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

Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration(1-4). Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1) is a central regulator of this neurodegenerative process(5-8), and its Toll/interleukin-1 receptor (TIR) domain exerts its pro-neurodegenerative action through NADase activity(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(+) 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. NAD(+) is shown to be a ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1, and it is suggested that this binding of NAD(+) mediates self-inhibition of SARM1.