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The Structure and Function of Murine Factor V and Its Inactivation by
Protein C
Tony L. Yang,
Jisong Cui,
Alnawaz Rehumtulla,
Angela Yang,
Micheline Moussalli,
Randal J. Kaufman, and
David Ginsburg
From the Departments of Human Genetics, Radiation Oncology,
Biological Chemistry, and Internal Medicine, University of Michigan
Medical School, Ann Arbor, MI; and the Howard Hughes Medical Institute,
University of Michigan, Ann Arbor, MI.
Factor V (FV) is a central regulator of hemostasis, serving both as
a critical cofactor for the prothrombinase activity of factor Xa and
the target for proteolytic inactivation by the anticoagulant, activated
protein C (APC). To examine the evolutionary conservation of FV
procoagulant activity and functional inactivation by APC, we cloned and
sequenced the coding region of murine FV cDNA and generated recombinant
wild-type and mutant murine FV proteins. The murine FV cDNA encodes a
2,183-amino acid protein. Sequence comparison shows that the A1-A3 and
C1-C2 domains of FV are highly conserved, demonstrating greater than
84% sequence identity between murine and human, and 60% overall amino
acid identity among human, bovine, and murine FV sequences. In
contrast, only 35% identity among all three species is observed for
the poorly conserved B domain. The arginines at all thrombin cleavage
sites and the R305 and R504 APC cleavage sites (corresponding to amino
acid residues R306 and R506 in human FV) are invariant in all three
species. Point mutants were generated to substitute glutamine at R305, R504, or both (R305/R504). Wild-type and all three mutant FV
recombinant proteins show equivalent FV procoagulant activity. Single
mutations at R305 or R504 result in partial resistance of FV to APC
inactivation, whereas recombinant murine FV carrying both mutations
(R305Q/R504Q) is nearly completely APC resistant. Thus, the structure
and function of FV and its interaction with APC are highly conserved
across mammalian species.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4593-4599
© 1998 by The American Society of Hematology.
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