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Proteolytic interactions of factor IXa with human factor VIII and factor
VIIIa
BJ Lamphear and PJ Fay
Department of Medicine, University of Rochester School of Medicine and
Dentistry, NY.
Factor IXa was shown to inactivate both factor VIII and factor VIIIa in a
phospholipid-dependent reaction that could be blocked by an antifactor IX
antibody. Factor IXa-catalyzed inactivation correlated with proteolytic
cleavages within the A1 subunit of factor VIIIa and within the heavy chain
(contiguous A1-A2-B domains) of factor VIII. Furthermore, a relatively slow
conversion of factor VIII light chain to a 68-Kd fragment was observed
after prolonged incubation. Sites of cleavage were identified within the A1
domain at Arg336-Met337 and within the factor VIII light chain at
Arg1719-Asn1720. Factor IXa failed to cleave isolated factor VIII heavy
chains, yet cleaved isolated factor VIII light chain. In addition, the
purified A1/A3-C1-C2 dimer derived from factor VIIIa was a substrate for
factor IXa; however, cleavage of the A1 subunit occurred at less than 30%
the rate of cleavage of A1 in trimeric factor VIIIa. These data suggest
that factor VIII light chain contributes to the binding site for factor IXa
and also support a role for a heavy chain determinant located within the A2
subunit in the association of factor VIIIa with factor IXa. Furthermore,
the capacity of factor IXa to proteolytically inactivate its cofactor,
factor VIIIa, suggests a mode of regulation within the intrinsic tenase
complex.
Volume 80,
Issue 12,
pp. 3120-3126,
12/15/1992
Copyright © 1992 by The American Society of Hematology
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