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J Biol Chem, Vol. 274, Issue 34, 23734-23739, August 20, 1999
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From the Departments of In the present study, the interaction between the
endocytic receptor low density lipoprotein receptor-related protein
(LRP) and coagulation factor VIII (FVIII) was investigated. Using
purified components, FVIII was found to bind to LRP in a reversible and dose-dependent manner (Kd Plasma Protein Technology and
** Blood Coagulation, CLB, 1066 CX Amsterdam The Netherlands and the
¶ Department of Biochemistry, Academic Medical Center/University
of Amsterdam, 1105 AZ Amsterdam, The Netherlands
60 nM). The interaction appeared to be specific because the
LRP antagonist receptor-associated protein readily inhibited binding of
FVIII to LRP (IC50 1 nM). In addition, a
12-fold molar excess of the physiological carrier of FVIII,
i.e. von Willebrand factor (vWF), reduced the binding of
FVIII to LRP by over 90%. Cellular degradation of
125I-labeled FVIII by LRP-expressing cells ( 8 fmol/105 cells after a 4.5-h incubation) was reduced by
approximately 70% in the presence of receptor-associated protein.
LRP-directed antibodies inhibited degradation to a similar extent,
indicating that LRP indeed contributes to binding and transport of
FVIII to the intracellular degradation pathway. Degradation of FVIII was completely inhibited by vWF. Because vWF binding by FVIII involves
its light chain, LRP binding to this subunit was studied. In ligand
blotting experiments, binding of FVIII light chain to LRP could be
visualized. More detailed analysis revealed that FVIII light chain
interacts with LRP with moderate affinity (kon 5 × 104 M
1
s1; koff 2.5 × 103 s1; Kd 50 nM). Furthermore, experiments using recombinant FVIII C2
domain showed that this domain contributes to the interaction with LRP.
In contrast, no association of FVIII heavy chain to LRP could be
detected under the same experimental conditions. Collectively, our data
demonstrate that in vitro LRP is able to bind FVIII at the
cell surface and to mediate its transport to the intracellular
degradation pathway. FVIII-LRP interaction involves the FVIII light
chain, and FVIII-vWF complex formation plays a regulatory role in LRP
binding. Our findings may explain the beneficial effect of vWF on the
in vivo survival of FVIII.
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