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Prepublished online as a Blood First Edition Paper on May 24, 2002; DOI 10.1182/blood-2002-02-0418.
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Blood, 15 September 2002, Vol. 100, No. 6, pp. 2094-2101
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Disruption of the long-range GPIIIa
Cys5-Cys435 disulfide bond results in the
production of constitutively active GPIIb-IIIa
( IIb 3) integrin complexes
Qi-Hong Sun,
Chao-Yan Liu,
Ronggang Wang,
Cathy Paddock, and
Peter J. Newman
From the Blood Research Institute, Blood Center of
Southeastern Wisconsin, and the Cardiovascular Center, Departments of
Pharmacology and Cellular Biology, Medical College of Wisconsin,
Milwaukee.
The major platelet integrin  IIb 3,
also known as the platelet glycoprotein (GP) IIb-IIIa complex, mediates
platelet aggregation by serving as the receptor for fibrinogen and von
Willebrand factor. In addition to its physiologic role, GPIIb-IIIa also
bears a number of clinically important alloantigenic determinants.
Previous studies have shown that disruption of the long-range
Cys5-Cys435 disulfide bond of the
3 subunit results in the production of isoforms that bind some, but not all, anti-PlA1 alloantibodies,
suggesting that mutations in this so-called long-range disulfide bond
can alter the conformation of GPIIIa. The purpose of this study was to
examine the effects of either the Cys5Ala or Cys435Ala substitution of
GPIIIa on the adhesive properties of the GPIIb-IIIa complex. We found
that both Ala5GPIIIa and Ala435GPIIIa were capable of associating with
GPIIb and were expressed normally on the cell surface when
cotransfected into Chinese hamster ovary (CHO) cells. CHO cells
expressing GPIIb-Ala5GPIIIa or GPIIb-Ala435IIIa bound
well-characterized, conformationally sensitive ligand-induced binding
site (LIBS) antibodies, and were capable of constitutively binding the
fibrinogen-mimetic monoclonal antibodies Pl-55 and PAC-1, as well as
soluble fibrinogen. Both GPIIb-Ala5IIIa- and GPIIb-Ala435IIIa-transfected CHO cells also bound more avidly to
immobilized fibrinogen and were capable of mediating the tyrosine phosphorylation of pp125FAK on cell adhesion.
These data are consistent with the notion that these regions of GPIIIa
participate in the conformational change associated with receptor
activation. Additionally, these studies may provide a molecular
explanation for the previously reported ability of mild reducing agents
to activate the GPIIb-IIIa complex and promote platelet aggregation.
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