Structural basis for sarm1 inhibition and activation under energetic stress

Michael Sporny, Julia Guez-Haddad, Tami Khazma, Avraham Yaron, Moshe Dessau, Yoel Shkolnisky, Carsten Mim, Michail N. Isupov, Ran Zalk, Michael Hons, Yarden Opatowsky

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition and its activation under stress conditions are still unknown. Here, we present cryo-EM maps of SARM1 at 2.9 and 2.7 Å resolutions. These indicate that SARM1 homo-octamer avoids premature activation by assuming a packed conformation, with ordered inner and peripheral rings, that prevents dimerization and activation of the catalytic domains. This inactive conformation is stabilized by binding of SARM1’s own substrate NAD+ in an allosteric location, away from the catalytic sites. This model was validated by mutagenesis of the allosteric site, which led to constitutively active SARM1. We propose that the reduction of cellular NAD+ concentration contributes to the disassembly of SARM1’s peripheral ring, which allows formation of active NADase domain dimers, thereby further depleting NAD+ to cause an energetic catastrophe and cell death.

Original languageEnglish
Article numbere62021
Pages (from-to)1-25
Number of pages25
JournaleLife
Volume9
DOIs
StatePublished - 1 Oct 2020

ASJC Scopus subject areas

  • Neuroscience (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Immunology and Microbiology (all)

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