A structure of human Scap bound to Insig-2 suggests how their interaction is regulated by sterols
Open accessAbstract
The sterol regulatory element-binding protein (SREBP) pathway controls cellular homeostasis of sterols. The key players in this pathway, Scap and Insig-1 and -2, are membrane-embedded sterol sensors. The 25-hydroxycholesterol (25HC)-dependent association of Scap and Insig acts as the master switch for the SREBP pathway. Here, we present cryo-electron microscopy analysis of the human Scap and Insig-2 complex in the presence of 25HC, with the transmembrane (TM) domains determined at an average resolution of 3.7 angstrom. The sterol-sensing domain in Scap and all six TMs in Insig-2 were resolved. A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. Unwinding of the middle of the Scap-S4 segment is crucial for 25HC binding and Insig association.
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The binding of 25HC to the Insig-Scap interface retains the Scap-Srebp2 complex in the ER, precluding its proteolytic processing in the Golgi.
“The binding of 25HC to the Insig-Scap interface retains the Scap-Srebp2 complex in the ER precluding its proteolytic processing in the Golgi (59).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [59]
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Cashikar, A. G., Toral-Rios, D., Timm, D., Romero, J., Strickland, M., Long, J. M., Han, X., Holtzman, D. M., & Paul, S. M. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100350 · Cited by 72 · see citing works
- Authors
- Yan, R., Cao, P., Song, W., Qian, H., Du, X., Coates, H. W., Zhao, X., Li, Y., Gao, S., Gong, X., Liu, X., Sui, J., Lei, J., Yang, H., Brown, A. J., Zhou, Q., Yan, C., & Yan, N.
- Affiliations
- Westlake University (CN)
- Center for Life Sciences (CN)
- Princeton University (US)
- UNSW Sydney (AU)
- Southern University of Science and Technology (CN)
- National Institute of Biological Sciences, Beijing (CN)
- Tsinghua University (CN)
- Corresponding author
- Yan, Renhong
- Cao, Pingping
- Song, Wenqi
- Yan, Chuangye
- Yan, Nieng
- ORCID
- Venue
- Science
- Published
- 2021-03-05
- Volume
- 371
- Issue
- 6533
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3119674414
- Cited by
- 100
- References
- 0
- Citations by year
- 2026: 15 · 2025: 26 · 2024: 18 · 2023: 14 · 2022: 21 · 2021: 6
- FWCI
- 14.08
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-nd
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- Funders
- National Natural Science Foundation of China (31971123)
- Ministry of Science and Technology of the People’s Republic of China (2020YFA0509301)
- China Postdoctoral Science Foundation (2020M681937)
- Beijing Nova Program (Z201100006820039)
- National Postdoctoral Program for Innovative Talents of China (BX20200304)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- SCAP, INSIG2, INSIG1, SREBP pathway, SREBP, 25-hydroxycholesterol, sterol sensing, transmembrane domain, protein-protein complex structure, sterol homeostasis
- MeSH terms
- Humans, Hydroxycholesterols, Membrane Proteins, Mutation, Cryoelectron Microscopy, Intracellular Signaling Peptides and Proteins, Protein Interaction Domains and Motifs
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