Protein structure studies demonstrate how SARM1 senses cellular energy status to trigger axon degeneration

Two recent articles published by Needleman Center researchers dissect the structure of SARM1, an enzyme responsible for initiating programmed axon degeneration, and shed light on how the balance of key cellular metabolites regulate its activity. SARM1 forms an octamer in which each monomer contains an N-terminal autoinhibitory domain, domains that mediate multimerization, and a C-terminal TIR domain that cleaves the cellular metabolite NAD+.  

Experiments published in the Proceedings of the National Academy of Sciences USA, largely conducted by Milbrandt lab post-doc Dr. Mihir Vohra, used peptide mapping and cryo-electron microscopy to discover multiple intramolecular and intermolecular interfaces required for SARM1 autoinhibition. Dr. Vohra and colleagues demonstrated that mutation of residues constituting any of five distinct interfaces lead to loss of autoinhibition, constitutive SARM1 activity and spontaneous axon loss, information likely to enhance the development of inhibitors that stabilize SARM1 in its autoinhibited state. In a separate article authored by Dr. Matthew Figley, a post-doc in the DiAntonio lab, structural, biochemical, biophysical, and cellular assays were all employed to demonstrate that SARM1 is activated by a change in the ratio of NAD and its precursor NMN. The two metabolites compete to bind the enzyme’s auto-inhibitory domain rendering SARM1 a metabolic sensor that responds to a rising NMN/NAD+ ratio by further cleaving NAD+, leading to metabolic catastrophe and axon destruction. This work was published in the journal Neuron