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Role of the B domain for factor VIII and factor V expression and function
DD Pittman, KA Marquette and RJ Kaufman
Genetics Institute, Cambridge, MA.
Factor V and factor VIII are homologous cofactors in the blood coagulation
cascade that have the domain structure A1-A2-B-A3-C1-C2, of which the B
domain has extensively diverged. In transfected COS-1 monkey cells,
expression of factor VIII is approximately 10-fold less efficient than that
of factor V, primarily because of inefficient protein secretion and, to a
lesser extent, reduced mRNA expression. To study the functional
significance and effect of the B domain on expression and activity,
chimeric cDNAs were constructed in which the B domains of factor V and
factor VIII were exchanged. Expression of a factor VIII chimera harboring
the B-domain of factor V yielded a fully functional factor VIII molecule
that was expressed twofold more efficiently than wild-type factor VIII
because of increased mRNA expression. Thus, sequences within the factor
VIII B domain were not responsible for the inefficient secretion of factor
VIII compared with factor V. Expression of a factor V chimera harboring the
B domain of factor VIII was slightly reduced compared with wild-type factor
V, although the secreted molecule had significantly reduced procoagulant
activity correlating with dissociated heavy and light chains and resistance
to thrombin activation. Interestingly, the factor V chimera containing the
factor VIII B domain was efficiently activated by Russell's viper venum
(RVV). A factor V B domain deletion (residues 710- 1545) molecule also
exhibited significantly reduced procoagulant activity caused by resistance
to thrombin cleavage and activation, although this molecule was activatable
by RVV. These results show that, in contrast to factor VIII, thrombin
activation of factor V requires sequences within the B domain. In addition,
thrombin activation of factor V occurs through a different mechanism than
activation by RVV.
Volume 84,
Issue 12,
pp. 4214-4225,
12/15/1994
Copyright © 1994 by The American Society of Hematology
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