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Activation of the fibrinogen binding site on platelets isolated from a
patient with the Strasbourg I variant of Glanzmann's thrombasthenia
WC Kouns, B Steiner, TJ Kunicki, S Moog, J Jutzi, LK Jennings, JP Cazenave and F Lanza
F. Hoffmann-La Roche Ltd, Basel Switzerland.
One proposed ligand binding site on platelet integrin alpha IIb beta 3 is
the region of the beta 3 subunit encompassing amino acids 211-221. However,
we recently showed that synthetic peptides corresponding to amino acids
211-221 inhibit fibrinogen binding to alpha IIb beta 3 by binding to alpha
IIb beta 3 and not to fibrinogen. In this study, we show that AP6, a
monoclonal antibody (MoAb) directed against amino acids 214-221 of beta 3,
bound to immobilized active alpha IIb beta 3 but did not inhibit fibrinogen
binding to the complex. We then determined whether nonfunctional alpha IIb
beta 3 on platelets with a beta 3 Arg-214-->Trp mutation (Strasbourg I
variant of Glanzmann's thrombasthenia or GTV) could be induced to aggregate
after treatment with dithiothreitol (DTT). DTT has been shown to expose the
fibrinogen receptor on normal platelets. DTT treatment of GTV platelets did
result in the formation of the fibrinogen binding site as indicated by the
binding of pI-55, an MoAb that only binds to the activated form of alpha
IIb beta 3. Furthermore, DTT-treated GTV platelets aggregated in the
presence of fibrinogen and divalent cations. This aggregation was inhibited
by EDTA, RGDS, and the selective alpha IIb beta 3 antagonist, Ro 43-5054.
These data show that Arg-214 of beta 3 is not required for fibrinogen
binding or for platelet aggregation. However, this amino acid appears to be
critical for the formation and for the maintenance of the correct tertiary
structure of the fibrinogen binding site on alpha IIb beta 3.
Volume 84,
Issue 4,
pp. 1108-1115,
08/15/1994
Copyright © 1994 by The American Society of Hematology
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