations and mechanism of inhibition in immune thrombotic thrombocytopenic purpura. Halkidis K, Zheng XL. J Thromb Haemost 20 2197-2203 (2022)
  4. Conformational plasticity of ADAMTS13 in hemostasis and autoimmunity. Ercig B, Arfman T, Hrdinova J, Wichapong K, Reutelingsperger CPM, Vanhoorelbeke K, Nicolaes GAF, Voorberg J. J Biol Chem 297 101132 (2021)

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  1. Thrombotic Thrombocytopenic Purpura: Pathophysiology, Diagnosis, and Management. Sukumar S, Lämmle B, Cataland SR. J Clin Med 10 536 (2021)
  2. Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13. Yang J, Wu Z, Long Q, Huang J, Hong T, Liu W, Lin J. Front Immunol 11 610696 (2020)
  3. ADAMTS proteases in cardiovascular physiology and disease. Santamaria S, de Groot R. Open Biol 10 200333 (2020)
  4. ADAMTS-5: A difficult teenager turning 20. Santamaria S. Int J Exp Pathol 101 4-20 (2020)
  5. Regulation of ADAMTS Proteases. Rose KWJ, Taye N, Karoulias SZ, Hubmacher D. Front Mol Biosci 8 701959 (2021)
  6. TTP: From empiricism for an enigmatic disease to targeted molecular therapies. Graça NAG, Joly BS, Voorberg J, Vanhoorelbeke K, Béranger N, Veyradier A, Coppo P. Br J Haematol 197 156-170 (2022)
  7. Platelet dysfunction after trauma: From mechanisms to targeted treatment. Sloos PH, Vulliamy P, van 't Veer C, Gupta AS, Neal MD, Brohi K, Juffermans NP, Kleinveld DJB. Transfusion 62 Suppl 1 S281-S300 (2022)
  8. Structural insights into regulation of CCN protein activities and functions. Monsen VT, Attramadal H. J Cell Commun Signal 17 371-390 (2023)
  9. Concurrence of immune thrombocytopenic purpura and thrombotic thrombocytopenic purpura: a case report and review of the literature. Lin HC, Huang J, Huang J, Zhang LJ, Yin XW, Yang JC, Huang XY. J Med Case Rep 17 38 (2023)
  10. Pitfalls of Thrombotic Microangiopathies in Children: Two Case Reports and Literature Review. Mocanu A, Bogos RA, Lazaruc TI, Cianga AL, Lupu VV, Ioniuc I, Alecsa M, Lupu A, Ivanov AV, Miron IC, Starcea IM. Diagnostics (Basel) 13 1228 (2023)
  11. The Highs and Lows of ADAMTS13 Activity. Shaw RJ, Abrams ST, Badu S, Toh CH, Dutt T. J Clin Med 13 5152 (2024)

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