8izd
Cryo-EM structure of the C26-CoA-bound Lac1-Lip1 complex
Structural highlights
FunctionLAC1_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 PubMedCeramide 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
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