School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.
Agriculture and Food, Commonwealth Scientific and Industrial Research Organisation, Canberra, ACT 2601, Australia.
Science. 2019 Aug 23;365(6455):793-799. doi: 10.1126/science.aax1911.
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.
SARM1（ sterile alpha and TIR motif containing 1 ）在与神经病变相关的 Wallerian 变性过程中负责消耗其氧化形式（NAD）中的烟酰胺腺嘌呤二核苷酸。植物核苷酸结合亮氨酸重复（NLR）免疫受体识别病原体效应蛋白并触发局部细胞死亡以限制病原体感染。这两个过程都依赖于这些蛋白质中密切相关的 Toll/白细胞介素-1 受体（TIR）结构域，正如我们所展示的，这些结构域具有与细胞死亡信号相关的自我关联依赖性 NAD 切割活性。我们进一步表明，SARM1 SAM（无菌α基序）结构域形成八聚体对于轴突退化是必不可少的，这有助于 TIR 结构域的酶活性。SARM1 和植物 NLR RUN1 TIR 结构域的核糖和 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保守的底物结合位点。因此，TIR 结构域的 NAD 切割是动物和植物细胞死亡信号通路的保守特征。
