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J. Biol. Chem., Vol. 266, Issue 11, 6866-6871, Apr, 1991
GL Hortin and BL Trimpe
Acidic synthetic peptides corresponding to segments of several
nonhomologous proteins (hirudin, residues 54-65; heparin cofactor II,
residues 54-75; and fibrinogen, residues 410-427 of the gamma B-chain)
inhibit thrombin's cleavage of fibrinogen without blocking the enzyme's
active site. Here, we examined effects of these peptides on thrombin's
cleavage of protein C and small peptides. Activation of protein C by
thrombin in the absence of calcium was inhibited by all of the peptides.
Maximal inhibition was 60%, and no greater inhibition was produced by
higher peptide concentrations. This differed from progressive inhibition of
protein C activation by increasing peptide concentrations in the presence
of thrombomodulin and calcium. Potencies of the peptides were in the order
hirudin-(54-65) greater than heparin cofactor II-(54-75) greater than gamma
B-chain-(410-427). Sulfation of the tyrosine residue in hirudin-(54-65)
increased its potency about 10- fold, similar to changes in anticlotting
activity. The peptides were activators rather than inhibitors of the
cleavage of small chromogenic substrates. In the presence of the peptides,
the affinity of thrombin for the substrates S-2366
(pyro-Glu-Pro-Arg-4-nitroanilide), Chromozyme TH
(tosyl-Gly-Pro-Arg-4-nitroanilide), and S-2251 (D-Val-Leu-Lys-4-
nitroanilide) increased 1.5-2-fold with little change in the Vmax of
substrate cleavage. Potencies of peptides in these allosteric effects on
thrombin was in the same order as for their other effects. The similar
actions of these nonhomologous peptides, which are believed to bind to
thrombin's anion-binding exosite, suggest that binding of any peptide to
this site exerts the same allosteric effect on thrombin's active site.
Interactions of these peptides with thrombin may serve as models for
regulation of thrombin's interactions with natural substrates and
inhibitors.
Allosteric changes in thrombin's activity produced by peptides corresponding to segments of natural inhibitors and substrates
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
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