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-Structure paper
タイトル | Structural basis for SARM1 inhibition and activation under energetic stress. |
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ジャーナル・号・ページ | Elife, Vol. 9, Year 2020 |
掲載日 | 2020年11月13日 |
著者 | Michael Sporny / Julia Guez-Haddad / Tami Khazma / Avraham Yaron / Moshe Dessau / Yoel Shkolnisky / Carsten Mim / Michail N Isupov / Ran Zalk / Michael Hons / Yarden Opatowsky / |
PubMed 要旨 | 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 ...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. |
リンク | Elife / PubMed:33185189 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.68 - 7.7 Å |
構造データ | EMDB-11187, PDB-6zfx: EMDB-11190, PDB-6zg0: EMDB-11191, PDB-6zg1: EMDB-11834, PDB-7anw: |
化合物 | ChemComp-S1N: ChemComp-EDO: ChemComp-BME: ChemComp-PEG: ChemComp-PGE: ChemComp-NAD: |
由来 |
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キーワード | HYDROLASE / NADase / ARM domain / SAM domain / TIR domain / APOPTOSIS |