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J. Biol. Chem., Vol. 277, Issue 38, 35616-35624, September 20, 2002

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The N-terminal Epidermal Growth Factor-like Domain of Coagulation Factor IX
PROBING ITS FUNCTIONS IN THE ACTIVATION OF FACTOR IX AND FACTOR X WITH A MONOCLONAL ANTIBODY^*

Kristina E. M. Persson, Bruno O. Villoutreix^§¶, Ann-Marie Thämlitz, Karin E. Knobe, and Johan Stenflo^**

From the Departments of  Clinical Chemistry and  Pediatrics, Lund University, University Hospital, Malmö, S-205 02 Malmö, Sweden and the ^§ Institut National de la Santé et de la Recherche Médicale, INSERM U428, Université Paris V, 4 Ave de L'Observatoire, Paris 75006, France

The absence or reduced activity of coagulation factor IX (FIX) causes the severe bleeding disorder hemophilia B. FIX contains an N-terminal Gla domain followed by two epidermal growth factor-like (EGF) domains and a serine protease domain. In this study, the epitope of monoclonal antibody AW, which is directed against the C-terminal part of the first EGF domain in human FIX, was defined, and the antibody was used to study interactions between the EGF domain of FIX and other coagulation proteins. Antibody AW completely blocks activation of FIX by activated factor XI, but activation by activated factor FVII-tissue factor is inhibited only slightly. The antibody also causes a marginal reduction in the apparent k_cat for factor X both in the presence and absence of activated factor VIII. Based on these results, we produced a preliminary model of the structure of the activated factor IX-activated factor VIII-AW complex on the surface of phospholipid. The model suggests that in the Xase complex, EGF1 of activated factor IX is not involved in direct binding to activated factor VIII. Studies of the interaction of antibody AW with a mutated FIX molecule (R94D) also suggest that the Glu⁷⁸-Arg⁹⁴ salt bridge is not important for maintaining the structure of FIX.

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