Blood coagulation factor IX residues Glu78 and Arg94 provide a link between both epidermal growth factor-like domains that is crucial in the interaction with factor VIII light chain.

The Journal of Biological Chemistry
O D ChristopheK Mertens

Abstract

Recently, we established that mutations at calcium-binding sites within the first epidermal growth factor (EGF)-like domain of activated factor IX affect its interaction with factor VIIIa (Lenting, P. J., Christophe, O. D., ter Maat, H., Rees, D. J. G., and Mertens, K. (1996) J. Biol. Chem. 271, 25332-25337). In the present study, we have investigated the functional role of residue Glu78, which is not involved in calcium binding. Glu78 is also located in the first EGF-like domain and, when mutated to Lys, is associated with severe hemophilia B. Because Glu78 is conserved in related vitamin K-dependent proteins, it is difficult to understand how a mutation at this position is associated with factor IX-specific function. In this study, we addressed the hypothesis that Glu78 exerts its biological activity by interacting with another residue. One candidate was found to be the second EGF-like domain residue, Arg94, which is also associated with severe hemophilia B when mutated. We constructed a series of mutants that included mutations at position 78 alone (Glu78 to Lys/Glu78 to Asp) or at both positions 78 and 94 (Glu78 to Lys and Arg94 to Asp). The functional parameters of immunopurified and activated mutants were compared with no...Continue Reading

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Citations

Aug 31, 2001·Biochemical and Biophysical Research Communications·K E PerssonJ Stenflo
Dec 20, 2003·Blood Reviews·Philip J Fay
May 1, 2010·Current Cardiology Reports·Becky WoodruffRichard C Becker
Jul 19, 2014·Expert Opinion on Drug Delivery·Estrella Lopez-GordoAndrew H Baker
Aug 17, 2005·Journal of Thrombosis and Haemostasis : JTH·L AutinB O Villoutreix
Jul 14, 2011·Cardiovascular Therapeutics·Christopher Roser-JonesRichard C Becker
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Dec 1, 2001·The Journal of Biological Chemistry·Frank H WilkinsonPeter N Walsh
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