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Blood, 15 June 2002, Vol. 99, No. 12, pp. 4422-4427
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Site-directed mutagenesis of platelet glycoprotein Ib
demonstrating residues involved in the sulfation of tyrosines 276, 278, and 279
A. Sasha Tait,
Jing-Fei Dong,
José A. López,
Ian W. Dawes, and
Beng H. Chong
From the Department of Haematology, Prince of
Wales Hospital, New South Wales, Australia; Baylor College of Medicine,
Houston, TX; School of Biochemistry and Molecular Genetics and the
Department of Medicine, St George Clinical School, University of New
South Wales, New South Wales, Australia.
The interaction between platelet glycoprotein (GP) Ib
and von Willebrand factor (VWF) is essential for initiation of
hemostasis. The sulfation of the 3 tyrosine residues 276, 278, and 279 in GPIb is an important posttranslational modification that
seems to promote the interaction with VWF. The environment where
sulfation of tyrosines occurs has been proposed to contain highly
acidic residues. This investigation has examined the highly acidic
region from Asp249 to Asp287 in the mature GPIb protein.
Changes to most of the carboxylic acids in this region resulted in
decreased reactivity to VWF. Only 3 mutants (Glu270Gln,
Asp283Asn, Asp283Asn/Glu285Gln/Asp287Asn) resulted in the abolition of
sulfation. Two novel mutations were also created. First, a deletion of
the 7 amino acids from Tyr276 to Glu282 led to a loss of sulfation and
totally abolished VWF binding in the presence of botrocetin. This
confirms that it is these 3 tyrosines that undergo sulfation and that
this region is crucial for botrocetin-mediated VWF binding. The second
mutation involves changing the lysine residues at 253, 258, and 262 to alanine. This also led to distinct changes in VWF binding and abolition
of sulfation.
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