The structure of the Orm2-containing serine palmitoyltransferase complex reveals distinct inhibitory potentials of yeast Orm proteins
Carolin Körner,
Jan-Hannes Schäfer,
Bianca M. Esch,
Kristian Parey,
Stefan Walter,
David Teis,
Dovile Januliene,
Oliver Schmidt,
Arne Moeller,
Florian Fröhlich
Affiliations
Carolin Körner
Bioanalytical Chemistry Section, Department of Biology/Chemistry, Osnabrück University, 49076 Osnabrück, Germany
Jan-Hannes Schäfer
Structural Biology Section, Department of Biology/Chemistry, Osnabrück University, 49076 Osnabrück, Germany
Bianca M. Esch
Bioanalytical Chemistry Section, Department of Biology/Chemistry, Osnabrück University, 49076 Osnabrück, Germany
Kristian Parey
Structural Biology Section, Department of Biology/Chemistry, Osnabrück University, 49076 Osnabrück, Germany; Center of Cellular Nanoanalytics Osnabrück (CellNanOs), 49076 Osnabrück, Germany
Stefan Walter
Center of Cellular Nanoanalytics Osnabrück (CellNanOs), 49076 Osnabrück, Germany
David Teis
Institute of Molecular Biochemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
Dovile Januliene
Structural Biology Section, Department of Biology/Chemistry, Osnabrück University, 49076 Osnabrück, Germany; Center of Cellular Nanoanalytics Osnabrück (CellNanOs), 49076 Osnabrück, Germany
Oliver Schmidt
Institute of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria; Corresponding author
Arne Moeller
Structural Biology Section, Department of Biology/Chemistry, Osnabrück University, 49076 Osnabrück, Germany; Center of Cellular Nanoanalytics Osnabrück (CellNanOs), 49076 Osnabrück, Germany; Corresponding author
Florian Fröhlich
Bioanalytical Chemistry Section, Department of Biology/Chemistry, Osnabrück University, 49076 Osnabrück, Germany; Center of Cellular Nanoanalytics Osnabrück (CellNanOs), 49076 Osnabrück, Germany; Corresponding author
Summary: Sphingolipid 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.
