RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors
Open accessAbstract
The multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) forms a complex with a receptor-associated protein (RAP) within the secretory pathway. RAP inhibits ligand binding to LRP and is required for normal functional expression of LRP in vivo, suggesting a physiological function as a specialized chaperone. We have used RAP-deficient mice, generated by gene targeting, to investigate the role of RAP in the biosynthesis and biological activity of LRP and other members of the LDL receptor gene family in various organs and in embryonic fibroblasts. Our results demonstrate that RAP is required for the proper folding and export of the receptors from the endoplasmic reticulum (ER) by preventing the premature binding of co-expressed ligands. Overexpression of apolipoprotein E (apoE), a high affinity ligand for LRP, results in dramatically reduced cellular LRP expression, an effect that is prevented by co-expression of RAP. RAP thus defines a novel class of molecular chaperones that selectively protect endocytic receptors by binding to newly synthesized receptor polypeptides, thereby preventing ligand-induced aggregation and subsequent degradation in the ER.
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“RAP binds tightly to most LDL receptor family members and functions as a molecular chaperone that assists in delivering the receptors to the cell surface (Willnow et al., 1996).”
Background
- Authors
- Willnow, T. E., Rohlmann, A., Horton, J., Otani, H., Braun, J. R., Hammer, R. E., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- The EMBO Journal
- Published
- 1996-06-01
- Volume
- 15
- Issue
- 11
- Pages
- 2632-2639
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC450198
- OpenAlex
- W339018046
- Cited by
- 276
- References
- 37
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 9 · 2014: 5 · 2013: 6 · 2012: 4
- FWCI
- 30.81
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- receptor-associated protein, rap, LDL receptor-related protein, LRP, molecular chaperones, endoplasmic reticulum retention, receptor folding, apolipoprotein E, endocytic receptor, secretory pathway, receptor biosynthesis
- MeSH terms
- Animals, Apolipoproteins E, Cell Compartmentation, Endocytosis, Endoplasmic Reticulum, Ligands, Liver, Membrane Glycoproteins, Microsomes, Liver, Receptors, Immunologic, Receptors, LDL, Mice, Knockout, Molecular Chaperones, Low Density Lipoprotein Receptor-Related Protein-1, Heymann Nephritis Antigenic Complex, Mice
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