Shielding of the A1 domain by the D′D3 domains of von Willebrand factor modulates its interaction with platelet glycoprotein Ib-IX-V

Hans Ulrichts, Miklós Udvardy, Peter J. Lenting, Inge Pareyn, Nele Vandeputte, Karen Vanhoorelbeke, Hans Deckmyn

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Soluble von Willebrand factor (VWF) has a low affinity for platelet glycoprotein (GP) Ibα and needs immobilization and/or high shear stress to enable binding of its A1 domain to the receptor. The previously described anti-VWF monoclonal antibody 1C1E7 enhances VWF/GPIbα binding and recognizes an epitope in the amino acids 764-1035 region in the N-terminal D′D3 domains. In this study we demonstrated that the D′D3 region negatively modulates the VWF/GPIb-IX-V interaction; (i) deletion of the D′D3 region in VWF augmented binding to GPIbα, suggesting an inhibitory role for this region, (ii) the isolated D′D3 region inhibited the GPIbα interaction of a VWF deletion mutant lacking this region, indicating that intramolecular interactions limit the accessibility of the A1 domain, (iii) using a panel of anti-VWF monoclonal antibodies, we next showed that the D′D3 region is in close proximity with the A1 domain in soluble VWF but not when VWF was immobilized; (iv) destroying the epitope of 1C1E7 resulted in a mutant VWF with an increased affinity for GPIbα. Our results support a model of domain translocation in VWF that allows interaction with GPIbα. The suggested shielding interaction of the A1 domain by the D′D3 region then becomes disrupted by VWF immobilization.

Original languageEnglish
Pages (from-to)4699-4707
Number of pages9
JournalJournal of Biological Chemistry
Issue number8
Publication statusPublished - Feb 24 2006


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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