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Blood, 15 September 2001, Vol. 98, No. 6, pp. 1812-1818
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
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
A. Sasha Tait,
Susan L. Cranmer,
Shaun P. Jackson,
Ian W. Dawes, and
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.
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 GPIb 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 GPIb 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
GPIb, thereby influencing the stability of the GPIb-vWf interaction.
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