The structural basis for SARM1 inhibition and activation under energetic stress
- Bar Ilan University, Israel
- The Weizmann Institute of Science, Israel
- Tel-Aviv University, Israel
- Royal Technical Institute (KTH), Sweden
- University of Exeter, United Kingdom
- Ben-Gurion University of the Negev, Israel
- European Molecular Biology Laboratory, France
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 resolution. 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.
Data availability
Coordinates and structure factors have been deposited in the Protein Data Bank with accession numbers 6ZFX, 7ANW, 6ZG0, 6ZG1, and in the EMDB with accession numbers 11187, 11834, 11190, 11191 for the GraFix-ed, NAD+ supplemented, not treated, and SAM1-2 models and maps, respectively.
Article and author information
Author details
Funding
Israel Science Foundation (1425/15)
- Yarden Opatowsky
Israel Science Foundation (909/19)
- Yarden Opatowsky
I declare that the funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Sporny et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The structural basis for SARM1 inhibition and activation under energetic stress
eLife 9:e62021.
https://doi.org/10.7554/eLife.62021
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