Cholesterol Addition to ER Membranes Alters Conformation of SCAP, the SREBP Escort Protein that Regulates Cholesterol Metabolism
Open accessAbstract
Sterol accumulation in membranes blocks the exit of SCAP from the ER, preventing SREBP cleavage and reducing cholesterol synthesis. Sterols act through SCAP's sterol-sensing domain by an obscure mechanism. Here, we show that addition of cholesterol to ER membranes in vitro causes a conformational change in SCAP, detected by the unmasking of closely spaced trypsin cleavage sites. Two mutant forms of SCAP (Y298C and D443N) that are refractory to sterol regulation in vivo are also refractory to sterol-induced conformational change in vitro. 25-hydroxycholesterol, a potent regulator of SCAP in vivo, fails to change SCAP's conformation in vitro, suggesting that oxysterols act in intact cells by translocating cholesterol from plasma membrane to ER. These studies demonstrate an in vitro effect of cholesterol on the sterol regulatory machinery.
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Astrocytes are a major cell type in the brain for cholesterol biosynthesis, which is controlled by Srebf2 and may play an important role in the pathogenesis of AD.
“Astrocytes are a major cell type in the brain for cholesterol biosynthesis, which is controled by Srebf2 (42) and may play an important role in the pathogenesis of AD.”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [42]
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- Authors
- Brown, A. J., Sun, L., Feramisco, J. D., Brown, M. S., & Goldstein, J. L.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Brown, Michael S
- Goldstein, Joseph L
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 10
- Issue
- 2
- Pages
- 237-245
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2086024671
- Cited by
- 417
- References
- 0
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 11 · 2022: 11 · 2021: 14 · 2020: 15 · 2019: 15 · 2018: 14 · 2017: 26 · 2016: 16 · 2015: 18 · 2014: 13 · 2013: 13 · 2012: 15
- FWCI
- 27.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- W. M. Keck Foundation
- National Institutes of Health (HL-20948, GM-08014)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- SCAP, SREBP, cholesterol, endoplasmic reticulum membrane, protein conformational change, sterol-sensing domain, 25-hydroxycholesterol, oxysterols, cholesterol metabolism, sterol accumulation, trypsin cleavage site
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Cholesterol, DNA-Binding Proteins, Endoplasmic Reticulum, Cricetinae, Humans, Intracellular Membranes, Membrane Proteins, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Processing, Post-Translational, Transcription Factors, Trypsin, CHO Cells, Palmitic Acid, Intracellular Signaling Peptides and Proteins, Sterol Regulatory Element Binding Protein 2
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