Journal
NEURON
Volume 109, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2021.02.009
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Funding
- Institute of Structural and Chemical Biology, University of Leicester, UK
- Electron BioImaging Centre (eBIC), Diamond, UK
- National Computational Infrastructure (NCI) Australia [cj47]
- Queensland Cyber Infrastructure Foundation (QCIF) [fi49]
- National Health and Medical Research Council (NHMRC) [1107804, 1160570, 1071659, 1108859]
- Australian Research Council (ARC) Laureate Fellowship [FL180100109]
- National Institutes of Health [R01CA219866, RO1NS087632, RF1AG013730]
- Disarm Therapeutics
- ARC DECRA [DE170100783]
- Griffith University Postdoctoral Fellowship Scheme
- UQ International Scholarship (UQI)
- Australian Government Research Training Program Scheme
- University of Queensland Research Training Scholarship
- National Health and Medical Research Council of Australia [1107804, 1108859, 1160570] Funding Source: NHMRC
- Australian Research Council [DE170100783] Funding Source: Australian Research Council
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SARM1 is a nicotinamide adenine dinucleotide (NAD+)-cleaving enzyme that is activated by an increase in the ratio of NMN to NAD+, triggering axon destruction. The structural analysis showed that both NMN and NAD+ compete for binding to the auto inhibitory N-terminal armadillo repeat (ARM) domain of SARM1.
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.
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