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. jing.yang@pku.edu.cn.
5 State Key Laboratory of Membrane Biology, Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China. zzhang01@pku.edu.cn.

PMID: 33053563 DOI: 10.1038/s41586-020-2862-z

Abstract

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.

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