The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1

Abstract

Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration1,2,3,4. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process5,6,7,8, and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity9,10. However, the mechanisms by which the activation of SARM1 is stringently controlled are unclear. Here we report the cryo-electron microscopy structures of full-length SARM1 proteins. We show that NAD+ is an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1. This binding of NAD+ to the ARM domain facilitated the inhibition of the TIR-domain NADase through the domain interface. Disruption of the NAD+-binding site or the ARM–TIR interaction caused constitutive activation of SARM1 and thereby led to axonal degeneration. These findings suggest that NAD+ mediates self-inhibition of this central pro-neurodegenerative protein.

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Fig. 1: SARM1TIR is maintained in the inactive state by interacting with SARM1ARM.
Fig. 2: Functional verification of the self-inhibitory interaction between SARM1ARM and SARM1TIR.
Fig. 3: The NAD+-binding site within SARM1ARM.
Fig. 4: The binding of NAD+ to SARM1ARM facilitates the self-inhibition of SARM1.

Data availability

Cryo-EM density maps of SARM1, NAD+-bound SARM1 and NAD+-bound SARM1(E642A) have been deposited in the Electron Microscopy Data Bank (EMDB) under the accession codes EMD-30401, EMD-30402 and EMD-30403. Their atomic coordinates have been deposited in the Protein Data Bank (PDB) under the accession codes 7CM5, 7CM6 and 7CM7. All of the structural models used in this study are accessible in the Protein Data Bank under the following codes: SARM1SAM (6O0S and 6QWV), SARM1TIR (6O0Q), SARM1TIR(G601P) (6O0V), importin-α (1IAL), β-catenin (2BCT), RRS1/RPS4 heterodimer (4C6T) and TLR10 homodimer (2J67). Source data are provided with this paper.

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Acknowledgements

We thank the Cryo-EM platform and the School of Life Sciences of Peking University for cryo-EM data collection. We are grateful to Z. Guo, G. Wang, B. Shao, X. Pei and N. Gao for their help in the cryo-EM experiments and discussion. We thank the National Center for Protein Sciences at Peking University for assistance with the initial exploration of the SARM1–NAD+ binding assay, the liquid chromatography–mass spectrometry experiment and the HPLC analysis. We are indebted to X. Li for critical comments on the manuscript. The computation was supported by the High-Performance Computing Platform of Peking University. This research was funded by the Center for Life Sciences, School of Life Sciences of Peking University and the State Key Laboratory of Membrane Biology of China. The study was also supported by the National Natural Science Foundation of China (to J.Y., nos. 31522024, 31771111 and 31970974).

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Authors

Contributions

Y.J. and Z.Z. performed all of the cloning and cell cultures. Y.J. prepared all of the protein samples, performed data collection for cryo-EM samples and carried out the NAD+ cleavage assay. Z.Z. processed the cryo-EM data, and built and refined the structural models. Z.Z. and C.-H.L. analysed the structures. J.Y. and T.L. performed the experiments with cultured neurons. Q.C. carried out the MST analysis. Z.Z., J.Y. and C.-H.L. wrote and revised the manuscript with input and support from all co-authors.

Corresponding authors

Correspondence to Jing Yang or Zhe Zhang.

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The authors declare no competing interests.

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Peer review information Nature thanks Andrew Bowie, Liang Tong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Cryo-EM data processing of the wild-type SARM1 dataset. Workflow for the sample preparation and cryo-EM data processing of the wild-type SARM1 dataset

.

Extended Data Fig. 2 Data and model quality assessment for the wild-type SARM1 dataset.

a, Angular distributions for all the particles used in the final refinement. Red and higher cylinders represent more particles assigned to a particular orientation, while blue and shorter cylinders represent less. b, Local resolution estimation calculated by RELION. c, Fourier shell correlation (FSC) curves between two half maps are plotted in black. For cross-validation, the FSC curves are calculated between the refined structure and three maps (full map: green; half-1 map: red; half-2 map: blue). d, Local cryo-EM densities and fitted atomic models for representative regions of the structure.

Extended Data Fig. 3 Cryo-EM data processing of the NAD+-bound wild-type SARM1 dataset.

a, Flowchart of the data processing. b, Angular distributions for all the particles used in the final refinement. Red and higher cylinders represent more particles assigned to a particular orientation, while blue and shorter cylinders represent less. c, Local resolution estimation calculated by RELION. d, FSC curves between two half maps are plotted in black. For cross-validation, the FSC curves are calculated between the refined structure and three maps (full map: green; half-1 map: red; half-2 map: blue). e, Local cryo-EM densities and fitted atomic models for representative regions of the structure.

Extended Data Fig. 4 Cryo-EM data processing of the NAD+-bound SARM1(E642A) dataset.

a, Flowchart of the data processing. b, Angular distributions for all the particles used in the final refinement. Red and higher cylinders represent more particles assigned to a particular orientation, while blue and shorter cylinders represent less. c, Local resolution estimation calculated by RELION. d, FSC curves between two half maps are plotted in black. For cross-validation, the FSC curves are calculated between the refined structure and three maps (full map: green; half-1 map: red; half-2 map: blue). e, Local cryo-EM densities and fitted atomic models for representative regions of the structure.

Extended Data Fig. 5 Analysis of the SARM1 assembly.

a, Structural comparison of the three full-length SARM1 structures. Yellow: SARM1; green: SARM1+NAD+; pink: SARM1(E642A)+NAD+. b, Superimposition of three different SARM1SAM octamers. Blue: SARM1SAM in the structure of the NAD+-bound full-length SARM1(E642A); green (PDB code: 6QWV) and yellow (PDB code: 6O0S): two reported structures of SARM1SAM alone. c, Assembly of the SARM1 octamer. Each protomer interacts with four adjacent ones. For instance, protomer A (red) interacts with protomers B (yellow), C (green), G (pink), and H (cyan). SARM1SAM and SARM1TIR within one protomer are linked with a stick to show the domain assignment. The density of detergent micelles is also shown. All the panels are shown in orthogonal views.

Extended Data Fig. 6 SARM1TIR is restricted in the inactive state through interactions with SARM1ARM.

a, Structural comparison of the ARM domains in SARM1, importin-α (PDB code: 1IAL), and β-catenin (PDB code: 2BCT). ARM1-8 of SARM1ARM, ARM3-10 of importin-α, and ARM5-12 of β-catenin are shown. The ARM motifs in the middle adopt the similar conformation and are coloured in grey. However, the conformations of ARM motifs on both ends of SARM1ARM (ARM1, ARM7-8, and the last helix of ARM6; coloured in green) are different from those of the corresponding ARM motifs in importin-α (ARM3, ARM9-10, and the last helix of ARM8; coloured in yellow) or β-catenin (ARM5, ARM11-12, and the last helix of ARM10; coloured in pink). The last helix of ARM6 in SARM1ARM and its corresponding helices in importin-α and β-catenin are marked out with dashed circles. Their orientations are indicated with arrows. b, Detailed interactions between the two neighbouring SARM1ARM (green box), and between SARM1ARM and the two closely packed SARM1SAM (pink boxes). c, Cryo-EM densities (black mesh) of the BB-loop in the NAD+-bound SARM1(E642A) structure. Atomic models of αA and BB-loop are coloured in wheat and red, respectively. Relevant residues are shown with side chains. d, Cryo-EM densities of the BB-loop in SARM1 (blue mesh) and NAD+-bound SARM1 (green mesh) structures. The atomic model of the BB-loop in NAD+-bound SARM1(E642A) structure is shown as a reference. The contour levels of the maps in c and d are 6.0. e, The inactive conformation of SARM1TIR is designated by its interactions with the two adjacent SARM1ARM. f, The αA helix and BB-loop of different TIR domains are prone to mediate protein–protein interactions. The RRS1/RPS4 heterodimer (PDB code: 4C6T) is formed through interactions between their αA helices (in wheat), and the TLR10 homodimer (PDB code: 2J67) is assembled via the BB-loop interaction (in red). Two subunits are coloured in cyan and green, respectively.

Extended Data Fig. 7 Sequence alignment of the SARM1 ARM motifs among several representative species.

a, Sequence alignment of ARM5. The positions of three helices (H1, H2, and H3) are indicated with green cylinders. The residues involved in SARM1ARM-SARM1TIR interaction are denoted by black arrowheads. b, Sequence alignment of ARM1-3. The residues participating in NAD+ binding are denoted by green (group 1) or yellow (group 2) arrowheads.

Extended Data Fig. 8 Purification of different SARM1 mutant proteins.

a, b,  Gel filtration profiles (a) and SDS–PAGE gels (b) of different SARM1 mutant proteins used in the NADase assay in Fig. 2. c, d,  Gel filtration profiles (c) and SDS–PAGE gels (d) of different SARM1ARM+SAM mutant proteins used for the microscale thermophoresis (MST) assay. The asterisk denotes the protein band of HSP70, as identified by LC–MS (liquid chromatography–mass spectrometry). e, f,  Gel filtration profiles (e) and SDS–PAGE gels (f) of different SARM1 mutant proteins used for the NADase assay in Fig. 4. The SDS–PAGE gels were stained with Coomassie blue. All the experiments were independently repeated three times. Each band of the molecular marker contains about 1–2 μg protein. For gel source data, see Supplementary Fig. 1.

Extended Data Fig. 9 The NAD+-binding site within SARM1ARM.

ac, Cryo-EM densities around the NAD+-binding site in three structures. NAD+ density is present in both the SARM1+NAD+ (b: blue mesh) and SARM1(E642A)+NAD+ (c: green mesh) structures but not the apo one (a). NAD+ is shown as magenta sticks. The density and atomic model of SARM1ARM are shown as surface and ribbon, respectively. d,e, Cryo-EM densities for the residues of SARM1ARM involved in the NAD+ binding. The densities of the SARM1+NAD+ structure are shown as orange mesh (d), and those of the SARM1(E642A)+NAD+ structure are shown as blue mesh (e). The residues are shown as sticks and coloured in green. The six residues interacting with NAD+ through their side chains are labelled. The contour levels of the maps in a–e are 6.0. fg, The NAD+ affinity to SARM1(E642A) (f) and SARM1ARM+TIR(WQH to A) (g). The experiments were biologically replicated twice and analysed (n = 2). The values of calculated Kd are presented as mean ± s.d. hi, The HPLC analysis of the NADase kinetics of SARM1(RRK to A) (h) and SARM1SAM+TIR (i). The background degradation of NAD+ was subtracted from each reaction. All the experiments were biologically replicated three times (n = 3). The kinetics of SARM1SAM+TIR in i was fitted to the Michaelis–Menten equation. j, The NMN affinity to SARM1ARM+SAM. The experiments were biologically replicated three times and analysed (n = 3). The value of calculated Kd is presented as mean ± s.d. Source data

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics

Supplementary information

Supplementary Figure 1

Uncropped TLC images for Fig. 2b and all the other TLC replicates used for the statistical analysis in Figs. 2c and 4c, together with the uncropped and replicated SDS-PAGE gels for Extended Data Fig. 8b, d, f. The cropping regions are indicated as red boxes.

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Jiang, Y., Liu, T., Lee, CH. et al. The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1. Nature (2020). https://doi.org/10.1038/s41586-020-2862-z

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