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

Yuefeng Jiang, Tingting Liu, Chia-Hsueh Lee, Qing Chang, Jing Yang () and Zhe Zhang ()
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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

Nature, 2020, vol. 588, issue 7839, 658-663

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2862-z

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