Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 06 2023
13 06 2023
Historique:
received:
19
12
2022
accepted:
02
06
2023
medline:
14
6
2023
pubmed:
13
6
2023
entrez:
12
6
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37308477
doi: 10.1038/s41467-023-39274-y
pii: 10.1038/s41467-023-39274-y
pmc: PMC10261145
doi:
Substances chimiques
Ceramides
0
Sphingolipids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3475Subventions
Organisme : NINDS NIH HHS
ID : R21 NS120128
Pays : United States
Informations de copyright
© 2023. The Author(s).
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