7YIY

Cryo-EM structure of SPT-ORMDL3 complex

Summary for 7YIY

• Entry DOI: 10.2210/pdb7yiy/pdb
• EMDB information: 33866
• Descriptor: Serine palmitoyltransferase 2, Serine palmitoyltransferase 1, ORM1-like protein 3, ... (7 entities in total)
• Functional Keywords: ceramide, transferase-inhibitor complex, transferase-inhibitor complex complex, transferase/inhibitor complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 144981.24

Authors

Xie, T.,Liu, P.,Gong, X. (deposition date: 2022-07-18, release date: 2023-07-05, Last modification date: 2024-03-20)

Primary citation

Xie, T.,Liu, P.,Wu, X.,Dong, F.,Zhang, Z.,Yue, J.,Mahawar, U.,Farooq, F.,Vohra, H.,Fang, Q.,Liu, W.,Wattenberg, B.W.,Gong, X.
Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
Nat Commun, 14:3475-3475, 2023

PubMed Abstract: 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.

PubMed: 37308477
DOI: 10.1038/s41467-023-39274-y

Experimental method

ELECTRON MICROSCOPY (2.7 Å)