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北京大学张哲/杨竞课题组揭示Sarm1自我抑制的新机制
作者:小柯机器人 发布时间:2020/10/15 16:11:31

北京大学张哲和杨竞研究组合作取得一项新突破。他们的最新研究探明了NAD+介导α和Toll /白细胞介素1受体结构域的蛋白1(Sarm1)自我抑制的机制。2020年10月14日出版的《自然》在线发表了这项成果。

研究人员解析了Sarm1蛋白的冷冻电镜结构,其分辨率为2.6-3.0Å。研究人员发现NAD+是ARM结构域(Sarm1ARM)的配体。NAD+结合有助于ARM结构域通过其结构域接口抑制TIR结构域的NADase活性。破坏NAD+的结合位点或其与ARM-oll /白细胞介素1受体(TIR)的相互作用会导致组成型激活Sarm1从而引起轴突变性。这些发现揭示了NAD+是调控该中央促神经退行性蛋白自我抑制的新调控因子。

据介绍,轴突的病理变性破坏神经回路,这是神经变性的标志之一。Sarm1是调控神经退行性过程的核心蛋白,其TIR结构域通过NADase活性来发挥促神经退行的功能。但是,调控Sarm1激活的机制仍有待阐明。

附:英文原文

Title: The NAD + -mediated self-inhibition mechanism of pro-neurodegenerative Sarm1

Author: Yuefeng Jiang, Tingting Liu, Chia-Hsueh Lee, Qing Chang, Jing Yang, Zhe Zhang

Issue&Volume: 2020-10-14

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 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- 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.

DOI: 10.1038/s41586-020-2862-z

Source: https://www.nature.com/articles/s41586-020-2862-z

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html