C. Ettelaie et al., IDENTIFICATION OF A DOMAIN IN APOLIPOPROTEIN B-100 THAT INHIBITS THE PROCOAGULANT ACTIVITY OF TISSUE FACTOR, Biochemical journal, 333, 1998, pp. 433-438
The ability of low-density lipoprotein (LDL) to inhibit the procoagula
nt activity of tissue factor is mediated by a direct protein-protein i
nteraction involving apolipoprotein (apo) B-100. A lysine-rich sequenc
e within apo B-100 (residues 3121-3217), which we have termed lysine-r
ich apo B-100-derived (KRAD)-98 peptide, may be responsible for its ac
tivity. Within this region, residues 3147-3160 (KRAD-14) contain an ex
ceptionally high proportion of positive amino acids. Both recombinant
KRAD-98 and KRAD-14 peptides inhibited the procoagulant activity of ti
ssue factor by preventing the activation of factor VII. KRAD-14 also i
nhibited the prothrombinase components, factors Xa and V. In compariso
n with the parent protein (apo B-100), KRAD-14 peptide displayed a 20-
fold enhancement in the rate of inhibition, whereas KRAD-98 peptide ex
hibited a rate closer to that of apo B-100. Mutational analysis of KRA
D-14 peptide revealed three adjacent amino acids, alteration of which
greatly reduced the inhibitory potential of this peptide. A peptide de
rived from tissue factor (residues 58-66) was found to act co-operativ
ely with tissue factor itself, but also augmented the inhibition of ti
ssue-factor activity by apo B-100. In conclusion, LDL may be a physiol
ogical regulator of haemostatic mechanisms through the interactions of
lysine-rich domains of apo B-100 with tissue factor.