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-Structure paper
タイトル | Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1. |
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ジャーナル・号・ページ | Cell Rep, Vol. 32, Issue 5, Page 107999, Year 2020 |
掲載日 | 2020年8月4日 |
著者 | Matthew Bratkowski / Tian Xie / Desiree A Thayer / Shradha Lad / Prakhyat Mathur / Yu-San Yang / Gregory Danko / Thomas C Burdett / Jean Danao / Aaron Cantor / Jennifer A Kozak / Sean P Brown / Xiaochen Bai / Shilpa Sambashivan / |
PubMed 要旨 | 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 ...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 Å) and active SARM1 (6.8 Å) 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. |
リンク | Cell Rep / PubMed:32755591 |
手法 | EM (単粒子) |
解像度 | 3.3 - 6.8 Å |
構造データ | EMDB-21863, PDB-6wpk: EMDB-21869: |
由来 |
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キーワード | HYDROLASE / NADase / ARM / SAM / TIR |