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TitleCeramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 3475, Year 2023
Publish dateJun 13, 2023
AuthorsTian Xie / Peng Liu / Xinyue Wu / Feitong Dong / Zike Zhang / Jian Yue / Usha Mahawar / Faheem Farooq / Hisham Vohra / Qi Fang / Wenchen Liu / Binks W Wattenberg / Xin Gong /
PubMed AbstractThe ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is the initiating and rate-limiting enzyme in sphingolipid biosynthesis. This ...The ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is the initiating and rate-limiting enzyme in sphingolipid biosynthesis. This complex is tightly regulated by cellular sphingolipid levels, but the sphingolipid sensing mechanism is unknown. Here we show that purified human SPT-ORMDL complexes are inhibited by the central sphingolipid metabolite ceramide. We have solved the cryo-EM structure of the SPT-ORMDL3 complex in a ceramide-bound state. Structure-guided mutational analyses reveal the essential function of this ceramide binding site for the suppression of SPT activity. Structural studies indicate that ceramide can induce and lock the N-terminus of ORMDL3 into an inhibitory conformation. Furthermore, we demonstrate that childhood amyotrophic lateral sclerosis (ALS) variants in the SPTLC1 subunit cause impaired ceramide sensing in the SPT-ORMDL3 mutants. Our work elucidates the molecular basis of ceramide sensing by the SPT-ORMDL complex for establishing sphingolipid homeostasis and indicates an important role of impaired ceramide sensing in disease development.
External linksNat Commun / PubMed:37308477 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.1 Å
Structure data

33864

7yiu

EMDB-33864: Cryo-EM structure of C6-ceramide-bound SPT-ORMDL3 complex
PDB-7yiu: Cryo-EM structure of the C6-ceramide-bound SPT-ORMDL3 complex
Method: EM (single particle) / Resolution: 2.9 Å

33866

7yiy

EMDB-33866, PDB-7yiy:
Cryo-EM structure of SPT-ORMDL3 complex
Method: EM (single particle) / Resolution: 2.7 Å

33868

7yj1

EMDB-33868, PDB-7yj1:
Cryo-EM structure of SPT-ORMDL3 (ORMDL3-deltaN2) complex
Method: EM (single particle) / Resolution: 3.1 Å

33869

7yj2

EMDB-33869, PDB-7yj2:
Cryo-EM structure of SPT-ORMDL3 (ORMDL3-N13A) complex
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-PLP:
PYRIDOXAL-5'-PHOSPHATE

ChemComp-6CM:
N-((E,2S,3R)-1,3-DIHYDROXYOCTADEC-4-EN-2-YL)HEXANAMIDE

ChemComp-R16:
HEXADECANE

ChemComp-Z1T:
N-[(2S,3R,4E)-1,3-dihydroxyoctadec-4-en-2-yl]tetracosanamide

Source
  • homo sapiens (human)
KeywordsTRANSFERASE/inhibitor / ceramide / TRANSFERASE-inhibitor complex / TRANSFERASE/INHIBITOR COMPLEX / TRANSFERASE-INHIBITOR COMPLEX complex

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