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-Structure paper
タイトル | SARM1 is a metabolic sensor activated by an increased NMN/NAD ratio to trigger axon degeneration. |
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ジャーナル・号・ページ | Neuron, Vol. 109, Issue 7, Page 1118-1136.e11, Year 2021 |
掲載日 | 2021年4月7日 |
著者 | Matthew D Figley / Weixi Gu / Jeffrey D Nanson / Yun Shi / Yo Sasaki / Katie Cunnea / Alpeshkumar K Malde / Xinying Jia / Zhenyao Luo / Forhad K Saikot / Tamim Mosaiab / Veronika Masic / Stephanie Holt / Lauren Hartley-Tassell / Helen Y McGuinness / Mohammad K Manik / Todd Bosanac / Michael J Landsberg / Philip S Kerry / Mehdi Mobli / Robert O Hughes / Jeffrey Milbrandt / Bostjan Kobe / Aaron DiAntonio / Thomas Ve / |
PubMed 要旨 | Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide ...Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD ratio by cleaving residual NAD, thereby inducing feedforward metabolic catastrophe and axonal demise. |
リンク | Neuron / PubMed:33657413 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 1.65 - 3.35 Å |
構造データ | EMDB-23278, PDB-7ld0: PDB-7lcy: PDB-7lcz: |
化合物 | ChemComp-NMN: ChemComp-EDO: ChemComp-NA: ChemComp-HOH: |
由来 |
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キーワード | HYDROLASE / NADase / Autoinhibition / ARM domain / Allostery / SIGNALING PROTEIN / Neurodegeneration / NAD / Toxin |