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. Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (Sarm1) is a central regulator of this neurodegenerative process, and its Toll/interleukin-1 receptor (TIR) domain exerts the pro-neurodegenerative action through the NADase activity. However, the mechanism underlying the stringent control of Sarm1 activation remains to be fully understood. Here, we report the cryo-EM structures of full-length Sarm1 proteins at 2.6- to 3.0-Å resolution. We discovered NAD⁺ as an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain. This NAD⁺ binding facilitated the ARM domain to inhibit the TIR-domain NADase through their domain interface. Disruption of the NAD+-binding site or the ARM-TIR interaction caused the constitutively-active Sarm1 leading to axonal degeneration. These findings have suggested the novel NAD⁺-mediated self-inhibition of this central pro-neurodegenerative protein.