Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1
Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1
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DOI：
10.1016/j.celrep.2020.107999
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发表时间：
2020-08-04
期刊：
影响因子：
8.8
通讯作者：
Sambashivan, Shilpa
中科院分区：
文献类型：
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作者：
Bratkowski, Matthew;Xie, Tian;Sambashivan, Shilpa
NADase SARM 1是损伤激活的轴突变性的中心开关，这是许多神经系统疾病的早期标志。在这里，我们展示了自抑制（3.3埃）和活性SARM 1（6.8埃）的冷冻电子显微镜（cryo-EM）结构，并提供了对SARM 1功能受局部代谢环境严格调节的机制见解。虽然这两种状态都保留了八聚体核心，但自抑制状态的定义特征是自抑制Armadillo/HEAT基序（ARM）和催化Toll/白细胞介素-1受体（TIR）结构域之间的锁定，其将SARM 1捕获在非活性状态。打破这种锁定的突变激活SARM 1，导致灾难性的神经元死亡。值得注意的是，突变体不能被内源性激活剂烟酰胺单核苷酸（NMN）进一步激活，并且活性SARM 1被烟酰胺（NAM）抑制，突出了SARM 1对NAD补救途径中关键代谢物的功能依赖性。我们的研究提供了SARM 1从自抑制到损伤激活状态转变的分子理解，并为未来基于SARM 1的治疗轴突病奠定了基础。
The NADase SARM1 is a central switch in injury-activated axon degeneration, an early hallmark of many neurological diseases, Here, we present cryo-electron microscopy (cryo-EM) structures of autoinhibited (3.3 angstrom) and active SARM1 (6.8 angstrom) and provide mechanistic insight into the tight regulation of SARM1's function by the local metabolic environment. Although both states retain an octameric core, the defining feature of the autoinhibited state is a lock between the autoinhibitory Armadillo/HEAT motif (ARM) and catalytic Toll/interleukin-1 receptor (TIR) domains, which traps SARM1 in an inactive state. Mutations that break this lock activate SARM1, resulting in catastrophic neuronal death. Notably, the mutants cannot be further activated by the endogenous activator nicotinamide mononucleotide (NMN), and active SARM1 is product inhibited by Nicotinamide (NAM), highlighting SARM1's functional dependence on key metabolites in the NAD salvage pathway. Our studies provide a molecular understanding of SARM1's transition from an autoinhibited to an injury-activated state and lay the foundation for future SARM1 -based therapies to treat axonopathies.