Evidence that catalytically-inactivated thrombin forms non-covalently linked dimers that bridge between fibrin/fibrinogen fibers and enhance fibrin polymerization

Biophysical Chemistry
Michael W MosessonK R Siebenlist

Abstract

Phe-pro-arg-chloromethyl ketone-inhibited alpha-thrombin [FPR alpha-thr] retains its fibrinogen recognition site (exosite 1), augments fibrin/fibrinogen [fibrin(ogen)] polymerization, and increases the incorporation of fibrin into clots. There are two 'low-affinity' thrombin-binding sites in each central E domain of fibrin, plus a non-substrate 'high affinity' gamma' chain thrombin-binding site on heterodimeric 'fibrin(ogen) 2' molecules (gamma(A), gamma'). 'Fibrin(ogen) 1' (gamma(A), gamma(A)) containing only low-affinity thrombin-binding sites, showed concentration-dependent FPR alpha-thr enhancement of polymerization, thus indicating that low-affinity sites are sufficient for enhancing polymerization. FPR gamma-thr, whose exosite 1 is non-functional, did not enhance polymerization of either fibrin(ogen)s 1 or 2 and DNA aptamer HD-1, which binds specifically to exosite 1, blocked FPR alpha-thr enhanced polymerization of both types of fibrin(ogen) (1>2). These results showed that exosite 1 is the critical element in thrombin that mediates enhanced fibrin polymerization. Des B beta 1-42 fibrin(ogen) 1, containing defective 'low-affinity' binding sites, was subdued in its FPR alpha-thr-mediated reactivity, whereas des B beta 1-4...Continue Reading

References

Nov 24, 1992·Biochemistry·K P Hopfner, E Di Cera
Mar 15, 1987·The Biochemical Journal·M Kaminski, J McDonagh
Sep 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·C Wolfenstein-Todel, M W Mosesson
Jul 14, 1995·The Journal of Biological Chemistry·M TsiangC S Gibbs
Jan 1, 1993·Thrombosis Research·M T Stubbs, W Bode
Sep 20, 1996·The Journal of Biological Chemistry·D A MehM W Mosesson
Jul 4, 2001·Thrombosis Research·D A MehG Di Minno
Jul 20, 2001·Annals of the New York Academy of Sciences·M RoccoF Ferri
Apr 19, 2003·The Journal of Biological Chemistry·Caroline H PospisilJeffrey I Weitz
Jul 23, 2003·Journal of Thrombosis and Haemostasis : JTH·R S LovelyD H Farrell
Feb 24, 2004·Proceedings of the National Academy of Sciences of the United States of America·Igor PechikLeonid Medved

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood Clotting Disorders

Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.