7yj2

From Proteopedia

Revision as of 05:38, 5 July 2023 by OCA (Talk | contribs)

(diff) ←Older revision | Current revision (diff) | Newer revision→ (diff)

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

Structural highlights

7yj2 is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.9Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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).^[1] ^[2]

Function

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]^[3] ^[4] ^[5]

Publication Abstract from PubMed

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.

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^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Murphy SM, Ernst D, Wei Y, Laurà M, Liu YT, Polke J, Blake J, Winer J, Houlden H, Hornemann T, Reilly MM. Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. Neurology. 2013 Jun 4;80(23):2106-11. PMID:23658386 doi:10.1212/WNL.0b013e318295d789
↑ Suriyanarayanan S, Auranen M, Toppila J, Paetau A, Shcherbii M, Palin E, Wei Y, Lohioja T, Schlotter-Weigel B, Schön U, Abicht A, Rautenstrauss B, Tyynismaa H, Walter MC, Hornemann T, Ylikallio E. The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy. Neuromolecular Med. 2016 Mar;18(1):81-90. PMID:26573920 doi:10.1007/s12017-015-8379-1
↑ Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH Jr, Harmon JM, Dunn TM. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8186-91. PMID:19416851 doi:10.1073/pnas.0811269106
↑ Hornemann T, Penno A, Rütti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L, von Eckardstein A. The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem. 2009 Sep 25;284(39):26322-30. PMID:19648650 doi:10.1074/jbc.M109.023192
↑ Rotthier A, Auer-Grumbach M, Janssens K, Baets J, Penno A, Almeida-Souza L, Van Hoof K, Jacobs A, De Vriendt E, Schlotter-Weigel B, Löscher W, Vondráček P, Seeman P, De Jonghe P, Van Dijck P, Jordanova A, Hornemann T, Timmerman V. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet. 2010 Oct 8;87(4):513-22. PMID:20920666 doi:10.1016/j.ajhg.2010.09.010
↑ 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. Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis. Nat Commun. 2023 Jun 13;14(1):3475. PMID:37308477 doi:10.1038/s41467-023-39274-y