Seipin forms a flexible cage at lipid droplet formation sites
Open accessPublished version of a preprint
Abstract
Lipid droplets (LDs) form in the endoplasmic reticulum by phase separation of neutral lipids. This process is facilitated by the seipin protein complex, which consists of a ring of seipin monomers, with a yet unclear function. Here, we report a structure of S. cerevisiae seipin based on cryogenic-electron microscopy and structural modeling data. Seipin forms a decameric, cage-like structure with the lumenal domains forming a stable ring at the cage floor and transmembrane segments forming the cage sides and top. The transmembrane segments interact with adjacent monomers in two distinct, alternating conformations. These conformations result from changes in switch regions, located between the lumenal domains and the transmembrane segments, that are required for seipin function. Our data indicate a model for LD formation in which a closed seipin cage enables triacylglycerol phase separation and subsequently switches to an open conformation to allow LD growth and budding.
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- Authors
- Arlt, H., Sui, X., Folger, B., Adams, C., Chen, X., Remme, R., Hamprecht, F. A., DiMaio, F., Liao, M., Goodman, J. M., Farese, R. V., & Walther, T. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- University of Washington (US)
- Heidelberg University (DE)
- Broad Institute (US)
- Corresponding author
- Goodman, Joel M.
- Farese, Robert V.
- Walther, Tobias C.
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2022-02-24
- Volume
- 29
- Issue
- 3
- Pages
- 194-202
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC8930772
- OpenAlex
- W4220940324
- Cited by
- 107
- References
- 6
- Citations by year
- 2026: 18 · 2025: 34 · 2024: 26 · 2023: 15 · 2022: 14
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Heart Association (18POST34030308)
- Deutsche Forschungsgemeinschaft (AR1164/1-1)
- Academia Sinica
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM124348, R01GM084210, R01GM123089)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- seipin, lipid droplet formation, phase separation, triglycerides, endoplasmic reticulum, switch regions, protein structure
- MeSH terms
- Endoplasmic Reticulum, Membrane Proteins, Saccharomyces cerevisiae, GTP-Binding Protein gamma Subunits, Lipid Metabolism, Lipid Droplets
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