NAD(+) hydrolase SARM1
NAD+ nucleosidase activity
The NAD<sup>+</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</sup>. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process<sup>5-8</sup>, and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity<sup>9,10</sup>. 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>+</sup> is an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1. This binding of NAD<sup>+</sup> to the ARM domain facilitated the inhibition of the TIR-domain NADase through the domain interface. Disruption of the NAD<sup>+</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>+</sup> mediates self-inhibition of this central pro-neurodegenerative protein.