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Cryo-EM structure of the yeast SPT-Orm2-Dimer complex
Structural highlights
FunctionSPTC1_YEAST Component of serine palmitoyltransferase (SPT), which catalyzes the committed step in the synthesis of sphingolipids, the condensation of serine with palmitoyl CoA to form the long chain base 3-ketosphinganine.[1] [2] Publication Abstract from PubMedSphingolipid levels are crucial determinants of neurodegenerative disorders and therefore require tight regulation. The Orm protein family and ceramides inhibit the rate-limiting step of sphingolipid biosynthesis-the condensation of L-serine and palmitoyl-coenzyme A (CoA). The yeast isoforms Orm1 and Orm2 form a complex with the serine palmitoyltransferase (SPT). While Orm1 and Orm2 have highly similar sequences, they are differentially regulated, though the mechanistic details remain elusive. Here, we determine the cryoelectron microscopy structure of the SPT complex containing Orm2. Complementary in vitro activity assays and genetic experiments with targeted lipidomics demonstrate a lower activity of the SPT-Orm2 complex than the SPT-Orm1 complex. Our results suggest a higher inhibitory potential of Orm2, despite the similar structures of the Orm1- and Orm2-containing complexes. The high conservation of SPT from yeast to man implies different regulatory capacities for the three human ORMDL isoforms, which might be key for understanding their role in sphingolipid-mediated neurodegenerative disorders. The structure of the Orm2-containing serine palmitoyltransferase complex reveals distinct inhibitory potentials of yeast Orm proteins.,Korner C, Schafer JH, Esch BM, Parey K, Walter S, Teis D, Januliene D, Schmidt O, Moeller A, Frohlich F Cell Rep. 2024 Aug 27;43(8):114627. doi: 10.1016/j.celrep.2024.114627. Epub 2024 , Aug 20. PMID:39167489[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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