7yj2

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== Disease ==
== Disease ==
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[https://www.uniprot.org/uniprot/SPTC2_HUMAN SPTC2_HUMAN] Hereditary sensory and autonomic neuropathy type 1. The disease is caused by variants affecting the gene represented in this entry. SPTLC2 disease mutations cause a shift in the substrate specificity of SPT resulting in the alternative use of L-alanine and L-glycine over its canonical substrate L-serine. This leads to the production of 1-deoxysphingolipids that cannot be correctly metabolized (PubMed:23658386).<ref>PMID:23658386</ref> <ref>PMID:26573920</ref>
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[https://www.uniprot.org/uniprot/ORML3_HUMAN ORML3_HUMAN] Disease susceptibility is associated with variants affecting the gene represented in this entry. SNPs on 17q21 locus that are associated with childhood asthma also show a consistent and strong association with transcript levels of ORMDL3, indicating that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.<ref>PMID:17611496</ref>
== Function ==
== Function ==
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[https://www.uniprot.org/uniprot/SPTC2_HUMAN SPTC2_HUMAN] Serine palmitoyltransferase (SPT). The heterodimer formed with LCB1/SPTLC1 constitutes the catalytic core. The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference. The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC2-SPTSSB complex displays a preference for C18-CoA substrate. Plays an important role in de novo sphyngolipid biosynthesis which is crucial for adipogenesis (By similarity).[UniProtKB:P97363]<ref>PMID:19416851</ref> <ref>PMID:19648650</ref> <ref>PMID:20920666</ref>
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[https://www.uniprot.org/uniprot/ORML3_HUMAN ORML3_HUMAN] Plays an essential role in the homeostatic regulation of sphingolipid de novo biosynthesis by modulating the activity of the serine palmitoyltransferase (SPT) in response to ceramide levels (PubMed:20182505, PubMed:30700557, PubMed:37308477). When complexed to SPT, the binding of ceramides to its N-terminus stabilizes a conformation that block SPT substrate entry, hence preventing SPT catalytic activity. Through this mechanism, maintains ceramide levels at sufficient concentrations for the production of complex sphingolipids, but which prevents the accumulation of ceramides to levels that trigger apoptosis (PubMed:37308477).<ref>PMID:20182505</ref> <ref>PMID:30700557</ref> <ref>PMID:37308477</ref>
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== Publication Abstract from PubMed ==
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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.
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Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.,Xie T, Liu P, Wu X, Dong F, Zhang Z, Yue J, Mahawar U, Farooq F, Vohra H, Fang Q, Liu W, Wattenberg BW, Gong X Nat Commun. 2023 Jun 13;14(1):3475. doi: 10.1038/s41467-023-39274-y. PMID:37308477<ref>PMID:37308477</ref>
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==See Also==
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*[[Serine palmitoyltransferase 3D structures|Serine palmitoyltransferase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
== References ==
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Current revision

Cryo-EM structure of SPT-ORMDL3 (ORMDL3-N13A) complex

PDB ID 7yj2

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