ArticleThe Journal of biological chemistry2017
Cholesterol-induced conformational changes in the sterol-sensing domain of the Scap protein suggest feedback mechanism to control 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 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- Cholesterol and Its Derivatives: Multifaceted Players in Breast Cancer Progression.Frontiers in oncology · 2022Pooled it
- Computational Elucidation of Sterol Recognition by SREBP Cleavage Activatory Protein.Journal of chemical information and modeling · 2025Article
- PI3K Signaling at the Crossroads of Lipid Metabolism and Cancer.Advances in experimental medicine and biology · 2025Review
- DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER.Cell metabolism · 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
- Impact of De Novo Cholesterol Biosynthesis on the Initiation and Progression of Breast Cancer.Biomolecules · 2024Review
- Carbon dioxide regulates cholesterol levels through SREBP2.PLoS biology · 2023Article
- Relationship between Cholesterol-Related Lipids and Severe Acute Pancreatitis: From Bench to Bedside.Journal of clinical medicine · 2023Review
- Cholesterol-Lowering Activity of Vitisin A Is Mediated by Inhibiting Cholesterol Biosynthesis and Enhancing LDL Uptake in HepG2 Cells.International journal of molecular sciences · 2023Article
- The role of cholesterol binding in the control of cholesterol by the Scap-Insig system.European biophysics journal : EBJ · 2022Article
- Prostate Cancer-Focus on Cholesterol.Cancers · 2021Review
- Scap structures highlight key role for rotation of intertwined luminal loops in cholesterol sensing.Cell · 2021Article
- NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C.Developmental cell · 2021Article
- Mechanisms and regulation of cholesterol homeostasis.Nature reviews. Molecular cell biology · 2020Review
- Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.Journal of lipid research · 2019Article
- Industrial Trans Fatty Acids Stimulate SREBP2-Mediated Cholesterogenesis and Promote Non-Alcoholic Fatty Liver Disease.Molecular nutrition & food research · 2019Article
- Therapeutic targets of hypercholesterolemia: HMGCR and LDLR.Diabetes, metabolic syndrome and obesity : targets and therapy · 2019Article
- Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease.International journal of molecular sciences · 2018Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Scap is a polytopic protein of endoplasmic reticulum (ER) membranes that transports sterol regulatory element-binding proteins to the Golgi complex for proteolytic activation. Cholesterol accumulation in ER membranes prevents Scap transport and decreases cholesterol synthesis. Previously, we provided evidence that cholesterol inhibition is initiated when cholesterol binds to loop 1 of Scap, which projects into the ER lumen. Within cells, this binding causes loop 1 to dissociate from loop 7, another luminal Scap loop. However, we have been unable to demonstrate this dissociation when we added cholesterol to isolated complexes of loops 1 and 7. We therefore speculated that the dissociation requires a conformational change in the intervening polytopic sequence separating loops 1 and 7. Here we demonstrate such a change using a protease protection assay in sealed membrane vesicles. In the absence of cholesterol, trypsin or proteinase K cleaved cytosolic loop 4, generating a protected fragment that we visualized with a monoclonal antibody against loop 1. When cholesterol was added to these membranes, cleavage in loop 4 was abolished. Because loop 4 is part of the so-called sterol-sensing domain separating loops 1 and 7, these results support the hypothesis that cholesterol binding to loop 1 alters the conformation of the sterol-sensing domain. They also suggest that this conformational change helps transmit the cholesterol signal from loop 1 to loop 7, thereby allowing separation of the loops and facilitating the feedback inhibition of cholesterol synthesis. These insights suggest a new structural model for cholesterol-mediated regulation of Scap activity.
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Registered trials
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