9W3Z

Cryo-EM structure of the 4:4 Lac1-Lip1 complex

Summary for 9W3Z

• Entry DOI: 10.2210/pdb9w3z/pdb
• EMDB information: 65613
• Descriptor: Ceramide synthase LAC1, Ceramide synthase subunit LIP1 (2 entities in total)
• Functional Keywords: complex, transferase
• Biological source: Saccharomyces cerevisiae S288C; More
• Total number of polymer chains: 8
• Total formula weight: 270071.06

Authors

Xie, T.,Gong, X. (deposition date: 2025-07-30, release date: 2026-04-08, Last modification date: 2026-06-03)

Primary citation

Fang, Q.,Yang, C.,Yao, N.,Xie, T.,Gong, X.
Structural and functional dissection of a higher-order oligomerization interface in yeast ceramide synthase.
Nat Commun, 17:-, 2026

PubMed Abstract: Ceramide synthases (CerSs) are crucial enzymes in sphingolipid metabolism and have shown therapeutic potential for treating various metabolic disorders. However, their regulatory mechanisms remain poorly understood. In this study, we report the cryo-electron microscopy structure of a yeast CerS (yCerS), composed of a catalytic Lac1 subunit and a regulatory Lip1 subunit, organized into a higher-order 4:4 assembly. This assembly is formed by dimerization of two 2:2 Lac1-Lip1 subcomplexes via an interface primarily involving the Lac1 subunit. Notably, within this interface, the C-terminal transmembrane helix (TM8) of Lac1 adopts a dramatically twisted conformation and engages in extensive interactions with TMs 6/7/8 of the adjacent Lac1 subunit. This structural rearrangement sterically occludes the catalytic chamber and blocks acyl-CoA substrate entry. Functional assays further demonstrate that, although structurally reminiscent of an autoinhibitory conformation, this interface is required for the regulation of ceramide output and cellular adaption during perturbation of complex sphingolipid biosynthesis. Together, our findings uncover a complex oligomerization-mediated regulatory mechanism in yCerS, advancing the mechanistic understanding of ceramide synthesis control and highlighting the nuanced role of oligomerization in modulating CerS activity.

PubMed: 41917020
DOI: 10.1038/s41467-026-71272-8

Experimental method

ELECTRON MICROSCOPY (3.36 Å)