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Multiple domain interfaces mediate SARM1 autoinhibition.

Chen Shen1,2, Mihir Vohra3, Pengfei Zhang1,2

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|January 20, 2021
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Protein SARM1 triggers axon degeneration by depleting NAD+. Researchers identified key interfaces regulating SARM1

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Structural Biology

Background:

  • Axon degeneration is an active process regulated by the protein SARM1.
  • In healthy neurons, SARM1 is kept inactive (autoinhibited).
  • Upon neuronal injury, SARM1 becomes active, depleting NAD+ and causing axon self-destruction.

Purpose of the Study:

  • To elucidate the structural mechanisms underlying SARM1 autoinhibition.
  • To identify specific protein domain interfaces critical for regulating SARM1 activity.
  • To lay the groundwork for developing SARM1 inhibitors.

Main Methods:

  • Peptide mapping to identify inhibitory regions of SARM1.
  • Cryo-electron microscopy (cryo-EM) to determine the structure of SARM1.
  • Site-directed mutagenesis to test the function of identified interfaces.

Main Results:

  • Identified a high-affinity inhibitory peptide derived from the SARM1 ARM domain.
  • Cryo-EM revealed a compact, autoinhibited SARM1 octamer structure.
  • Discovered five distinct intramolecular and intermolecular interfaces essential for SARM1 autoinhibition.

Conclusions:

  • Defined the structural basis of SARM1 autoinhibition.
  • Demonstrated that disruption of these interfaces leads to constitutive SARM1 activation and axon loss.
  • These findings are crucial for designing therapeutics that stabilize the autoinhibited state of SARM1.