7yj2

Structural highlights

Disease

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.^[1]

Function

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).^{[2] [3] [4]}

See Also

• Serine palmitoyltransferase 3D structures

References

1. ↑ Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007 Jul 26;448(7152):470-3. PMID:17611496 doi:10.1038/nature06014
2. ↑ Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A, Ejsing CS, Weissman JS. Orm family proteins mediate sphingolipid homeostasis. Nature. 2010 Feb 25;463(7284):1048-53. PMID:20182505 doi:10.1038/nature08787
3. ↑ Davis DL, Gable K, Suemitsu J, Dunn TM, Wattenberg BW. The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes. J Biol Chem. 2019 Mar 29;294(13):5146-5156. PMID:30700557 doi:10.1074/jbc.RA118.007291
4. ↑ 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