Proteopedia

8izf

Cryo-EM structure of the Lac1-Lip1 (Lip1-S74F) complexCryo-EM structure of the Lac1-Lip1 (Lip1-S74F) complex

Structural highlights

8izf is a 4 chain structure with sequence from Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.85Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LAC1_YEAST Component of the ceramide synthase complex that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward hexacosanoyl-CoA (C26:0-CoA) (PubMed:11694577, PubMed:15692566). N-acylates sphinganine and phytosphingosine bases to form dihydroceramides and phytoceramides, respectively (PubMed:11694577, PubMed:15692566). Redundant with LAG1. Facilitates ER-to-Golgi transport of GPI-anchored proteins.[1] [2] [3] [4]

Publication Abstract from PubMed

Ceramide synthases (CerS) catalyze ceramide formation via N-acylation of a sphingoid base with a fatty acyl-CoA and are attractive drug targets for treating numerous metabolic diseases and cancers. Here, we present the cryo-EM structure of a yeast CerS complex, consisting of a catalytic Lac1 subunit and a regulatory Lip1 subunit, in complex with C26-CoA substrate. The CerS holoenzyme exists as a dimer of Lac1-Lip1 heterodimers. Lac1 contains a hydrophilic reaction chamber and a hydrophobic tunnel for binding the CoA moiety and C26-acyl chain of C26-CoA, respectively. Lip1 interacts with both the transmembrane region and the last luminal loop of Lac1 to maintain the proper acyl chain binding tunnel. A lateral opening on Lac1 serves as a potential entrance for the sphingoid base substrate. Our findings provide a template for understanding the working mechanism of eukaryotic ceramide synthases and may facilitate the development of therapeutic CerS modulators.

Structure and mechanism of a eukaryotic ceramide synthase complex.,Xie T, Fang Q, Zhang Z, Wang Y, Dong F, Gong X EMBO J. 2023 Dec 11;42(24):e114889. doi: 10.15252/embj.2023114889. Epub 2023 Nov , 13. PMID:37953642[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Barz WP, Walter P. Two endoplasmic reticulum (ER) membrane proteins that facilitate ER-to-Golgi transport of glycosylphosphatidylinositol-anchored proteins. Mol Biol Cell. 1999 Apr;10(4):1043-59. PMID:10198056 doi:10.1091/mbc.10.4.1043
  2. ↑ Guillas I, Kirchman PA, Chuard R, Pfefferli M, Jiang JC, Jazwinski SM, Conzelmann A. C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p. EMBO J. 2001 Jun 1;20(11):2655-65. PMID:11387200 doi:10.1093/emboj/20.11.2655
  3. ↑ Schorling S, Vallée B, Barz WP, Riezman H, Oesterhelt D. Lag1p and Lac1p are essential for the Acyl-CoA-dependent ceramide synthase reaction in Saccharomyces cerevisae. Mol Biol Cell. 2001 Nov;12(11):3417-27. PMID:11694577 doi:10.1091/mbc.12.11.3417
  4. ↑ Vallée B, Riezman H. Lip1p: a novel subunit of acyl-CoA ceramide synthase. EMBO J. 2005 Feb 23;24(4):730-41. PMID:15692566 doi:10.1038/sj.emboj.7600562
  5. ↑ Xie T, Fang Q, Zhang Z, Wang Y, Dong F, Gong X. Structure and mechanism of a eukaryotic ceramide synthase complex. EMBO J. 2023 Dec 11;42(24):e114889. PMID:37953642 doi:10.15252/embj.2023114889

8izf, resolution 3.85Å

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OCA
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