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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3260-3267
Adhesive and Signaling Properties of a Naturally Occurring Allele
of Glycoprotein IIIa With an Amino Acid Substitution Within the
Ligand Binding Domain The Pena/Penb
Platelet Alloantigenic Epitopes
Ronggang Wang and
Peter J. Newman
From the Blood Research Institute, The Blood Center
of Southeastern Wisconsin, Milwaukee; and the Departments
of Cellular Biology and Pharmacology, Medical College of
Wisconsin, Milwaukee, WI.
Platelet membrane glycoprotein IIIa (GPIIIa) is the most polymorphic
integrin subunit in man, with at least seven recognized allelic
isoforms present in the human gene pool. Whether these allelic variants
of the GPIIb-IIIa complex differ in the ability to interact with the
adhesive ligand fibrinogen (Fg) is still unknown. Since the
Pena and Penb allelic forms of GPIIIa are
distinguished by a single Arg143Gln amino acid substitution within the
RGD binding domain of GPIIIa and anti-Pena human
alloantibodies have been shown to bind GPIIb-IIIa on the platelet
surface and inhibit ADP-induced platelet aggregation, we expressed both
forms of this integrin in Chinese hamster ovary (CHO)
cells and examined the relative adhesive properties. Both allelic forms
of GPIIb-IIIa were expressed on the cell surface and were recognized by
a well-characterized panel of murine and human monoclonal and
polyclonal antibodies. Like Pena, the Penb form
of GPIIb-IIIa could undergo conformational changes in response to RGD
peptide binding, and could be induced by activating antibodies to bind
Fg and the Fg mimetic antibody P1-55. The binding affinity for Fg of
the Pena form of the GPIIb-IIIa complex was not
significantly different from that of the Penb form, nor was
its ability to signal to focal adhesion kinase, suggesting that
Arg143Gln polymorphism has little or no effect on integrin function.
Examination of the functional consequences of other integrin
polymorphisms may be necessary to determine whether they constitute a
risk factor for thrombosis or hemorrhage.
© 1998 by The American Society of Hematology.
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