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Blood, 15 May 2001, Vol. 97, No. 10, pp. 3117-3122
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Model for a factor IX activation complex on blood
platelets: dimeric conformation of factor XIa
is essential
David Gailani,
David Ho,
Mao-Fu Sun,
Qiufang Cheng, and
Peter N. Walsh
From the Departments of Pathology and Medicine,
Vanderbilt University, Nashville, TN; and the Departments of Medicine,
Biochemistry, and Thrombosis Research, Temple University, Philadelphia,
PA.
Human coagulation factor XI (FXI) is a plasma serine protease
composed of 2 identical 80-kd polypeptides connected by a disulfide bond. This dimeric structure is unique among blood coagulation enzymes.
The hypothesis was tested that dimeric conformation is required for
normal FXI function by generating a monomeric version of FXI (FXI/PKA4)
and comparing it to wild-type FXI in assays requiring factor IX
activation by activated FXI (FXIa). FXI/PKA4 was made by replacing the
FXI A4 domain with the A4 domain from prekallikrein (PK). A dimeric
version of FXI/PKA4 (FXI/PKA4-Gly326) was prepared as a control.
Activated FXI/PKA4 and FXI/PKA4-Gly326 activate factor IX with kinetic
parameters similar to those of FXIa. In kaolin-triggered plasma
clotting assays containing purified phospholipid, FXI/PKA4 and
FXI/PKA4-Gly326 have coagulant activity similar to FXI. The surface of
activated platelets is likely to be a physiologic site for reactions
involving FXI/FXIa. In competition binding assays FXI/PKA4,
FXI/PKA4-Gly326, and FXI have similar affinities for activated
platelets (Ki = 12-16 nM). In clotting assays in which
phospholipid is replaced by activated platelets, the dimeric proteins
FXI and FXI/PKA4-Gly326 promote coagulation similarly; however,
monomeric FXI/PKA4 has greatly reduced activity. Western immunoblot
analysis confirmed that activated monomeric FXI/PKA4 activates
factor IX poorly in the presence of activated platelets. These
findings demonstrate the importance of the dimeric state to FXI
activity and suggest a novel model for factor IX activation in which
FXIa binds to activated platelets by one chain of the dimer, while
binding to factor IX through the other.
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