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

Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z
Nature 588 658-663 (2020)
Related entries: 7cm6, 7cm7

Cited: 75 times
EuropePMC logo PMID: 33053563

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.

Articles - 7cm5 mentioned but not cited (1)

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Reviews citing this publication (27)

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Articles citing this publication (47)

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