title: Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo.
abstract: The 39-kDa receptor-associated protein (RAP) associates with the multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) and thereby prevents the binding of all known ligands, including alpha 2-macroglobulin and chylomicron remnants. RAP is predominantly localized in the endoplasmic reticulum, raising the possibility that it functions as a chaperone or escort protein in the biosynthesis or intracellular transport of LRP. Here we have used gene targeting to show that RAP promotes the expression of functional LRP in vivo. The amount of mature, processed LRP is reduced in liver and brain of RAP-deficient mice. As a result, hepatic clearance of alpha 2-macroglobulin is impaired and remnant lipoproteins accumulate in the plasma of RAP-deficient mice that also lack functional LDL receptors. These results are consistent with the hypothesis that RAP stabilizes LRP within the secretory pathway. They also suggest a further mechanism by which the activity of an endocytic receptor may be modulated in vivo.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Willnow
authors.forename: S A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: R E
authors.initials: RE
authors.lastname: Hammer
authors.forename: J
authors.initials: J
authors.lastname: Herz
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000097:blood / Q000302:isolation & purification; D001212:Asialoglycoproteins / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002417:Cattle; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D004705:Endocytosis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D060748:Fetuins; D015698:Genomic Library; D006023:Glycoproteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D026563:LDL-Receptor Related Protein-Associated Protein; D008099:Liver / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D008565:Membrane Proteins / Q000302:isolation & purification / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009838:Oligodeoxyribonucleotides; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D011973:Receptors, LDL / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D014280:Triglycerides / Q000097:blood; D000509:alpha-Fetoproteins / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D001053:Apolipoproteins; D001212:Asialoglycoproteins; D002352:Carrier Proteins; D060748:Fetuins; D006023:Glycoproteins; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D014280:Triglycerides; D000509:alpha-Fetoproteins; D000511:alpha-Macroglobulins; C017029:asialofetuin; D002784:Cholesterol