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Originally published In Press as doi:10.1074/jbc.M212748200 on December 20, 2002

J. Biol. Chem., Vol. 278, Issue 10, 7981-7987, March 7, 2003
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The Factor IX gamma -Carboxyglutamic Acid (Gla) Domain Is Involved in Interactions between Factor IX and Factor XIa*

Aysar AktimurDagger , Melanie A. Gabriel§, David GailaniDagger , and John R. Toomey§

From the Dagger  Departments of Pathology and Medicine, Vanderbilt University, Nashville, Tennessee 37232 and the § Cardiovascular and Urogenital Diseases Center of Excellence, GlaxoSmithKline, King of Prussia, Pennsylvania 19406

During hemostasis, factor IX is activated to factor IXabeta by factor VIIa and factor XIa. The glutamic acid-rich gamma -carboxyglutamic acid (Gla) domain of factor IX is involved in phospholipid binding and is required for activation by factor VIIa. In contrast, activation by factor XIa is not phospholipid-dependent, raising questions about the importance of the Gla for this reaction. We examined binding of factors IX and IXabeta to factor XIa by surface plasmon resonance. Plasma factors IX and IXabeta bind to factor XIa with Kd values of 120 ± 11 nM and 110 ± 8 nM, respectively. Recombinant factor IX bound to factor XIa with a Kd of 107 nM, whereas factor IX with a factor VII Gla domain (rFIX/VII-Gla) and factor IX expressed in the presence of warfarin (rFIX-desgamma ) did not bind. An anti-factor IX Gla monoclonal antibody was a potent inhibitor of factor IX binding to factor XIa (Ki 34 nM) and activation by factor XIa (Ki 33 nM). In activated partial thromboplastin time clotting assays, the specific activities of plasma and recombinant factor IX were comparable (200 and 150 units/mg), whereas rFIX/VII-Gla activity was low (<2 units/mg). In contrast, recombinant factor IXabeta and activated rFIX/VIIa-Gla had similar activities (80 and 60% of plasma factor IXabeta ), indicating that both proteases activate factor X and that the poor activity of zymogen rFIX/VII-Gla was caused by a specific defect in activation by factor XIa. The data demonstrate that factor XIa binds with comparable affinity to factors IX and IXabeta and that the interactions are dependent on the factor IX Gla domain.

* This work was supported by Grant HL58837 from the NHLBI, National Institutes of Health.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.

Established investigator of the American Heart Association. To whom correspondence should be addressed: Division of Hematology/Oncology, Vanderbilt University, 777 Preston Research Bldg., 2220 Pierce Ave., Nashville, TN 37232-6305. Tel.: 615-936-1505; Fax: 615-936-3853; E-mail: dave.gailani@mcmail.vanderbilt.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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