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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 164-172
Structure and function of the von Willebrand factor A1 domain:
analysis with monoclonal antibodies reveals distinct binding sites
involved in recognition of the platelet membrane glycoprotein
Ib-IX-V complex and ristocetin-dependent activation
Mariagrazia De Luca,
David A. Facey,
Emmanuel J. Favaloro,
Mark S. Hertzberg,
James C. Whisstock,
Tracy McNally,
Robert K. Andrews, and
Michael
C. Berndt
From the Hazel and Pip Appel Vascular Biology Laboratory, Baker
Medical Research Institute, Melbourne; the Department of Hematology,
Westmead Hospital, Westmead, New South Wales; and the Department of
Biochemistry and Molecular Biology, Monash University, Clayton,
Australia.
Binding of the adhesive glycoprotein, von Willebrand factor (vWf),
to the platelet membrane glycoprotein (GP) Ib-IX-V complex initiates
platelet adhesion and aggregation at high shear stress in hemostasis
and thrombosis. In this study, the GP Ib-IX-V binding site within the
vWf A1 domain was analyzed using a panel of murine monoclonal
antibodies raised against a 39/34-kd vWf fragment
(Leu-480/Val-481-Gly-718) encompassing the A1 domain. One antibody,
6G1, strongly inhibited ristocetin-dependent vWf binding to platelets,
but had no effect on botrocetin- or jaracetin-dependent binding, or
asialo-vWf-dependent platelet aggregation. The 6G1 epitope was mapped
to Glu-700-Asp-709, confirming the importance of this region for
modulation of vWf by ristocetin. Like ristocetin, 6G1 activated the vWf
A1 domain, because it enhanced binding of the 39/34-kd
fragment to platelets. In contrast, 5D2 and CR1 completely inhibited
asialo-vWf-induced platelet aggregation and ristocetin-induced vWf
binding to GP Ib-IX-V. However, only 5D2 blocked botrocetin- and
jaracetin-induced vWf binding to platelets and binding of vWf to
botrocetin- and jaracetin-coated beads. Epitopes for 5D2 and CR1 were
conformationally dependent, but not congruent. Other antibodies mapped
to epitopes within the A1 domain (CR2 and CR15, Leu-494-Leu-512; CR2,
Phe-536-Ala-554; CR3, Arg-578-Glu-596; CR11 and CR15,
Ala-564-Ser-582) were not functional, identifying regions of the vWf
A1 domain not directly involved in vWf-GP Ib-IX-V interaction. The
combined results provide evidence that the proline-rich sequence
Glu-700-Asp-709 constitutes a regulatory site for ristocetin, and that
ristocetin and botrocetin induce, at least in part, separate
receptor-recognition sites on vWf. (Blood. 2000;95:164-172)
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