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(Received for publication, June 7, 1994; and in revised form, September 26, 1994) The 39-kDa receptor-associated protein (RAP) is co-synthesized
and co-purifies with the low density lipoprotein receptor-related
protein (LRP)/
Volume 270,
Number 2,
Issue of January 13, 1995 pp. 536-540
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
-macroglobulin receptor and is thought
to modulate ligand binding to LRP. In addition to binding LRP, RAP
binds two other members of the low density lipoprotein (LDL) receptor
family, gp330 and very low density lipoprotein (VLDL) receptors. Here,
we show that RAP binds to LDL receptors as well. In normal human
foreskin fibroblasts, RAP inhibited LDL receptor-mediated binding and
catabolism of LDL and VLDL with S 20-60 or
100-400. RAP inhibited
I-labeled LDL and
S
100-400 lipoprotein binding at 4 °C
with K
values of 60 and 45 nM,
respectively. The effective concentrations for 50% inhibition
(EC
) of cellular degradation of 2.0 nM
I-labeled LDL, 4.7 nM
I-labeled S
20-60, and
3.6 nM
I-labeled S
100-400 particles were 40, 70, and 51 nM,
respectively. Treatment of cells with lovastatin to induce LDL
receptors increased cellular binding, internalization, and degradation
of RAP by 2.3-, 1.7-, and 2.6-fold, respectively. In solid-phase
assays, RAP bound to partially purified LDL receptors in a
dose-dependent manner. The dissociation constant (K
) of RAP binding to LDL receptors in
the solid-phase assay was 250 nM, which is higher than that
for LRP, gp330, or VLDL receptors in similar assays by a factor of 14
to 350. Also, RAP inhibited
I-labeled LDL and
S
100-400 VLDL binding to LDL receptors in
solid-phase assays with K
values of 140
and 130 nM, respectively. Because LDL bind via apolipoprotein
(apo) B100 whereas VLDL bind via apoE, our results show that RAP
inhibits LDL receptor interactions with both apoB100 and apoE. These
studies establish that RAP is capable of binding to LDL receptors and
modulating cellular catabolism of LDL and VLDL by this pathway.
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M. S. Nielsen, A. Nykjær, I. Warshawsky, A. L. Schwartz, and Jør. Gliemann Analysis of Ligand Binding to the alpha(2)-Macroglobulin Receptor/Low Density Lipoprotein Receptor-related Protein J. Biol. Chem., October 6, 1995; 270(40): 23713 - 23719. [Abstract] [Full Text] [PDF]
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T. Hiesberger, M. Hermann, L. Jacobsen, S. Novak, R. A. Hodits, H. Bujo, M. Meilinger, M. Httinger, W. J. Schneider, and J. Nimpf The Chicken Oocyte Receptor for Yolk Precursors as a Model for Studying the Action of Receptor-associated Protein and Lactoferrin J. Biol. Chem., August 4, 1995; 270(31): 18219 - 18226. [Abstract] [Full Text] [PDF]
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A. A. Troussard, J. Khallou, C. J. Mann, P. André, D. K. Strickland, B. E. Bihain, and F. T. Yen Inhibitory Effect on the Lipolysis-stimulated Receptor of the 39-kDa Receptor-associated Protein J. Biol. Chem., July 21, 1995; 270(29): 17068 - 17071. [Abstract] [Full Text] [PDF]
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M. Z. Kounnas, D. A. Chappell, H. Wong, W. S. Argraves, and D. K. Strickland The Cellular Internalization and Degradation of Hepatic Lipase Is Mediated by Low Density Lipoprotein Receptor-related Protein and Requires Cell Surface Proteoglycans J. Biol. Chem., April 21, 1995; 270(16): 9307 - 9312. [Abstract] [Full Text] [PDF]
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I. Mikhailenko, M. Z. Kounnas, and D. K. Strickland Low Density Lipoprotein Receptor-related Protein/[IMAGE][IMAGE]-Macroglobulin Receptor Mediates the Cellular Internalization and Degradation of Thrombospondin J. Biol. Chem., April 21, 1995; 270(16): 9543 - 9549. [Abstract] [Full Text] [PDF]
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O. M. Andersen, L. L. Christensen, P. A. Christensen, E. S. Sorensen, C. Jacobsen, S. K. Moestrup, M. Etzerodt, and H. C. Thogersen Identification of the Minimal Functional Unit in the Low Density Lipoprotein Receptor-related Protein for Binding the Receptor-associated Protein (RAP). A CONSERVED ACIDIC RESIDUE IN THE COMPLEMENT-TYPE REPEATS IS IMPORTANT FOR RECOGNITION OF RAP J. Biol. Chem., July 7, 2000; 275(28): 21017 - 21024. [Abstract] [Full Text] [PDF]
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M. J. LaDu, J. A. Shah, C. A. Reardon, G. S. Getz, G. Bu, J. Hu, L. Guo, and L. J. Van Eldik Apolipoprotein E Receptors Mediate the Effects of beta -Amyloid on Astrocyte Cultures J. Biol. Chem., October 20, 2000; 275(43): 33974 - 33980. [Abstract] [Full Text] [PDF]
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E. Van Uden, Y. Sagara, J. Van Uden, R. Orlando, M. Mallory, E. Rockenstein, and E. Masliah A Protective Role of the Low Density Lipoprotein Receptor-related Protein against Amyloid beta -Protein Toxicity J. Biol. Chem., September 22, 2000; 275(39): 30525 - 30530. [Abstract] [Full Text] [PDF]
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R. Sakthivel, J.-C. Zhang, D. K. Strickland, M. Gafvels, and K. R. McCrae Regulation of the Ligand Binding Activity of the Human Very Low Density Lipoprotein Receptor by Protein Kinase C-dependent Phosphorylation J. Biol. Chem., January 5, 2001; 276(1): 555 - 562. [Abstract] [Full Text] [PDF]
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J. C. Obunike, E. P. Lutz, Z. Li, L. Paka, T. Katopodis, D. K. Strickland, K. F. Kozarsky, S. Pillarisetti, and I. J. Goldberg Transcytosis of Lipoprotein Lipase across Cultured Endothelial Cells Requires Both Heparan Sulfate Proteoglycans and the Very Low Density Lipoprotein Receptor J. Biol. Chem., March 16, 2001; 276(12): 8934 - 8941. [Abstract] [Full Text] [PDF]
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W. Xu, Y. Takahashi, T. Sakashita, T. Iwasaki, H. Hattori, and T. Yoshimoto Low Density Lipoprotein Receptor-related Protein Is Required for Macrophage-mediated Oxidation of Low Density Lipoprotein by 12/15-Lipoxygenase J. Biol. Chem., September 21, 2001; 276(39): 36454 - 36459. [Abstract] [Full Text] [PDF]
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