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Originally published In Press as doi:10.1074/jbc.M001255200 on March 24, 2000

J. Biol. Chem., Vol. 275, Issue 22, 16435-16442, June 2, 2000
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Role of Proexosite I in Factor Va-dependent Substrate Interactions of Prothrombin Activation*

Patricia J. AndersonDagger , Anna Nesset, Kumudini R. Dharmawardana, and Paul E. Bock§

From the Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Regulatory exosite I of thrombin is present on prothrombin in a precursor state (proexosite I) that specifically binds the Tyr63-sulfated peptide, hirudin54-65 (Hir54-65(SO3-)) and the nonsulfated analog. The role of proexosite I in the mechanism of factor Va acceleration of prothrombin activation was investigated in kinetic studies of the effects of peptide binding. The initial rate of human prothrombin activation by factor Xa was inhibited by the peptides in the presence of factor Va but not in the absence of the cofactor. Factor Xa and factor Va did not bind the peptide with significant affinity compared with prothrombin. Maximum inhibition reduced the factor Va-accelerated rate to a level indistinguishable from the rate in the absence of the cofactor. The effect of Hir54-65(SO3-) on the kinetics of prothrombin activation obeyed a model in which binding of the peptide to proexosite I prevented productive prothrombin interactions with the factor Xa-factor Va complex. Comparison of human and bovine prothrombin as substrates demonstrated a similar correlation between peptide binding and inhibition of factor Va acceleration. Inhibition of prothrombin activation by hirudin peptides was opposed by assembly on phospholipid vesicles of the membrane-bound factor Xa-factor-Va-prothrombin complex. Factor Va interactions of human and bovine prothrombin activation are concluded to share a common mechanism in which proexosite I participates in productive interactions of prothrombin as the substrate of the factor Xa-factor Va complex, possibly by directly mediating productive prothrombin-factor Va binding.

* This work was supported by National Institutes of Health (NIH) Grant HL38779 and NIH Research Career Development Award HL02832 (to P. E. B.).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.

Dagger Supported by NIH Instituional Training Grant HL07751 and, subsequently, by American Heart Association Southeastern Consortium Postdoctoral Fellowship Grant SE-9820133V.

§ To whom correspondence should be addressed: Dept. of Pathology, Vanderbilt University School of Medicine, C3321A Medical Center North, Nashville, TN 37232-2561. Tel.: 615-343-9863; Fax: 615-343-7023; E-mail: paul.bock@mcmail.vanderbilt.edu.

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