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Blood, 1 January 2002, Vol. 99, No. 1, pp. 145-150
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Functional analysis of the C-terminal flanking sequence of
platelet glycoprotein Ib using canine-human chimeras
Yang Shen,
Jing-fei Dong,
Gabriel M. Romo,
Wendy Arceneaux,
Andrea Aprico,
Elizabeth E. Gardiner,
José A. López,
Michael C. Berndt, and
Robert K. Andrews
From the Hazel and Pip Appel Vascular Biology
Laboratory, Baker Medical Research Institute, Melbourne, Australia, and
the Departments of Medicine and of Molecular and Human Genetics, Baylor
College of Medicine and Veterans Affairs Medical Center, Houston, TX.
Platelet glycoprotein Ib-IX-V (GPIb-IX-V) mediates adhesion to von
Willebrand factor (vWF) in (patho)physiological thrombus formation. vWF
binds the N-terminal 282 residues of GPIb , consisting of an
N-terminal flank (His1-Ile35), 7 leucine-rich repeats (Leu36-Ala200), a C-terminal flank (Phe201-Gly268), and a sulfated tyrosine sequence (Asp269-Glu282). By expressing canine-human chimeras of GPIb on
Chinese hamster ovary cells, binding sites for functional anti-GPIb antibodies to individual domains were previously mapped, and it was
shown that leucine-rich repeats 2 to 4 were required for optimal vWF
recognition under static or flow conditions. Using novel
canine-human chimeras dissecting the C-terminal flank, it is now
demonstrated that (1) Phe201-Glu225 contains the epitope for AP1, an
anti-GPIb monoclonal antibody that inhibits both ristocetin- and
botrocetin-dependent vWF binding; (2) VM16d, an antibody that
preferentially inhibits botrocetin-dependent vWF binding, recognizes
the sequence Val226-Gly268, surrounding Cys248, which forms a
disulfide-bond with Cys209; (3) vWF binding to chimeric GPIb is
comparable to wild-type in 2 chimeras in which the sixth leucine-rich
repeat was of the same species as the first disulfide loop
(Phe201-Cys248) of the C-terminal flank, suggesting an interaction
between these domains may be important for optimal vWF binding; and (4)
replacing the C-terminal flank second disulfide loop (Asp249-Gly268) in
human GPIb with the corresponding canine sequence enhanced vWF
binding under static and flow conditions, providing the first evidence
for a gain-of-function phenotype associated with the second loop of the
C-terminal flank.
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