ArticleThe Journal of biological chemistry2017
A conserved degron containing an amphipathic helix regulates the cholesterol-mediated turnover of human squalene monooxygenase, a rate-limiting enzyme in cholesterol synthesis.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Squalene Epoxidase: Its Regulations and Links with Cancers.International journal of molecular sciences · 2024Pooled it
- Low temperature rather than hypoxia drives cholesterol synthesis and oxygen consumption in plateau zokors.iScience · 2026Article
- Squalene Epoxidase: A Key Enzymatic Component in the Triterpenoid Biosynthesis Pathway.Applied biochemistry and biotechnology · 2026Review
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation.Nature communications · 2025Article
- Mechanism and therapeutic potential of liver injury induced by cholesterol-associated proteins.Frontiers in pharmacology · 2025Review
- The contribution of mitochondria-associated ER membranes to cholesterol homeostasis.bioRxiv : the preprint server for biology · 2024Article
- Substrate recognition mechanism of the endoplasmic reticulum-associated ubiquitin ligase Doa10.Nature communications · 2024Article
- Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE.Nature communications · 2024Article
- Substrate recognition mechanism of the endoplasmic reticulum-associated ubiquitin ligase Doa10.bioRxiv : the preprint server for biology · 2024Article
- Review
- Exploring the "misfolding problem" by systematic discovery and analysis of functional-but-degraded proteins.Molecular biology of the cell · 2023Article
- Mechanisms of substrate processing during ER-associated protein degradation.Nature reviews. Molecular cell biology · 2023Review
- Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase.eLife · 2023Article
- An inducible amphipathic α-helix mediates subcellular targeting and membrane binding of RPE65.Life science alliance · 2023Article
- PI(4,5)PAdvances in experimental medicine and biology · 2023Article
- Endoplasmic Reticulum-Associated Protein Degradation.Cold Spring Harbor perspectives in biology · 2022Review
- Elements of the ERAD ubiquitin ligase Doa10 regulating sequential poly-ubiquitylation of its targets.iScience · 2022Article
- Order through destruction: how ER-associated protein degradation contributes to organelle homeostasis.The EMBO journal · 2022Review
- Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cholesterol biosynthesis in the endoplasmic reticulum (ER) is tightly controlled by multiple mechanisms to regulate cellular cholesterol levels. Squalene monooxygenase (SM) is the second rate-limiting enzyme in cholesterol biosynthesis and is regulated both transcriptionally and post-translationally. SM undergoes cholesterol-dependent proteasomal degradation when cholesterol is in excess. The first 100 amino acids of SM (designated SM N100) are necessary for this degradative process and represent the shortest cholesterol-regulated degron identified to date. However, the fundamental intrinsic characteristics of this degron remain unknown. In this study, we performed a series of deletions, point mutations, and domain swaps to identify a 12-residue region (residues Gln-62-Leu-73), required for SM cholesterol-mediated turnover. Molecular dynamics and circular dichroism revealed an amphipathic helix within this 12-residue region. Moreover, 70% of the variation in cholesterol regulation was dependent on the hydrophobicity of this region. Of note, the earliest known Doa10 yeast degron, Deg1, also contains an amphipathic helix and exhibits 42% amino acid similarity with SM N100. Mutating SM residues Phe-35/Ser-37/Leu-65/Ile-69 into alanine, based on the key residues in Deg1, blunted SM cholesterol-mediated turnover. Taken together, our results support a model whereby the amphipathic helix in SM N100 attaches reversibly to the ER membrane depending on cholesterol levels; with excess, the helix is ejected and unravels, exposing a hydrophobic patch, which then serves as a degradation signal. Our findings shed new light on the regulation of a key cholesterol synthesis enzyme, highlighting the conservation of critical degron features from yeast to humans.
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