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

  • Nature. 2020 Dec;588(7839):658-663. doi: 10.1038/s41586-020-2862-z.
Yuefeng Jiang  1 ,  Tingting Liu  1 ,  Chia-Hsueh Lee  2 ,  Qing Chang  3 ,  Jing Yang  4 ,  Zhe Zhang  5
Affiliations
  • 1. State Key Laboratory of Membrane Biology, Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China.
  • 2. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3. Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China.
  • 4. State Key Laboratory of Membrane Biology, Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China. [email protected].
  • 5. State Key Laboratory of Membrane Biology, Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China. [email protected].
PMID: 33053563 DOI: 10.1038/s41586-020-2862-z
Abstract

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 its pro-neurodegenerative action through NADase activity9,10. 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.