FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors
Open accessAbstract
The E3 ubiquitin ligase IDOL (inducible degrader of the LDL receptor) regulates LDL receptor (LDLR)-dependent cholesterol uptake, but its mechanism of action, including the molecular basis for its stringent specificity, is poorly understood. Here we show that IDOL uses a singular strategy among E3 ligases for target recognition. The IDOL FERM domain binds directly to a recognition sequence in the cytoplasmic tails of lipoprotein receptors. This physical interaction is independent of IDOL's really interesting new gene (RING) domain E3 ligase activity and its capacity for autoubiquitination. Furthermore, IDOL controls its own stability through autoubiquitination of a unique FERM subdomain fold not present in other FERM proteins. Key residues defining the IDOL–LDLR interaction and IDOL autoubiquitination are functionally conserved in their insect homologs. Finally, we demonstrate that target recognition by IDOL involves a tripartite interaction between the FERM domain, membrane phospholipids, and the lipoprotein receptor tail. Our data identify the IDOL–LDLR interaction as an evolutionarily conserved mechanism for the regulation of lipid uptake and suggest that this interaction could potentially be exploited for the pharmacologic modulation of lipid metabolism.
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IDOL controls the abundance of LDLR, VLDLR, and ApoER2 via ubiquitination, which targets the proteins for lysosomal degradation.
“IDOL controls the abundance of three proteins (LDLR, VLDLR, and ApoER2) via ubiquitination, which targets the proteins for lysosomal degradation9,13.”
From IDOL regulates systemic energy balance through control of neuronal VLDLR expression (2019) · cites this paper as [13]
Co-expression of an IDOL-resistant ApoER2 mutant (F894A) rescues the reduction in filopodia density induced by IDOL overexpression.
“On the other hand, co-expression of an IDOL-resistant ApoER2 mutant (F894A) (Calkin et al., 2011) rescued the reduction in filopodia density induced by IDOL overexpression”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Calkin et al., 2011
An IDOL-resistant VLDLR mutant (F832A) fails to rescue the reduction in filopodia density induced by IDOL overexpression.
“while an IDOL-resistant VLDLR mutant (F832A) (Calkin et al., 2011) failed to do so (Figure 3C).”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Calkin et al., 2011
Cites
Hong, C., Duit, S., Jalonen, P., Out, R., Scheer, L., Sorrentino, V., Boyadjian, R., Rodenburg, K. W., Foley, E., Korhonen, L., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.123729 · Cited by 142 · see citing works
Self-citationWeissglas-Volkov, D., Calkin, A. C., Tusie-Luna, T., Sinsheimer, J. S., Zelcer, N., Riba, L., Tino, A. M. V., Ordoñez-Sánchez, M. L., Cruz-Bautista, I., Aguilar-Salinas, C. A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45504 · Cited by 66 · see citing works
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Mechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980 · see citing works
Nair, J. K., Willoughby, J. L. S., Chan, A., Charisse, K., Alam, M. R., Wang, Q., Hoekstra, M., Kandasamy, P., Kel’in, A. V., Milstein, S., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja505986a · Cited by 1,141 · see citing works
Self-citationTranscriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR
Calkin, A. C., & Tontonoz, P. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3312 · Cited by 779 · see citing works
Self-citationLiver X receptors in lipid signalling and membrane homeostasis
Wang, B., & Tontonoz, P. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0037-x · Cited by 722 · see citing works
Self-citationGray, S. P., Di Marco, E., Kennedy, K., Chew, P., Okabe, J., El-Osta, A., Calkin, A. C., Biessen, E. A. L., Touyz, R. M., Cooper, M. E., et al. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.115.307012 · Cited by 189 · see citing works
Self-citationFeedback Regulation of Cholesterol Uptake by the LXR–IDOL–LDLR Axis
Zhang, L., Reue, K., Fong, L. G., Young, S. G., & Tontonoz, P. (2012) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.112.250571 · Cited by 137 · see citing works
Self-citationThe LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice
Hong, C., Marshall, S. M., McDaniel, A. L., Graham, M., Layne, J. D., Cai, L., Scotti, E., Boyadjian, R., Kim, J., Chamberlain, B. T., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.001 · Cited by 87 · see citing works
Self-citationChoi, J., Gao, J., Kim, J., Hong, C., Kim, J., & Tontonoz, P. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aad1904 · Cited by 49 · see citing works
Self-citationGao, J., Marosi, M., Choi, J., Achiro, J. M., Kim, S., Li, S., Otis, K., Martin, K. C., Portera-Cailliau, C., & Tontonoz, P. (2017) · eLife · doi:10.7554/elife.29178 · Cited by 30 · see citing works
Self-citationIDOL regulates systemic energy balance through control of neuronal VLDLR expression
Lee, S. D., Priest, C., Bjursell, M., Gao, J., Arneson, D. V., Ahn, I. S., Diamante, G., van Veen, J. E., Massa, M. G., Calkin, A. C., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0127-7 · Cited by 26 · see citing works
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- Authors
- Calkin, A. C., Goult, B. T., Zhang, L., Fairall, L., Hong, C., Schwabe, J. W. R., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Leicester (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-11-22
- Volume
- 108
- Issue
- 50
- Pages
- 20107-20112
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3250164
- OpenAlex
- W2037654209
- Cited by
- 62
- References
- 2
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 8 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 5 · 2015: 4 · 2014: 11 · 2013: 4 · 2012: 3
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Wellcome Trust (WT091820, 091820, WT085408)
- National Heart, Lung, and Blood Institute (HL030568, HL066088, P01HL030568, R01HL066088)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- FERM domain, LDL receptor, target recognition, autoubiquitination, cytoplasmic tail, membrane phospholipids, cholesterol absorption, lipid metabolism, protein stability
- MeSH terms
- Amino Acid Sequence, Amino Acids, Animals, Cell Membrane, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Conserved Sequence, Protein Structure, Tertiary, Receptors, Lipoprotein, Amino Acid Motifs, Ubiquitin-Protein Ligases, Mice, Ubiquitination, Protein Stability, HEK293 Cells, Proteolysis
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