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

Author

Listed:
  • Yuefeng Jiang

    (Peking University)

  • Tingting Liu

    (Peking University)

  • Chia-Hsueh Lee

    (St. Jude Children’s Research Hospital)

  • Qing Chang

    (Tsinghua University)

  • Jing Yang

    (Peking University)

  • Zhe Zhang

    (Peking University)

Abstract

Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration1–4. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process5–8, 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.

Suggested Citation

  • Yuefeng Jiang & Tingting Liu & Chia-Hsueh Lee & Qing Chang & Jing Yang & Zhe Zhang, 2020. "The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1," Nature, Nature, vol. 588(7839), pages 658-663, December.
    • Handle: RePEc:nat:nature:v:588:y:2020:i:7839:d:10.1038_s41586-020-2862-z
    DOI: 10.1038/s41586-020-2862-z
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    Cited by:

    1. Xiangkai Zhen & Biao Zhou & Zihe Liu & Xurong Wang & Heyu Zhao & Shuxian Wu & Zekai Li & Jiamin liang & Wanyue Zhang & Qingjian Zhu & Jun He & Xiaoli Xiong & Songying Ouyang, 2024. "Mechanistic basis for the allosteric activation of NADase activity in the Sir2-HerA antiphage defense system," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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