ArticleCell2021
Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing.
Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 33 citations in OpenAlex.
- The SLC-ome of membrane transport: from molecular discovery to physiology and clinical applications.Physiological reviews · 2026Review
- A membrane homeostatic response to lipid overload coordinates fatty acid metabolism.bioRxiv : the preprint server for biology · 2026Article
- SREBP1-activated lipid metabolism drives ferroptosis and progression of clear cell renal cell carcinoma.Science China. Life sciences · 2026Article
- Crosstalk between protein lipidation and ubiquitination in tumor biology.Apoptosis : an international journal on programmed cell death · 2026Review
- Competition between a transmembrane helix on Scap and a membrane cholesterol regulates Scap-Insig interaction and SREBP activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The endo-lysosomal-lipid axis: bidirectional interactions between membrane trafficking dysfunction and lipid metabolic disorders.Frontiers in cell and developmental biology · 2026Review
- SPRINGing off the lock: the role of SPRING in S1P activity and SREBP-regulated lipid metabolism.Current opinion in lipidology · 2025Review
- Computational Elucidation of Sterol Recognition by SREBP Cleavage Activatory Protein.Journal of chemical information and modeling · 2025Article
- TRIM25-Mediated INSIG1 Ubiquitination Promotes MASH Progression Through Reprogramming Lipid Metabolism.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- SREBP2 as a central player in cancer progression: potential for targeted therapeutics.Frontiers in pharmacology · 2025Review
- Phosphorylation of Insig-2 mediates inhibition of fatty acid synthesis by polyunsaturated fatty acids.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain.Nature communications · 2024Article
- A cholesterol-binding bacterial toxin provides a strategy for identifying a specific Scap inhibitor that blocks lipid synthesis in animal cells.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The Role of SCAP/SREBP as Central Regulators of Lipid Metabolism in Hepatic Steatosis.International journal of molecular sciences · 2024Review
- Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1.Nature communications · 2023Article
- Identifying the Transcriptional Drivers of Metastasis Embedded within Localized Melanoma.Cancer discovery · 2023Article
- Dietary Cholesterol Metabolite Regulation of Tissue Immune Cell Development and Function.Journal of immunology (Baltimore, Md. : 1950) · 2022Review
- Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics.Signal transduction and targeted therapy · 2022Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The cholesterol-sensing protein Scap induces cholesterol synthesis by transporting membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) from the endoplasmic reticulum (ER) to the Golgi apparatus for proteolytic activation. Transport requires interaction between Scap's two ER luminal loops (L1 and L7), which flank an intramembrane sterol-sensing domain (SSD). Cholesterol inhibits Scap transport by binding to L1, which triggers Scap's binding to Insig, an ER retention protein. Here we used cryoelectron microscopy (cryo-EM) to elucidate two structures of full-length chicken Scap: (1) a wild-type free of Insigs and (2) mutant Scap bound to chicken Insig without cholesterol. Strikingly, L1 and L7 intertwine tightly to form a globular domain that acts as a luminal platform connecting the SSD to the rest of Scap. In the presence of Insig, this platform undergoes a large rotation accompanied by rearrangement of Scap's transmembrane helices. We postulate that this conformational change halts Scap transport of SREBPs and inhibits cholesterol synthesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.