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.

中文翻译：

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NAD+介导的促神经退行性Sarm1的自我抑制机制

轴突的病理变性破坏了神经回路，代表了神经变性 1-4 的标志之一。无菌 α 和 Toll/interleukin-1 受体基序蛋白 1 (Sarm1) 是该神经退行性过程的中枢调节因子 5-8，其 Toll/interleukin-1 受体 (TIR) 结构域通过 NADase 活性发挥促神经退行性作用 9 ,10。然而，严格控制 Sarm1 激活的机制仍有待充分了解。在这里，我们报告了分辨率为 2.6 至 3.0 Å 的全长 Sarm1 蛋白的冷冻电镜结构。我们发现 NAD+ 是犰狳/热重复基序 (ARM) 域的意外配体。这种 NAD+ 结合促进了 ARM 结构域通过其结构域界面抑制 TIR 结构域 NADase。NAD+结合位点或ARM-TI​​R相互作用的破坏导致组成型活性Sarm1导致轴突变性。这些发现表明这种中枢前神经退行性蛋白的新型 NAD+ 介导的自我抑制。