Interactions of the Low Density Lipoprotein Receptor Gene Family with Cytosolic Adaptor and Scaffold Proteins Suggest Diverse Biological Functions in Cellular Communication and Signal Transduction
Open accessAbstract
The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum of extracellular ligands. Traditionally, they had been regarded as mere cargo receptors that promote the endocytosis and lysosomal delivery of these ligands. However, recent genetic experiments in mice have revealed critical functions for two LDL receptor family members, the very low density lipoprotein receptor and the apoE receptor-2, in the transmission of extracellular signals and the activation of intracellular tyrosine kinases. This process regulates neuronal migration and is crucial for brain development. Signaling through these receptors requires the interaction of their cytoplasmic tails with the intracellular adaptor protein Disabled-1 (DAB1). Here, we identify an extended set of cytoplasmic proteins that might also participate in signal transmission by the LDL receptor gene family. Most of these novel proteins are adaptor or scaffold proteins that contain PID or PDZ domains and function in the regulation of mitogen-activated protein kinases, cell adhesion, vesicle trafficking, or neurotransmission. We show that binding of DAB1 interferes with receptor internalization suggesting a mechanism by which signaling through this class of receptors might be regulated. Taken together, these findings imply much broader physiological functions for the LDL receptor family than had previously been appreciated. They form the basis for the elucidation of the molecular pathways by which cells respond to the diversity of ligands that bind to these multifunctional receptors on the cell surface.
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The intracellular domain of the LDLR forms a scaffold for protein-protein interactions essential for proper function and trafficking of the receptor.
“The intracellular domain of the LDLR forms a scaffold for protein-protein interactions essential for proper function and trafficking of the receptor (42).”
From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [42]
The Discussion reports adaptor and scaffold proteins interacting with LDL receptor family cytoplasmic tails, and the Results show that DAB1 binding to the LDL receptor tail affects its endocytosis. But the Results explicitly say there is no indication that DAB1 binding to the LDL receptor tail has a critical physiological function in vivo. The claim’s assertion that these interactions are essential for proper LDLR function and trafficking is therefore stronger than the evidence. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIDOL interacts with the LDLR at or near the plasma membrane.
“As such, the straightforward interpretation of this result is that IDOL interacts with the LDLR at or near the plasma membrane, akin to other adaptor proteins like DAB1 and ARH involved in receptor endocytosis (6,30,31).”
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Cites
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- Authors
- Gotthardt, M., Trommsdorff, M., Nevitt, M. F., Shelton, J., Richardson, J. A., Stockinger, W., Nimpf, J., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Vienna (AT)
- Corresponding author
- Herz, Joachim
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-08
- Volume
- 275
- Issue
- 33
- Pages
- 25616-25624
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2006300948
- Cited by
- 450
- References
- 7
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 12 · 2020: 11 · 2019: 7 · 2018: 7 · 2017: 11 · 2016: 9 · 2015: 7 · 2014: 11 · 2013: 15 · 2012: 10
- FWCI
- 43.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-20948, HL63762, R37HL063762, P01HL020948)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- VLDLR, Disabled-1, adaptor proteins, scaffold proteins, PDZ domain, signal transduction, receptor internalization, neuronal migration, brain development, tyrosine kinase activation, mitogen-activated protein kinase, cell adhesion, vesicle trafficking, neurotransmission
- MeSH terms
- Amino Acid Sequence, Animals, Brain, Cell Adhesion, Cell Communication, Cells, Cultured, Cytosol, Endocytosis, Multigene Family, Glutathione Transferase, Kidney, Lipoproteins, LDL, Liver, Models, Biological, Molecular Sequence Data, Nerve Tissue Proteins, Plasmids, Receptors, LDL, Recombinant Fusion Proteins, Time Factors, Signal Transduction, Sequence Homology, Amino Acid, In Situ Hybridization, Protein Structure, Tertiary, DNA Primers, Two-Hybrid System Techniques, Mice
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