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Originally published In Press as doi:10.1074/jbc.M004142200 on June 2, 2000

J. Biol. Chem., Vol. 275, Issue 33, 25239-25246, August 18, 2000
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Recombinant Fibrinogen Studies Reveal That Thrombin Specificity Dictates Order of Fibrinopeptide Release*

Jennifer L. MullinDagger , Oleg V. Gorkun§, Cameron G. Binnie§, and Susan T. LordDagger §||

From the Departments of Dagger  Chemistry and § Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525

During cleavage of fibrinogen by thrombin, fibrinopeptide A (FpA) release precedes fibrinopeptide B (FpB) release. To examine the basis for this ordered release, we synthesized A'beta fibrinogen, replacing FpB with a fibrinopeptide A-like peptide, FpA' (G14V). Analyses of fibrinopeptide release from A'beta fibrinogen showed that FpA release and FpA' release were similar; the release of either peptide followed simple first-order kinetics. Specificity constants for FpA and FpA' were similar, demonstrating that these peptides are equally competitive substrates for thrombin. In the presence of Gly-Pro-Arg-Pro, an inhibitor of fibrin polymerization, the rate of FpB release from normal fibrinogen was reduced 3-fold, consistent with previous data; in contrast, the rate of FpA' release from A'beta fibrinogen was unaffected. Thus, with A'beta fibrinogen, fibrinopeptide release from the beta  chain is similar to fibrinopeptide release from the alpha  chain. We conclude that the ordered release of fibrinopeptides is dictated by the specificity of thrombin for its substrates. We analyzed polymerization, following changes in turbidity, and found that polymerization of A'beta fibrinogen was similar to that of normal fibrinogen. We analyzed clot structure by scanning electron microscopy and found that clots from A'beta fibrinogen were similar to clots from normal fibrinogen. We conclude that premature release of the fibrinopeptide from the N terminus of the beta  chain does not affect polymerization of fibrinogen.

* This work was supported by National Institutes of Health Grant R01-HL31048 (to S. T. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Human Genetics, Glaxo Wellcome, 5 Moore Dr., Research Triangle Park, NC 27709.

|| To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, CB 7525, 605 Brinkhous-Bullitt Bldg., University of North Carolina, Chapel Hill, NC 27599-7525. Tel.: 919-966-2617; Fax: 919-966-6718; E-mail: stl@med.unc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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