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Investigating von Willebrand Factor Pathophysiology Using a Flow Chamber Model of von Willebrand Factor-platelet String Formation
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A novel binding site for ADAMTS13 constitutively exposed on the surface of globular VWF

Sara Zanardelli1, Alain C K Chion, Evelyn Groot

  • 1Department of Haematology, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom. sara.zanardelli03@imperial.ac.uk

Blood
|July 10, 2009
PubMed

Insights

Researchers discovered a new binding site on von Willebrand factor (VWF) that interacts with ADAMTS13 metalloprotease. This interaction, involving VWF

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hematology

Background:

  • ADAMTS13 metalloprotease cleaves von Willebrand factor (VWF) to regulate its multimeric size.
  • The precise mechanisms of VWF recognition by ADAMTS13 remain incompletely understood.
  • Previous research primarily focused on VWF A2 domain exosites interacting with the ADAMTS13 spacer domain.

Purpose of the Study:

  • To identify novel binding sites between ADAMTS13 and VWF.
  • To investigate the role of VWF C-terminal domains in ADAMTS13 interaction.
  • To elucidate the initial steps in VWF recognition by ADAMTS13.

Main Methods:

  • Expression of C-terminal VWF fragments.
  • Plate binding assays.
  • Surface plasmon resonance (SPR) analysis.
  • Evaluation of binding to ADAMTS13 and its mutants (MDTCS, del(TSP5-CUB)).

Main Results:

  • A novel ADAMTS13 binding site was identified in VWF residues 1874-2813 (including the D4 domain), with a K(D) of approximately 86 nM.
  • This interaction occurs with the C-terminal domains of ADAMTS13 and is observed even when VWF is in a static, globular conformation (A2 domain hidden).
  • VWF C-terminal fragments and an anti-D4 domain antibody inhibited VWF proteolysis by ADAMTS13 under shear conditions.

Conclusions:

  • A previously unrecognized C-terminal binding site on VWF interacts with ADAMTS13.
  • This novel interaction site may be crucial for initiating the multistep process of VWF cleavage by ADAMTS13.
  • Understanding this interaction could offer new insights into VWF regulation and related disorders.

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