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The role of amino-terminal residues of the heavy chain of factor IXa in the
binding of its cofactor, factor VIIIa
N Hamaguchi, SP Bajaj, KJ Smith and DW Stafford
Department of Biochemistry, Duke University Medical Center, Durham, NC.
The purpose of this study is to determine which residues of the factor IXa
heavy chain are important for interaction with the cofactor of factor IXa,
factor VIIIa. Because the monoclonal antibody (MoAb) FXC008 inhibits
interaction between factors IXa and VIIIa, and because it also reacts with
residues 181-310 of the factor IXa heavy chain, we used the
computer-modelled structure of the factor IXa heavy chain to select charged
surface residues likely to interact with FXC008 and/or factor VIIIa. We
made mutations in the region of residues 181-310 of the heavy chain of
factor IX, and replaced these amino acids individually with those located
at the same position in factor X. The mutated factor IX retained complete
clotting activity and thus interacted normally with factor VIIIa. Five
mutant proteins (factor IXK214F, factor IXK228R, factor IXE240Q, factor
IXK247V, and factor IXN260K) reacted with heavy chain-specific MoAbs FXC008
and A-5. Neither factor IXD276K nor factor IXR248H bound to FXC008. Factor
IXR252V had reduced affinity to FXC008. Our results suggest the following:
(1) factor IXa residues 214, 228, 240, 247, 248, 252, 260, and 276 are not
involved in specific interaction with factor VIIIa; and (2) the FXC008 and
factor VIIIa binding sites may not share critical residues.
Volume 84,
Issue 6,
pp. 1837-1842,
09/15/1994
Copyright © 1994 by The American Society of Hematology
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