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Blood, 15 November 2000, Vol. 96, No. 10, pp. 3459-3465
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Activation of factor IX zymogen results in
exposure of a binding site for low-density lipoprotein
receptor-related protein
Jaap G. Neels,
Birgit M. M. van den Berg,
Koen Mertens,
Hans ter Maat,
Hans Pannekoek,
Anton-Jan van Zonneveld, and
Peter J. Lenting
From the Department of Biochemistry, Academic Medical
Center, University of Amsterdam, Amsterdam, The
Netherlands; Department of Pharmaceutics, Utrecht Institute for
Pharmaceutical Sciences, Utrecht University, Utrecht, The
Netherlands; and the Department of Plasma Proteins, CLB
Division, Sanquin Blood Supply Foundation, Amsterdam, The
Netherlands.
The interaction between the endocytic receptor low density
lipoprotein receptor-related protein (LRP) and either coagulation factor IX or its active derivative factor IXa was studied. Purified factor IX was unable to associate with LRP when analyzed by surface plasmon resonance. By contrast, factor XIa-mediated conversion of
factor IX into factor IXa resulted in reversible dose- and calcium-dependent binding to LRP. Active-site blocking of factor IXa
did not affect binding to LRP, whereas LRP binding was efficiently inhibited in the presence of heparin or antibodies against factor IX or
LRP. The factor IXa-LRP interaction could be described by a 2-site
binding model with equilibrium dissociation constants of 27 nmol/L and
69 nmol/L. Consistent with this model, it was observed that factor IXa
binds to 2 different recombinant receptor fragments of LRP (denoted
cluster II and cluster IV) with equilibrium dissociation constants of
227 nmol/L and 53 nmol/L, respectively. The amount of factor IXa
degraded by LRP-deficient cells was 35% lower than by LRP-expressing
cells, demonstrating that LRP contributes to the transport of factor
IXa to the intracellular degradation pathway. Because ligand binding to
LRP is often preceded by binding to proteoglycans, the contribution of
proteoglycans to the catabolism of factor IXa was addressed by
employing proteoglycan-deficient cells. Degradation of factor IXa by
proteoglycan-deficient cells proceeded at a 83% lower rate than
wild-type cells. In conclusion, the data presented here indicate that
both LRP and proteoglycans have the potential to contribute to the
catabolism of factor IXa.
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