气候变化领域集成服务门户(CCPortal): Multiple domain interfaces mediate SARM1 autoinhibition

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DOI	10.1073/pnas.2023151118
	Multiple domain interfaces mediate SARM1 autoinhibition
	Shen C.; Vohra M.; Zhang P.; Mao X.; Figley M.D.; Zhu J.; Sasaki Y.; Wu H.; DiAntonio A.; Milbrandt J.
发表日期	2021
ISSN	00278424
卷号	118 期号:4
英文摘要	Axon degeneration is an active program of self-destruction mediated by the protein SARM1. In healthy neurons, SARM1 is autoinhibited and, upon injury autoinhibition is relieved, activating the SARM1 enzyme to deplete NAD+ and induce axon degeneration. SARM1 forms a homomultimeric octamer with each monomer composed of an N-terminal autoinhibitory ARM domain, tandem SAM domains that mediate multimerization, and a C-terminal TIR domain encoding the NADase enzyme. Here we discovered multiple intramolecular and intermolecular domain interfaces required for SARM1 autoinhibition using peptide mapping and cryo-electron microscopy (cryo-EM). We identified a candidate autoinhibitory region by screening a panel of peptides derived from the SARM1 ARM domain, identifying a peptide mediating high-affinity inhibition of the SARM1 NADase. Mutation of residues in full-length SARM1 within the region encompassed by the peptide led to loss of autoinhibition, rendering SARM1 constitutively active and inducing spontaneous NAD+ and axon loss. The cryo-EM structure of SARM1 revealed 1) a compact autoinhibited SARM1 octamer in which the TIR domains are isolated and prevented from oligomerization and enzymatic activation and 2) multiple candidate autoinhibitory interfaces among the domains. Mutational analysis demonstrated that five distinct interfaces are required for autoinhibition, including intramolecular and intermolecular ARM-SAM interfaces, an intermolecular ARM-ARM interface, and two ARM-TIR interfaces formed between a single TIR and two distinct ARM domains. These autoinhibitory regions are not redundant, as point mutants in each led to constitutively active SARM1. These studies define the structural basis for SARM1 autoinhibition and may enable the development of SARM1 inhibitors that stabilize the autoinhibited state. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Axonopathy; Metabolism; Neurodegeneration; Neuropathy; NMN
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180881
作者单位	Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States; Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, United States; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States; Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO 63110, United States
推荐引用方式 GB/T 7714	Shen C.,Vohra M.,Zhang P.,et al. Multiple domain interfaces mediate SARM1 autoinhibition[J],2021,118(4).
APA	Shen C..,Vohra M..,Zhang P..,Mao X..,Figley M.D..,...&Milbrandt J..(2021).Multiple domain interfaces mediate SARM1 autoinhibition.Proceedings of the National Academy of Sciences of the United States of America,118(4).
MLA	Shen C.,et al."Multiple domain interfaces mediate SARM1 autoinhibition".Proceedings of the National Academy of Sciences of the United States of America 118.4(2021).