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

Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration.sup.1-4. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process.sup.5-8, and its Toll/interleukin-1...

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Bibliographic Details
Published in:Nature (London) 2020-12, Vol.588 (7839), p.658
Main Authors: Jiang, Yuefeng, Liu, Tingting, Lee, Chia-Hsueh, Chang, Qing, Yang, Jing, Zhang, Zhe
Format: Article
Language:English
Subjects:
Axons
Cell receptors
Degeneration
NAD (Coenzyme)
Nervous system
Physiological aspects
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Summary:Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration.sup.1-4. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process.sup.5-8, and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity.sup.9,10. 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.sup.+ is an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1. This binding of NAD.sup.+ to the ARM domain facilitated the inhibition of the TIR-domain NADase through the domain interface. Disruption of the NAD.sup.+-binding site or the ARM-TIR interaction caused constitutive activation of SARM1 and thereby led to axonal degeneration. These findings suggest that NAD.sup.+ mediates self-inhibition of this central pro-neurodegenerative protein.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-020-2862-z