Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex

Human serine palmitoyltransferase (SPT) complex catalyzes the initial and rate-limiting step in the de novo biosynthesis of all sphingolipids. ORMDLs regulate SPT function, with human ORMDL3 being related to asthma. Here we report three high-resolution cryo-EM structures: the human SPT complex, composed of SPTLC1, SPTLC2 and SPTssa; the SPT-ORMDL3 complex; and the SPT-ORMDL3 complex bound to two substrates, PLP-l-serine (PLS) and a non-reactive palmitoyl-CoA analogue. SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic core. SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity. ORMDL3 is located in the center of the complex, serving to stabilize the SPT assembly. Our structural and biochemical analyses provide a molecular basis for the assembly and substrate selectivity of the SPT and SPT-ORMDL3 complexes, and lay a foundation for mechanistic understanding of sphingolipid homeostasis and for related therapeutic drug development. Cryo-EM structures of serine palmitoyltransferase complexes mediating a key reaction of sphingolipid biosynthesis elucidate principles of its multimeric assembly, regulation and substrate selectivity

Automated summary

The study presents high-resolution cryo-EM structures of human SPT complex and SPT-ORMDL3 complex, revealing the basis for their assembly and substrate selectivity. These structures provide important insights for understanding sphingolipid homeostasis and development of related therapeutic drugs.