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

Abstract

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.

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Fig. 1: In vitro functional characterization and structural determination of human SPT–ORMDL3 complex.
Fig. 2: Assembly of the monomeric SPT–ORMDL3 complex.
Fig. 3: Structure of SPT–ORMDL3 complex bound to two substrates.
Fig. 4: Acyl-CoA substrate selectivity and a working model for SPT–ORMDL assembly and regulation.

Data availability

EM density maps have been deposited in the EMDB under the accession codes EMD-30081 (SPT, dimer), EMD-30082 (SPT, monomer), EMD-30079 (SPT–ORMDL3, dimer), EMD-30080 (SPT–ORMDL3, monomer), EMD-30441 (substrate-bound SPT–ORMDL3, monomer, class I) and EMD-30442 (substrate-bound SPT–ORMDL3, monomer, class II). Atomic coordinates have been deposited in the PDB under the accession codes PDB 6M4N (SPT–ORMDL3, dimer), PDB 6M4O (SPT–ORMDL3, monomer), PDB 7CQI (substrate-bound SPT–ORMDL3, monomer, class I) and PDB 7CQK (substrate-bound SPT–ORMDL3, monomer, class II). Source data are available with the paper online. Source data are provided with this paper.

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Acknowledgements

We thank the cryo-EM facilities of Southern University of Science and Technology and Princeton Imaging and Analysis Center for providing the facility support. We thank H. Ikushiro (Osaka Medical College, Japan) for providing the S-CoA. This work was supported by the National Natural Science Foundation of China (92057101, X.G.), the Natural Science Foundation of Guangdong Province of China for Distinguished Young Scientists (2019B151502047, X.G.) and the Guangdong Innovation Research Team Fund (2016ZT06S172, S.L.).

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Contributions

X.G. conceived and supervised the project. X.G., S.L and T.X. designed experiments. X.G., S.L., T.X., P.L. and L.W. performed the experiments. All authors contributed to data analysis. S.L. and T.X. contributed to manuscript preparation. X.G. wrote the manuscript.

Corresponding author

Correspondence to Xin Gong.

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The authors declare no competing interests.

Additional information

Peer review information Nature Structural & Molecular Biology thanks Binks Wattenberg, Ming Zhou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Florian Ullrich and Anke Sparmann were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 In vitro functional characterization and cryo-EM analysis of the SPT complex.

a, Size exclusion chromatography (SEC) profile and Coomassie blue−stained SDS-PAGE gel corresponding to the last SPT complex purification step. The peak fractions indicated by the arrow were pooled and concentrated for biochemical and structural characterization. b, Initial rate of reaction versus L-serine concentration measured using the purified wild-type (WT) SPT complex or catalytic mutant (K379A in SPTLC2) SPT complex. Each data point is the average of three independent experiments, and error bars represent the SEM. The data points were fitted with a Michaelis-Menten equation. c, Initial rate of reaction versus palmitoyl-CoA concentration for the WT SPT complex. The data points were fitted with an allosteric sigmoidal equation. Please refer to the Methods section for details of the SPT activity assay. d, Representative cryo-EM micrograph and 2D class averages of the SPT complex. e, Flowchart for cryo-EM data processing. f, Angular distribution of the particles used to reconstruct the dimeric SPT complex. g, Gold-standard FSC curves for the dimeric (black curve) and monomeric (purple curve) SPT complexes generated using Relion 3.0. h, Local resolution maps of the dimeric (left) and monomeric (right) SPT complexes. The color code for resolution, shown with the unit Å, was calculated using Relion 3.0. Uncropped image for a and data for graphs b,c are available as source data.

Source data

Extended Data Fig. 2 Cryo-EM analysis of the SPT–ORMDL3 complex.

a, Representative cryo-EM micrograph (left) and 2D class averages (right) of the SPTORMDL3 complex. b, Flowchart for cryo-EM data processing. c, Angular distribution of the particles used to reconstruct the dimeric SPTORMDL3 complex. d, Gold-standard FSC curves for the dimeric (black curve) and monomeric (purple curve) SPTORMDL3 complexes. e, Local resolution maps of the dimeric (left) and monomeric (right) SPTORMDL3 complexes. f, Directional FSC (dFSC) to assess directional isotropy for the monomeric SPTORMDL3 map. g, Calculated FSC curves between the refined model and the half map used for refinement (blue), the other half map (green), and the full map (red).

Extended Data Fig. 3 EM maps of the SPT–ORMDL3 complex.

a, 3D EM reconstruction of the dimeric SPTORMDL3 complex, with density covering individual subunits colored same as in Fig. 1e. The detergent micelles, displayed at a low contour level, are shown as gray, semi-transparent surface to indicate the orientation of transmembrane domain. b,c, EM maps corresponding to representative segments (b) and active/nonfunctional sites (c) of the monomeric substrate−free SPTORMDL3 complex. Electron density maps contoured at 5 σ were prepared in PyMol.

Extended Data Fig. 4 EM reconstruction of the SPT complex.

a, The 3D EM reconstruction of the SPT complex shown from two different views. The subunits are colored in the same manner used to color the SPTORMDL3 complex in Fig. 1e. b, Structural comparison of the SPT and SPTORMDL3 complexes. The EM density for monomeric SPT complex could be well fitted with the corresponding structural model from the SPTORMDL3 complex.

Extended Data Fig. 5 The dimerization interface in the SPT–ORMDL3 complex.

a, Structure of a dimer of SPTLC1SPTLC2 heterodimers. The dimer-dimer interface contains only limited interactions in the cytosol, which mainly involve the small helix α1 of SPTLC1 and the α6-β4 loop of SPTLC2. b, Biochemical validation of the structurally revealed dimer-dimer interface. The Mut2T variant of the SPT complex eluted around 1.5 ml later than the WT SPT complex in SEC. c, Representative cryo-EM micrograph and 2D class averages of the SPT Mut2T variant. d, The SPT Mut2T variant showed enzymatic activity comparable to that of the WT SPT complex when challenged with L-serine and palmitoyl-CoA. Uncropped image for b and data for graph d are available as source data.

Source data

Extended Data Fig. 6 Structural comparison of SPTLC1–SPTLC2 heterodimer and bacterial spSPT homodimer shown from two different views.

Superimposition of the spSPT homodimer (PDB 2JG2) onto the SPTLC1SPTLC2 heterodimer by Cα atoms. Except for the N-terminal extensions of SPTLC1 and SPTLC2, the two structures are highly similar: superimposition of the two structures over 586 aligned Cα atoms yielded an RMSD of 1.5 Å.

Extended Data Fig. 7 Cryo-EM analysis of the substrate-bound SPT–ORMDL3 complex.

a, Chemical structures of palmitoyl-CoA and S-(2-oxoheptadecyl)-CoA (S-CoA). The site of -CH2- group insertion in the S-CoA is indicated by a red arrow. b, Representative cryo-EM micrograph (left) and 2D class averages (right) of substrate-bound SPTORMDL3. c, Flowchart for cryo-EM data processing. d, Gold-standard FSC curves for the two monomeric reconstructions. e, Local resolution maps of the two monomeric substrate-bound reconstructions.

Extended Data Fig. 8 EM maps corresponding to representative segments (a) and substrate binding site (b) of the monomeric substrate-bound SPT–ORMDL3 complex (class I).

The map for ORMDL3-TM3 is contoured at 3σ, and all the other maps are contoured at 5 σ.

Extended Data Fig. 9 Purification of SPT–ORMDL3 mutants related to substrate binding and the substrate preferences of WT SPT and SPT–ORMDL3 complexes.

a, Purification of SPTORMDL3 complexes containing mutations related to PLS coordination. b, Relative catalytic activity of the WT SPT and SPTORMDL3 complexes against three different amino acid substrates. c, Purification of SPTORMDL3 complexes containing mutations related to S-CoA coordination. d, Relative catalytic activity of the WT SPT and SPTORMDL3 complexes against three different acyl-CoA substrates. e, Purification of SPTORMDL3 complexes containing SPTssaM28V or SPTssaM28G. Uncropped images for a, c, e and date for graphs b, d are available as source data.

Source data

Extended Data Fig. 10 Enzymatic kinetics of several SPT–ORMDL3 mutants and the effects of C6-ceramide on the enzymatic activities of purified SPT and SPT–ORMDL3 complexes.

a, Enzymatic kinetics of two SPTORMDL3 mutants related to PLS coordination. b, Enzymatic kinetics of two SPTORMDL3 mutants related to S-CoA coordination. c, C6-ceramide has little effect on the enzymatic activities for both SPT and SPTORMDL3 complexes. The SPT and SPTORMDL3 complexes were incubated with 30 μM DMSO-solubilized C6-ceramide before the enzymatic activities were measured. Date for graphs a-c are available as source data.

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Li, S., Xie, T., Liu, P. et al. Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex. Nat Struct Mol Biol 28, 249–257 (2021). https://doi.org/10.1038/s41594-020-00553-7

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