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Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.

Tian Xie1, Peng Liu1, Xinyue Wu1

  • 1Department of Chemical Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.

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|June 12, 2023
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Researchers discovered how ceramide, a key sphingolipid, regulates the serine palmitoyltransferase (SPT) complex. This finding explains sphingolipid homeostasis and links impaired ceramide sensing to childhood amyotrophic lateral sclerosis (ALS).

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Area of Science:

  • Biochemistry and Molecular Biology
  • Cellular Metabolism
  • Neuroscience

Background:

  • The serine palmitoyltransferase (SPT) complex initiates sphingolipid biosynthesis, a crucial cellular process.
  • ORM/ORMDL proteins are regulatory subunits of SPT, but the mechanism of sphingolipid sensing remains elusive.
  • Sphingolipid homeostasis is vital for cellular function, and its dysregulation is implicated in diseases.

Purpose of the Study:

  • To elucidate the molecular mechanism by which the SPT-ORMDL complex senses cellular sphingolipid levels.
  • To determine the structural basis of ceramide inhibition of the SPT-ORMDL complex.
  • To investigate the role of ceramide sensing defects in the pathogenesis of childhood amyotrophic lateral sclerosis (ALS).

Main Methods:

  • Purification and structural analysis (cryo-electron microscopy) of human SPT-ORMDL3 complexes.
  • Biochemical assays to assess SPT activity and inhibition by ceramide.
  • Structure-guided mutagenesis to identify key residues in ceramide binding and regulation.
  • Analysis of patient-derived variants in SPTLC1 associated with childhood ALS.

Main Results:

  • Purified SPT-ORMDL complexes are directly inhibited by ceramide, a central sphingolipid metabolite.
  • The cryo-EM structure reveals ceramide binding to the SPT-ORMDL3 complex, inducing an inhibitory conformation.
  • Mutational analysis confirms the ceramide binding site is essential for SPT activity suppression.
  • Childhood ALS variants in SPTLC1 lead to impaired ceramide sensing in SPT-ORMDL3 mutants.

Conclusions:

  • The study reveals the molecular basis of ceramide sensing by the SPT-ORMDL complex, explaining sphingolipid homeostasis.
  • Ceramide binding to SPT-ORMDL proteins acts as a feedback mechanism to regulate sphingolipid biosynthesis.
  • Impaired ceramide sensing due to genetic variants is implicated in the development of childhood ALS.