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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2001-12-0339.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2472-2478
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Sustained integrin ligation involves extracellular free
sulfhydryls and enzymatically catalyzed disulfide exchange
Judith Lahav,
Kerstin Jurk,
Oded Hess,
Michael J. Barnes,
Richard W. Farndale,
Jacob Luboshitz, and
Beate E. Kehrel
From the Coagulation Laboratory, Institute of
Hematology, Rabin Medical Center-Beilinson Campus, Petah-Tiqva,
Israel; Exp und Klin Hämostaseologie, Klinik und
Poliklinik fuer Anaesthesiologie und operative Intensivmedizin,
University of Muenster, Germany; and the Department of
Biochemistry, University of Cambridge, United Kingdom.
Studies have suggested a pivotal role for free sulfhydryls in
platelet integrin function, and enzyme-mediated reduction of disulfide
bonds on platelets has been implicated. The platelet fibrinogen
receptor  IIb 3 is the best-studied
platelet integrin and serves as a model system for studying the
structure-function relation in this family of adhesion receptors. The
demonstration of free sulfhydryls on the exofacial domain of purified
IIb3, specifically in its activated
conformation, prompted us to explore the potential for
activation-dependent, enzymatically catalyzed thiol expression on
intact platelets and the possible role of surface-associated
protein disulfide isomerase (PDI) in
IIb3 ligation. Using the
membrane-impermeant sulfhydryl blocker para-chloromercuriphenyl sulfonate, the inhibitor of disulfide exchange bacitracin, and the
monoclonal anti-PDI antibody RL90, we examined fibrinogen binding to
IIb3 as well as ligation-induced
allosteric changes in the conformation of
IIb3. We sought to distinguish the
possible involvement of disulfide exchange in agonist-induced platelet stimulation from its role in integrin ligation. Analysis of the role of
free thiols in platelet aggregation suggested a thiol-independent initial ligation followed by a thiol-dependent stabilization of binding. Flow cytometric analysis showed that sustained binding of
fibrinogen, as well as expression of ligand-induced binding site
epitopes and ligand-bound conformation, depended on free thiols and
disulfide exchange. Expression of P-selectin was minimally affected,
even with complete inhibition of IIb3
function. These data indicate that although agonist-induced platelet
stimulation is independent of ecto-sulfhydryls, engagement of integrin
IIb3 on the intact platelet depends
totally on their enzymatically catalyzed surface expression.
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