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Expression of human blood coagulation factor XI: characterization of the
defect in factor XI type III deficiency
JC Meijers, EW Davie and DW Chung
Department of Biochemistry, University of Washington, Seattle 98195.
Human factor XI (FXI) is a blood coagulation factor participating in the
early phase of the intrinsic pathway of blood coagulation. It circulates in
blood as a glycoprotein composed of two identical chains held together by a
single disulfide bond between the fourth apple domains. FXI has been
expressed in baby hamster kidney (BHK) cells, where it was synthesized as a
single-chain molecule that was converted to the dimer before secretion. The
recombinant protein was fully active in a clotting assay, indicating that
it interacted readily with other components of the coagulation cascade. A
mutant FXI in which Phe283 was converted to Leu (Phe283Leu) was also
expressed in BHK cells. This amino acid change occurs in the fourth apple
domain of FXI and corresponds to the type III deficiency in Ashkenazi Jews.
The mutant protein was secreted at reduced levels (about 8%) compared with
normal FXI. This was due to a defect in the dimerization of the molecule
rather than a decrease in the transcription of type III messenger RNA. Once
secreted, however, the mutant protein consisted of a dimer with full
biologic activity. The in vitro expression of FXI indicated that the
impaired dimerization and secretion of the Phe283Leu mutant can account for
the defect found in patients who are homozygous for the type III FXI
deficiency.
Volume 79,
Issue 6,
pp. 1435-1440,
03/15/1992
Copyright © 1992 by The American Society of Hematology
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