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Characterization of the gamma chain platelet binding site on fibrinogen
fragment D
NE Kirschbaum, MW Mosesson and DL Amrani
Sinai Samaritan Medical Center, Milwaukee, WI.
Glycoprotein (GP) IIb/IIIa on adenosine diphosphate (ADP)-activated human
platelets interacts with specific sites on the fibrinogen molecule leading
to aggregation. We characterized the platelet-binding site on the gamma
chains of fibrinogen using plasmic fragments D gamma A and D gamma'.
Fragment D gamma A, which contains the carboxy terminal gamma A400-411
platelet-binding sequence (HHLGGAKQAGDV), was 70-fold more active than the
synthetic gamma A400-411 peptide in inhibiting ADP- induced platelet
aggregation. Fragment D gamma A inhibited fibrinogen binding and also bound
directly to ADP-activated platelets. The Kd values determined for
fibrinogen and fragment D gamma A binding were 0.55 mumol/L and 1.2
mumol/L, respectively. In contrast, fragment D gamma', which differs from
fragment D gamma A with respect to its gamma chain sequence from position
408 to the COOH-terminus at position 427, did not inhibit platelet
aggregation or fibrinogen binding, and did not bind directly to the
platelet surface. Denaturation of fragment D gamma A with guanidine-HCl
caused a loss of inhibitory activity in platelet aggregation assays. These
data indicate that the native conformation of the gamma chain
platelet-binding site on fibrinogen is important for optimal binding to
GPIIb/IIIa.
Volume 79,
Issue 10,
pp. 2643-2648,
05/15/1992
Copyright © 1992 by The American Society of Hematology
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