Programmed axon degeneration represents a pathological feature of many neurodegenerative diseases. The central executioner of this process is SARM1, whose activation triggers injury-induced axon death. We seek to understand the mechanism of SARM1 function, permitting drug development against a range of neurodegenerative diseases.
SARM1 contains an N-terminal ARM domain, two central tandem SAM domains and a C-terminal TIR domain. We have shown that it exists as octamers in solution, with oligomerization mediated by the SAM domains. We have further shown that the TIR domain unexpectedly possesses NADase activity, essential for subsequent axon death, and the ARM domain regulates SARM1 activation by sensing the changes of the activator NMN/ the inhibitor NAD ratio in the axons. Our most recent work led to the discovery that the regulatory site in the ARM domain also permits the interaction with a diverse set of metabolites, including NaMN, another precursor of NAD, structurally similar to NMN that acts as SARM1 inhibitor; and VMN, a metabolite of pesticide vacor, which acts as a SARM1 activator during vacor neurotoxicity.
Our cryo-EM structure of SARM1 reveals that SARM1 is held in the inactive ring-shaped octamers, with ARM domains directly interacting with the TIR domains to prevent TIR domain assembly. Upon injury, NMN binding to the ARM domain leads to a more compact conformation, disrupting the ARM:TIR interaction and releasing the TIR domains. With the help of a small-molecule NAD analogue, we enabled to capture the active assembly of TIR domains, revealing two antiparallel, head-to-tail strands.
Together, our results explain the mechanisms of SARM1 auto-inhibition, activation and substrate recognition and present a foundation for drug development.