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Structural basis for SARM1 inhibition and activation under energetic stress
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 resolu...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688312/ https://www.ncbi.nlm.nih.gov/pubmed/33185189 http://dx.doi.org/10.7554/eLife.62021 |
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author | Sporny, Michael Guez-Haddad, Julia Khazma, Tami Yaron, Avraham Dessau, Moshe Shkolnisky, Yoel Mim, Carsten Isupov, Michail N Zalk, Ran Hons, Michael Opatowsky, Yarden |
author_facet | Sporny, Michael Guez-Haddad, Julia Khazma, Tami Yaron, Avraham Dessau, Moshe Shkolnisky, Yoel Mim, Carsten Isupov, Michail N Zalk, Ran Hons, Michael Opatowsky, Yarden |
author_sort | Sporny, Michael |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7688312 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-76883122020-11-30 Structural basis for SARM1 inhibition and activation under energetic stress Sporny, Michael Guez-Haddad, Julia Khazma, Tami Yaron, Avraham Dessau, Moshe Shkolnisky, Yoel Mim, Carsten Isupov, Michail N Zalk, Ran Hons, Michael Opatowsky, Yarden eLife Structural Biology and Molecular Biophysics 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. eLife Sciences Publications, Ltd 2020-11-13 /pmc/articles/PMC7688312/ /pubmed/33185189 http://dx.doi.org/10.7554/eLife.62021 Text en © 2020, Sporny et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Structural Biology and Molecular Biophysics Sporny, Michael Guez-Haddad, Julia Khazma, Tami Yaron, Avraham Dessau, Moshe Shkolnisky, Yoel Mim, Carsten Isupov, Michail N Zalk, Ran Hons, Michael Opatowsky, Yarden Structural basis for SARM1 inhibition and activation under energetic stress |
title | Structural basis for SARM1 inhibition and activation under energetic stress |
title_full | Structural basis for SARM1 inhibition and activation under energetic stress |
title_fullStr | Structural basis for SARM1 inhibition and activation under energetic stress |
title_full_unstemmed | Structural basis for SARM1 inhibition and activation under energetic stress |
title_short | Structural basis for SARM1 inhibition and activation under energetic stress |
title_sort | structural basis for sarm1 inhibition and activation under energetic stress |
topic | Structural Biology and Molecular Biophysics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688312/ https://www.ncbi.nlm.nih.gov/pubmed/33185189 http://dx.doi.org/10.7554/eLife.62021 |
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