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- PDB-9w3z: Cryo-EM structure of the 4:4 Lac1-Lip1 complex -

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Basic information

Entry
Database: PDB / ID: 9w3z
TitleCryo-EM structure of the 4:4 Lac1-Lip1 complex
Components
  • Ceramide synthase LAC1
  • Ceramide synthase subunit LIP1
KeywordsTRANSFERASE / Complex
Function / homology
Function and homology information


very-long-chain ceramide synthase / acyl-CoA ceramide synthase complex / Sphingolipid de novo biosynthesis / sphingosine N-acyltransferase activity / ceramide biosynthetic process / nuclear periphery / nuclear envelope / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
TRAM/LAG1/CLN8 homology domain / Sphingosine N-acyltransferase Lag1/Lac1-like / TLC domain / TLC domain profile. / TRAM, LAG1 and CLN8 homology domains.
Similarity search - Domain/homology
Ceramide synthase LAC1 / Ceramide synthase subunit LIP1
Similarity search - Component
Biological speciesSaccharomyces cerevisiae S288C (yeast)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsXie, T. / Gong, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2026
Title: Structural and functional dissection of a higher-order oligomerization interface in yeast ceramide synthase.
Authors: Qi Fang / Chang Yang / Nan Yao / Tian Xie / Xin Gong /
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 ...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.
History
DepositionJul 30, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 8, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ceramide synthase LAC1
C: Ceramide synthase LAC1
B: Ceramide synthase subunit LIP1
D: Ceramide synthase subunit LIP1
E: Ceramide synthase LAC1
G: Ceramide synthase LAC1
F: Ceramide synthase subunit LIP1
H: Ceramide synthase subunit LIP1


Theoretical massNumber of molelcules
Total (without water)270,0718
Polymers270,0718
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Ceramide synthase LAC1 / Very-long-chain ceramide synthase LAC1


Mass: 50289.082 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae S288C (yeast) / Gene: LAC1, DGT1, YKL008C, YKL156 / Production host: Homo sapiens (human)
References: UniProt: P28496, very-long-chain ceramide synthase
#2: Protein
Ceramide synthase subunit LIP1 / LAG1/LAC1-interacting protein 1


Mass: 17228.682 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae S288C (yeast) / Gene: LIP1, YMR298W / Production host: Homo sapiens (human) / References: UniProt: Q03579
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Lac1-Lip1 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1RELIONparticle selection
2PHENIX1.18.2_3874model refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 219798 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00415330
ELECTRON MICROSCOPYf_angle_d0.56220854
ELECTRON MICROSCOPYf_dihedral_angle_d35.5491998
ELECTRON MICROSCOPYf_chiral_restr0.042274
ELECTRON MICROSCOPYf_plane_restr0.0052562

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