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TitleThe structure of the Orm2-containing serine palmitoyltransferase complex reveals distinct inhibitory potentials of yeast Orm proteins.
Journal, issue, pagesCell Rep, Vol. 43, Issue 8, Page 114627, Year 2024
Publish dateAug 27, 2024
AuthorsCarolin Körner / Jan-Hannes Schäfer / Bianca M Esch / Kristian Parey / Stefan Walter / David Teis / Dovile Januliene / Oliver Schmidt / Arne Moeller / Florian Fröhlich /
PubMed AbstractSphingolipid 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 ...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.
External linksCell Rep / PubMed:39167489
MethodsEM (single particle)
Resolution2.8 - 3.3 Å
Structure data

EMDB-18533: Cryo-EM structure of the yeast SPT-Orm2-Dimer complex, local refinement of a monomer
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-18536, PDB-8qof:
Cryo-EM structure of the yeast SPT-Orm2-Dimer complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-18537, PDB-8qog:
Cryo-EM structure of the yeast SPT-Orm2-Monomer complex
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals


ChemComp, No image

ChemComp-WAR:
Unknown entry

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE

ChemComp-Q7G:
2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl}-4-{[(3beta,9beta,14beta,17beta,25R)-spirost-5-en-3-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranoside

Source
  • saccharomyces cerevisiae (brewer's yeast)
KeywordsTRANSFERASE / Serine-Palmitoyl-Transferase

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