The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1
The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1
复制标题
NAD（）介导的促神经退行性SARM1的自我抑制机制
DOI：
10.1038/s41586-020-2862-z
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发表时间：
2020-10-14
期刊：
影响因子：
64.8
通讯作者：
Zhang, Zhe
中科院分区：
文献类型：
--
作者：
Jiang, Yuefeng;Liu, Tingting;Zhang, Zhe
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.NAD(+) is shown to be a ligand of the armadillo/heat repeat motifs (ARM) domain of SARM1, and it is suggested that this binding of NAD(+) mediates self-inhibition of SARM1.
