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Structural basis fo...
Structural basis for SARM1 inhibition and activation under energetic stress
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- Sporny, Michael (author)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel.
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- Guez-Haddad, Julia (author)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel.
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- Khazma, Tami (author)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel.
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- Yaron, Avraham (author)
- Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.
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- Dessau, Moshe (author)
- Bar Ilan Univ, Azrieli Fac Med, Safed, Israel.
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- Shkolnisky, Yoel (author)
- Tel Aviv Univ, Sch Math Sci, Dept Appl Math, Tel Aviv, Israel.
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- Mim, Carsten (author)
- KTH,Strukturell bioteknik
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- Isupov, Michail N. (author)
- Univ Exeter, Biosci, Exeter, Devon, England.
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- Zalk, Ran (author)
- Ben Gurion Univ Negev, Natl Inst Biotechnol Negev, Beer Sheva, Israel.
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- Hons, Michael (author)
- European Mol Biol Lab, Grenoble, France.
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- Opatowsky, Yarden (author)
- Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel.
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Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel. (creator_code:org_t)
- eLife Sciences Publications, Ltd, 2020
- 2020
- English.
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In: eLIFE. - : eLife Sciences Publications, Ltd. - 2050-084X. ; 9
- Related links:
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https://doi.org/10.7...
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https://urn.kb.se/re...
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Abstract
Subject headings
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- 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 angstrom 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sporny, Michael
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Guez-Haddad, Jul ...
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Khazma, Tami
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Yaron, Avraham
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Dessau, Moshe
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Shkolnisky, Yoel
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Mim, Carsten
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Isupov, Michail ...
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Zalk, Ran
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Hons, Michael
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Opatowsky, Yarde ...
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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eLIFE
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Royal Institute of Technology