澳大利亚昆士兰大学、格里菲斯大学、联邦科学与工业研究组织牵头的国际合作团队取得一项新突破。他们的最新研究提出动物和植物TIR结构域在细胞死亡途径中的NAD+裂解活性。 该项研究成果发表在2019年8月23日出版的《科学》上。
SARM1(含1的不育α和TIR基序)负责在与神经病相关的华勒氏变性过程中，耗尽氧化型烟酰胺腺嘌呤二核苷酸(NAD+)。植物核苷结合富亮氨酸的重复序列(NLR)作为免疫受体识别病原体效应蛋白，触发局部细胞死亡，以限制病原体感染。以上两个过程都依赖于这些蛋白中紧密相关的Toll/白细胞介素-1受体(TIR)域。
研究发现，这些区域具有与细胞死亡信号传导相关的自联想依赖性NAD+分裂活性。进一步研究表明，SARM1 SAM(不育的α基序)结构域形成了轴突退化所必需的八聚体，这有助于提高TIR结构域的酶活性。SARM1和NLR RUN1 TIR区域的核糖和NADP+(烟酰胺腺嘌呤二核苷酸磷酸的氧化形式)复合物的晶体结构分别揭示了该保守的底物结合位点。因此，TIR域的NAD+裂解能力是动植物细胞死亡信号通路的一个保守特征。
附：英文原文
Title: NAD+ cleavage activity by animal and plant TIR domains in cell death pathways
Author: Shane Horsefield, Hayden Burdett, Xiaoxiao Zhang, Mohammad K. Manik, Yun Shi, Jian Chen, Tiancong Qi, Jonathan Gilley, Jhih-Siang Lai, Maxwell X. Rank, Lachlan W. Casey, Weixi Gu, Daniel J. Ericsson, Gabriel Foley, Robert O. Hughes, Todd Bosanac, Mark von Itzstein, John P. Rathjen, Jeffrey D. Nanson, Mikael Boden, Ian B. Dry, Simon J. Williams, Brian J. Staskawicz, Michael P. Coleman, Thomas Ve, Peter N. Dodds, Bostjan Kobe
Issue&Volume:Volume 365 Issue 6455
Abstract: SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD+) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association–dependent NAD+ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD+ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.
DOI: 10.1126/science.aax1911
Source:https://science.sciencemag.org/content/365/6455/793