Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)- cleaving enzyme whose activation triggers axon destruction [1-4]. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using crystallography, cryo-EM, NMR and biochemical 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 autoinhibitory N-terminal armadillo repeat (ARM) domain of SARM1 [5]. We show that NMN binding disrupts ARM-TIR interactions in the full-length SARM1 octamer, enabling its TIR domains to self-associate and form a catalytic site capable of cleaving NAD+. These structural insights identify SARM1 as a metabolic sensor of the NMN/NAD+ ratio, defines the mechanism of SARM1 activation and catalysis, and provide rational avenues for the design of new therapeutics targeting SARM1.
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