Hf. Ronning et al., SYNTHETIC PEPTIDE ANALOGS OF TISSUE FACTOR AND FACTOR-VII WHICH INHIBIT FACTOR XA FORMATION BY THE TISSUE FACTOR FACTOR VIIA COMPLEX, Thrombosis research, 84(2), 1996, pp. 73-81
Factor VII (FVII) and tissue factor (TF) form a binary complex which i
nitiates the extrinsic pathway of the blood coagulation cascade. The i
nfrequent tripeptide motif Trp-Lys-Ser (WKS) is found three times in T
F. It has been suggested that the motif is involved in binding of TF t
o FVII(a). Also, Lys(165) and Lys(166) of TF have been reported to be
important for factor X activation. To elucidate the molecular interact
ions between TF and FVIIa, and the interactions between the binary com
plex and FX, we examined the inhibitory effect of synthetic TF and FVI
I peptide analogs. One- and two-stage chromogenic assays were employed
, as well as one-stage coagulation assay. The peptide analogs of TF po
ssessed the WKS motif, the double lysine residues or other regions of
TF. Synthetic peptides of FVII encompassing sequences of the FVII285-3
05 region were included for comparative purposes. TF154-167 and FVII30
0-305 significantly inhibited both FX activation and plasma coagulatio
n. FVII285-294 acted synergistically, increasing the effect observed b
y FVII300-305 on FX activation. However, TF163-175 possessing the doub
le lysine residues did not inhibit FX activation, indicating that inhi
bition of FXa formation and coagulation by TF154-167 is due to the reg
ion 154-162 of TF. None of the peptides, including the WKS tripeptide,
interfered with the FVIIa activity of the TF/FVIIa complex. Thus, the
results do not suggest that the WKS motifs are necessary for binding
of TF to FVIIa but that the third WKS motif may be of importance for t
he activation of FX. Copyright (C) 1996 Elsevier Science Ltd.