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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1959-1968
Conformational Changes in the A3 Domain of von Willebrand Factor
Modulate the Interaction of the A1 Domain With Platelet Glycoprotein Ib
Bernadette Obert,
Anne Houllier,
Dominique Meyer, and
Jean-Pierre Girma
From INSERM U.143, Hôpital de Bicêtre, Paris, France.
Bitiscetin has recently been shown to induce von Willebrand factor
(vWF)-dependent aggregation of fixed platelets (Hamako J, et al,
Biochem Biophys Res Commun 226:273, 1996). We have
purified bitiscetin from Bitis arietans venom and investigated
the mechanism whereby it promotes a form of vWF that is reactive with
platelets. In the presence of bitiscetin, vWF binds to platelets in a
dose-dependent and saturable manner. The binding of vWF to platelets
involves glycoprotein (GP) Ib because it was totally blocked by
monoclonal antibody (MoAb) 6D1 directed towards the vWF-binding site of
GPIb. The binding also involves the GPIb-binding site of vWF located on
the A1 domain because it was inhibited by MoAb to vWF whose epitopes
are within this domain and that block binding of vWF to platelets
induced by ristocetin or botrocetin. However, in contrast to ristocetin
or botrocetin, the binding site of bitiscetin does not reside within
the A1 domain but within the A3 domain of vWF. Thus, among a series of
vWF fragments, 125I-bitiscetin only binds to those that
overlap the A3 domain, ie, SpIII (amino acid [aa] 1-1365), SpI (aa
911-1365), and rvWF-A3 domain (aa 920-1111). It does not bind to SpII
corresponding to the C-terminal part of vWF subunit (aa 1366-2050) nor
to the 39/34/kD dispase species (aa 480-718) or T116 (aa 449-728)
overlapping the A1 domain. In addition, bitiscetin that does not bind
to DeltaA3-rvWF (deleted between aa 910-1113) has no binding site
ouside the A3 domain. The localization of the binding site of
bitiscetin within the A3 domain was further supported by showing that
MoAb to vWF, which are specific for this domain and block the
interaction between vWF and collagen, are potent inhibitors of the
binding of bitiscetin to vWF and consequently of the bitiscetin-induced
binding of vWF to platelets. Thus, our data support the hypothesis that
an interaction between the A1 and A3 domains exists that may play a
role in the function of vWF by regulating the ability of the A1 domain
to bind to platelet GPIb.
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