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J Biol Chem, Vol. 273, Issue 30, 19049-19054, July 24, 1998
From the Departments of Factor VIIIa, the protein cofactor for factor
IXa, is comprised of A1, A2, and A3-C1-C2 subunits. Isolated subunits
of factor VIIIa were examined for their ability to accelerate the
factor IXa-catalyzed activation of factor X. The A2 subunit enhanced the kcat for this conversion by 100-fold
whereas the Km for factor X was unaffected. The
apparent Kd for the interaction of A2 subunit with
factor IXa was ~300 nM. Similar results were obtained
using purified A2 expressed as the isolated domain in Chinese hamster
ovary cells, although this material was less stable than the factor
VIIIa-derived material. Isolated A1 and A3-C1-C2 subunits showed no
effect on the rate of factor X conversion. A2 subunit increased the
fluorescence anisotropy of fluorescein-Phe-Phe-Arg-factor IXa
(
The A2 Subunit of Factor VIIIa Modulates the Active Site of
Factor IXa
§ and
Medicine and
§ Biochemistry and Biophysics, University of Rochester
School of Medicine and Dentistry, Rochester, New York 14642
r = 0.015) and markedly increased anisotropy in
the presence of factor X (r = 0.057), suggesting
that it contributes to the orientation of the factor IXa active site
and its relation to substrate. A synthetic peptide to A2 residues
558-565 inhibited the A2-dependent enhancement of factor X
activation with an IC50 = 40 µM, a value
similar to its Ki for inhibition of the intrinsic
factor Xase (105 µM). These results indicate that the
isolated A2 subunit modulates the active site of factor IXa and
identifies a functional role for this subunit in factor VIIIa.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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