The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor
Open accessAbstract
We previously identified the E3 ubiquitin ligase IDOL as a sterol-dependent regulator of the LDL receptor (LDLR). The molecular pathway underlying IDOL action, however, remains to be determined. Here we report the identification and biochemical and structural characterization of an E2–E3 ubiquitin ligase complex for LDLR degradation. We identified the UBE2D family (UBE2D1–4) as E2 partners for IDOL that support both autoubiquitination and IDOL-dependent ubiquitination of the LDLR in a cell-free system. NMR chemical shift mapping and a 2.1 Å crystal structure of the IDOL RING domain–UBE2D1 complex revealed key interactions between the dimeric IDOL protein and the E2 enzyme. Analysis of the IDOL–UBE2D1 interface also defined the stereochemical basis for the selectivity of IDOL for UBE2Ds over other E2 ligases. Structure-based mutations that inhibit IDOL dimerization or IDOL–UBE2D interaction block IDOL-dependent LDLR ubiquitination and degradation. Furthermore, expression of a dominant-negative UBE2D enzyme inhibits the ability of IDOL to degrade the LDLR in cells. These results identify the IDOL–UBE2D complex as an important determinant of LDLR activity, and provide insight into molecular mechanisms underlying the regulation of cholesterol uptake.
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The IDOL-UBE2D complex ubiquitinates the LDLR on its cytoplasmic domain, thereby targeting it for lysosomal degradation.
“The IDOL-UBE2D complex ubiquitinates the LDLR on its cytoplasmic domain, thereby targeting it for lysosomal degradation (Zhang et al., 2011).”
From The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning (2017) · cites this paper as Zhang et al., 2011
The section “UBE2D family proteins are the E2 enzymes for LDLR ubiquitination” reports that LDLR is ubiquitinated in the presence of IDOL and UBE2D2, and that bafilomycin blocks IDOL-dependent LDLR degradation, supporting a lysosomal pathway. Our copy does not establish that the ubiquitination occurs specifically on LDLR’s cytoplasmic domain. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIDOL is an E3 ubiquitin ligase that binds to LDLR cytoplasmic tail and triggers LDLR ubiquitination and degradation.
“Inducible degrader of the LDLR (IDOL) is an E3 ubiquitin ligase that binds to LDLR cytoplasmic tail and thereby triggers LDLR ubiquitination and degradation”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Zhang et al 2011
The Discussion reports that IDOL acts with UBE2D to ubiquitinate LDLR and that disrupting this complex inhibits LDLR degradation. Our copy does not establish that IDOL binds specifically to the LDLR cytoplasmic tail; it notes that studying the IDOL–LDLR interaction is challenging. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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- Authors
- Zhang, L., Fairall, L., Goult, B. T., Calkin, A. C., Hong, C., Millard, C. J., Tontonoz, P., & Schwabe, J. W. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Leicester (GB)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-06-15
- Volume
- 25
- Issue
- 12
- Pages
- 1262-1274
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3127428
- OpenAlex
- W2144091858
- Cited by
- 86
- References
- 4
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 3 · 2020: 8 · 2019: 7 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 8 · 2014: 4 · 2013: 6 · 2012: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (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 Foundation of Australia
- National Institutes of Health (HL090553, HL030568)
- National Heart, Lung, and Blood Institute (HL030568, P01HL090553, P01HL030568, HL090553)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- idols, LDL receptor, E3 ubiquitin ligase, RING domain, autoubiquitination, protein degradation, cholesterol absorption, structure-guided mutagenesis, sterol sensing
- MeSH terms
- Amino Acid Sequence, Humans, Iron, Models, Molecular, Receptors, LDL, Stereoisomerism, Sterols, Substrate Specificity, Protein Structure, Tertiary, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination, HEK293 Cells
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