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Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex
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Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex
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Journal Article
Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex
2021
Overview
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
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Acyl Coenzyme A - metabolism
/ Acyl Coenzyme A - ultrastructure
/ Assembly
/ Asthma
/ Biomedical and Life Sciences
/ Dimers
/ Humans
/ L-Serine
/ Membrane Proteins - chemistry
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Membrane Proteins - ultrastructure
/ Multiprotein Complexes - chemistry
/ Multiprotein Complexes - genetics
/ Multiprotein Complexes - metabolism
/ Multiprotein Complexes - ultrastructure
/ Mutation
/ Pyridoxal Phosphate - chemistry
/ Pyridoxal Phosphate - metabolism
/ Serine C-Palmitoyltransferase - chemistry
/ Serine C-Palmitoyltransferase - genetics
/ Serine C-Palmitoyltransferase - metabolism
