Dr. Jing Yang's Lab: The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative Sarm1
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 the pro-neurodegenerative action through the NADase activity9,10. 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.
Original Link: https://www.nature.com/articles/s41586-020-2862-z