Structure of the yeast ceramide synthase
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Abstract
Ceramides are essential lipids involved in forming complex sphingolipids and acting as signaling molecules. They result from the N-acylation of a sphingoid base and a CoA-activated fatty acid, a reaction catalyzed by the ceramide synthase (CerS) family of enzymes. Yet, the precise structural details and catalytic mechanisms of CerSs have remained elusive. Here we used cryo-electron microscopy single-particle analysis to unravel the structure of the yeast CerS complex in both an active and a fumonisin B1-inhibited state. Our results reveal the complex's architecture as a dimer of Lip1 subunits bound to the catalytic subunits Lag1 and Lac1. Each catalytic subunit forms a hydrophobic crevice connecting the cytosolic site with the intermembrane space. The active site, located centrally in the tunnel, was resolved in a substrate preloaded state, representing one intermediate in ceramide synthesis. Our data provide evidence for competitive binding of fumonisin B1 to the acyl-CoA-binding tunnel.
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- Authors
- Schäfer, J.-H., Clausmeyer, L., Körner, C., Esch, B. M., Wolf, V. N., Sapia, J., Ahmed, Y., Walter, S., Vanni, S., Januliene, D., Moeller, A., & Fröhlich, F.
- Affiliations
- Osnabrück University (DE)
- University of Fribourg (CH)
- Corresponding author
- Moeller, Arne
- Fröhlich, Florian
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2024-11-11
- Volume
- 32
- Issue
- 3
- Pages
- 441-449
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W4404224799
- Cited by
- 10
- References
- 6
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (FR 3647/2-2, SFB1557 P6, SFB1557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- ceramide synthase, yeast, LIP1, fumonisin B1, enzyme structure, N-acylation, ceramide synthesis, competitive inhibition, sphingolipids, cryo-electron microscopy
- MeSH terms
- Ceramides, Membrane Proteins, Models, Molecular, Oxidoreductases, Protein Binding, Protein Conformation, Saccharomyces cerevisiae, Catalytic Domain, Cryoelectron Microscopy, Saccharomyces cerevisiae Proteins, Fumonisins
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