Phenotype changes resulting in high-affinity binding of von Willebrand factor to recombinant glycoprotein Ib-IX: analysis of the platelet-type von Willebrand disease mutations

DOI PDF 被引用文献3件
  • A. Sasha Tait
    From the Department of Haematology, Prince of Wales Hospital, Sydney; the School of Biochemistry and Molecular Genetics, University of New South Wales; and the Australian Centre for Blood Diseases, Department of Medicine, Monash Medical School, Monash University, Melbourne, Australia.
  • Susan L. Cranmer
    From the Department of Haematology, Prince of Wales Hospital, Sydney; the School of Biochemistry and Molecular Genetics, University of New South Wales; and the Australian Centre for Blood Diseases, Department of Medicine, Monash Medical School, Monash University, Melbourne, Australia.
  • Shaun P. Jackson
    From the Department of Haematology, Prince of Wales Hospital, Sydney; the School of Biochemistry and Molecular Genetics, University of New South Wales; and the Australian Centre for Blood Diseases, Department of Medicine, Monash Medical School, Monash University, Melbourne, Australia.
  • Ian W. Dawes
    From the Department of Haematology, Prince of Wales Hospital, Sydney; the School of Biochemistry and Molecular Genetics, University of New South Wales; and the Australian Centre for Blood Diseases, Department of Medicine, Monash Medical School, Monash University, Melbourne, Australia.
  • Beng H. Chong
    From the Department of Haematology, Prince of Wales Hospital, Sydney; the School of Biochemistry and Molecular Genetics, University of New South Wales; and the Australian Centre for Blood Diseases, Department of Medicine, Monash Medical School, Monash University, Melbourne, Australia.

この論文をさがす

抄録

<jats:title>Abstract</jats:title><jats:p>To maintain hemostasis under shear conditions, there must be an interaction between the platelet glycoprotein (GP) Ib-IX receptor and the plasma ligand von Willebrand factor (vWf). In platelet-type von Willebrand disease (Pt-vWD), hemostasis is compromised. Two mutations in the GPIbα polypeptide chain have been identified in these patients—a glycine-233 to valine change and a methionine-239 to valine change. For this investigation, these mutant proteins have been expressed in a Chinese hamster ovary cell model system. Ligand-binding studies were performed at various concentrations of ristocetin, and adhesion assays were performed under flow conditions. The Pt-vWD mutations resulted in a gain-of-function receptor. vWf binding was increased at all concentrations of ristocetin examined, and adhesion on a vWf matrix was enhanced in terms of cell tethering, slower rolling velocity, and decreased detachment with increasing shear rate. Two other mutations were also introduced into the GPIbα chain. One mutation, encompassing both the Pt-vWD mutations, created an increase in the hydrophobicity of this region. The second mutation, involving a valine-234 to glycine change, decreased the hydrophobicity of this region. Both mutations also resulted in a gain-of-function receptor, with the double mutation producing a hyperreactive receptor for vWf. These data further support the hypothesis that ligand binding is regulated by conformational changes in the amino-terminal region of GPIbα, thereby influencing the stability of the GPIbα–vWf interaction.</jats:p>

収録刊行物

  • Blood

    Blood 98 (6), 1812-1818, 2001-09-15

    American Society of Hematology

被引用文献 (3)*注記

もっと見る

キーワード

詳細情報 詳細情報について

問題の指摘

ページトップへ