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Originally published In Press as doi:10.1074/jbc.M105221200 on November 30, 2001

J. Biol. Chem., Vol. 277, Issue 7, 4892-4899, February 15, 2002
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Characterization of the H-kininogen-binding Site on Factor XI
A COMPARISON OF FACTOR XI AND PLASMA PREKALLIKREIN*

Thomas RennéDagger §, David Gailani||, Joost C. M. Meijers**Dagger Dagger , and Werner Müller-EsterlDagger §§

From the Dagger  Institute for Biochemistry II, Johann Wolfgang Goethe-University of Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany, the  Departments of Pathology and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6305, and the ** Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, NL-1105 AZ Amsterdam and the Department of Haematology, University Medical Center Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands

Factor XI (FXI), the zymogen of the blood coagulation protease FXIa, and the structurally homologous protein plasma prekallikrein circulate in plasma in noncovalent complexes with H-kininogen (HK). HK binds to the heavy chains of FXI and of prekallikrein. Each chain contains four apple domains (F1-F4 for FXI and P1-P4 for prekallikrein). Previous studies indicated that the HK-binding site on FXI is located in F1, whereas the major HK-binding site on prekallikrein is in P2. To determine the contribution of each FXI apple domain to HK-FXI complex formation, we examined binding of recombinant single apple domain-tissue plasminogen activator fusion proteins to HK. The order of affinity from highest to lowest is F2 F4 > F1 F3. Monoclonal antibodies against F2 are superior to F4 or F1 antibodies as inhibitors of HK binding to FXI. Antibody alpha P2, raised against prekallikrein, cross-reacts with FXI F2 and inhibits FXI-HK binding with an IC50 of 8 nM. HK binding to a platelet-specific FXI variant lacking the N-terminal half of F2 is reduced > 5-fold compared with full-length FXI. A chimeric FXI molecule in which F2 is replaced by P2 is cleaved within P2 during activation by factor XIIa, resulting in greatly reduced HK binding capacity. In contrast, wild-type FXI is not cleaved within F2, and its binding capacity for HK is unaffected by factor XIIa. Our data show that HK binding to FXI involves multiple apple domains, with F2 being most important. The findings demonstrate a similarity in mechanism for FXI and prekallikrein binding to HK.

* This work was supported in part by Deutsche Forschungsgemeinschaft Grant Mu598/5-3, a grant from the Fonds der Chemischen Industrie (to W.M.E.), and Grants HL58837 and HL02917 from the NHLBI, National Institutes of Health (to D. G.).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.

§ Recipient of a scholarship from the Biomedical Exchange Program (Berlin). Present address: Inst. of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Versbacher Strasse 5, D-97078 Würzburg, Germany.

|| Established Investigator of the American Heart Association.

Dagger Dagger Established Investigator of the Netherlands Heart Foundation supported by Grant D96.021.

§§ To whom correspondence should be addressed. Tel.: 49-69-6301-5652; Fax: 49-69-6301-5577; E-mail: wme@biochem2.de.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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