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.