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The C-terminal sequences of the gamma 57.5 chain of human fibrinogen
constitute a plasmin sensitive epitope that is exposed in crosslinked
fibrin
PJ Haidaris, EI Peerschke, VJ Marder and CW Francis
Department of Medicine, University of Rochester School of Medicine and
Dentistry, NY 14642.
The gamma chain of human plasma fibrinogen is heterogeneous with three
forms differing in length at the C-terminus. Alternative RNA splicing
produces two gamma chain mRNAs encoding gamma 50 and gamma 57.5
polypeptides, while fibrinogen gamma 55 is produced by post- translational
modification of the gamma 57.5 chain. The composition of purified variant
gamma chain fibrinogens, which comprise 10% to 13% total plasma fibrinogen,
is predominantly heterodimeric (A alpha, B beta, gamma 50/gamma 55 or A
alpha, B beta, gamma 50/gamma 57.5), whereas the composition of purified
fibrinogen with the major form of the gamma chain is homodimeric (A alpha,
B beta, gamma 50/gamma 50). These gamma chain variations interrupt
sequences that mediate platelet- fibrinogen interactions. Therefore, the
structure and function of gamma 57.5 C-terminal sequences were investigated
using synthetic peptides and a specific monoclonal antibody (MoAb), L2B.
The L2B epitope was localized and included gamma 57.5 chain residues
409-412 (Arg-Pro-Glu- His), as determined by differential enzyme-linked
immunosorbent assay (ELISA) reactivity with a His-412 deleted synthetic
peptide and by Western blot analysis of plasmin cleaved fibrinogen gamma
57.5. L2B had no effect on adenosine diphosphate (ADP)-induced platelet
aggregation supported by either fibrinogen gamma 50 or gamma 57.5. High
concentrations (0.5 to 1 mmol/L) of synthetic peptide gamma 57.5 405- 416
only weakly inhibited ADP-induced platelet aggregation supported by either
fibrinogen gamma 50 or gamma 57.5. Binding of fibrinogen gamma 50 (IC50 =
780 mumol/L) or gamma 57.5 (IC50 = 650 mumol/L) to ADP- stimulated
platelets was weakly inhibited, and MoAb L2B failed to inhibit fibrinogen
gamma 57.5 binding. Peptide gamma 57.5 408-416 failed to dissociate
platelet-bound fibrinogens. These data indicate that the gamma 408-416
sequence of fibrinogen gamma 55 or gamma 57.5 alone is unlikely to bind to
the platelet fibrinogen receptor, glycoprotein llb-llla (GPllb-llla), in
support of platelet aggregation under physiologic conditions. The sequence
recognized by L2B does not resemble known GPllb-llla binding site peptide
sequences [Arg-Gly-Asp- Ser (RGDS) or gamma 50 400-411] as determined by
competitive inhibition ELISA comparing these binding site synthetic
peptides with gamma 57.5 408-416. This epitope is available for binding
MoAb L2B in gamma 55 or gamma 57.5 chain dimers and binds to all gamma 57.5
408-416 epitopes equally in non-crosslinked and factor Xllla crosslinked
fibrin clots.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 74,
Issue 7,
pp. 2437-2444,
11/15/1989
Copyright © 1989 by The American Society of Hematology
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