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Modeling and functional analysis of the interaction between von Willebrand factor A1 domain and glycoprotein Ib alpha

Academic Article
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Overview

authors

  • Vasudevan, S.
  • Roberts, J. R.
  • McClintock, R. A.
  • Dent, J. A.
  • Celikel, R.
  • Ware, J.
  • Varughese, K. I.
  • Ruggeri, Zaverio

publication date

  • April 2000

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Binding of the von Willebrand factor (vWF) A1 domain to the glycoprotein (GP) Ib-IX-V complex mediates platelet adhesion to reactive substrates under high shear stress conditions, a key event in hemostasis and thrombosis. We have now used the known three-dimensional structure of the A1 domain to model the interaction with the GP Ibalpha sequence 271-279, which has previously been implicated in ligand binding. Docking procedures suggested that A1 domain residues in strand beta3 and preceding loop (residues 559-566) as well as in helix alpha3 (residues 594-603) interact with Asp residues 272, 274, 277 and sulfated Tyr residues 278 and 279 in GP Ibalpha. To verify this model, 14 mutant A1 domain fragments containing single or multiple side chain substitutions were tested for their ability to mediate platelet adhesion under flow. Each of the vWF residues Tyr(565), Glu(596), and Lys(599) proved to be strictly required for A1 domain function, which, in agreement with previous findings, was also dependent on Gly(561). Moreover, an accessory functional role was apparent for a group of positively charged residues, including Arg at positions 629, 632, 636 and Lys at positions 643 and 645, possibly acting in concert. There was, however, no evidence from the model that these residues directly participate in forming the complex with GP Ibalpha. These results provide a partial model of the vWF-GP Ibalpha interaction linked to the manifestation of functional activity in platelet adhesion.

subject areas

  • Amino Acids
  • Blood Platelets
  • Cell Adhesion
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Mutagenesis
  • Platelet Glycoprotein GPIb-IX Complex
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins
  • von Willebrand Factor
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.275.17.12763

PubMed ID

  • 10777573
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Additional Document Info

start page

  • 12763

end page

  • 12768

volume

  • 275

issue

  • 17

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