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Molecular Modeling of Ligand and Mutation Sites of the Type A Domains
of Human von Willebrand Factor and Their Relevance to von Willebrand's
Disease
P. Vincent Jenkins,
K. John Pasi, and
Stephen J. Perkins
From the Katherine Dormandy Haemophilia and Haemostasis Centre,
Department of Haematology and the Department of Biochemistry and
Molecular Biology, Royal Free Hospital and School of Medicine, London,
UK.
von Willebrand factor (vWF) is a large multimeric, multidomain
glycoprotein found in platelets, endothelial cells and plasma. The A1,
A2, and A3 domains in vWF mediate binding to glycoprotein Ib,
ristocetin, botrocetin, collagen, sulphatides, and heparin and
provide a protease cleavage site. Mutations causing types 2B, 2M, and
2A von Willebrand's disease (vWD) are located in the A1 and A2
domains. Homology modeling was performed to provide a molecular
interpretation of vWF function and mutation sites. This was based on
our previous alignment of 75 vWF-A sequences, the doubly wound  /
fold seen in recent vWF-A crystal structures from complement receptor
type 3 and lymphocyte function-associated antigen-1, and our new
alignment of 28 vWF A1 and A2 sequences from different species. The
active site in doubly-wound / folds forms a crevice that is
located at the switch point between the two halves of the central
-sheet, and usually contains two metal-binding Asp residues in the
vWF-A superfamily. Although one of these Asp residues is absent from
the A1, A2, and A3 domains, this crevice is shown to correspond to the
ristocetin binding site in the A1 domain and the protease cleavage site
in the A2 domain. The residues R571-K572-R578-R579-K585 are found to be
conserved in 28 A1 sequences and are predicted to constitute the
heparin binding site in the A1 domain. Inspection of the type 2M vWD
mutation sites that are involved in downregulation of glycoprotein Ib
(GpIb) binding to vWF shows that these are spatially clustered at the
carboxyl-edge of the -sheet and above it in the A1 domain and may
directly perturb GpIb binding. In contrast, the type 2B vWD mutation
sites that are involved in upregulation of GpIb binding to vWF are
spatially clustered at the amino edge of this -sheet and below it
and are located on the opposite side of the A1 domain from the type 2M mutation sites. The type 2B mutations are located between the heparin
and GpIb binding sites. Because heparin binding inhibits the
interaction with GpIb, this provides an explanation of vWF upregulation. The type 2A vWD mutation sites in the A2 domain correspond to buried residues that are otherwise 100% conserved across
all 28 species, and are likely to be important for the correct folding
of the A2 domain and its physiologically important protease site.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2032-2044
© 1998 by The American Society of Hematology.
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