6ZG0

SARM1 SAM1-2 domains

6ZG0 の概要

• エントリーDOI: 10.2210/pdb6zg0/pdb
• EMDBエントリー: 11190
• 分子名称: NAD(+) hydrolase SARM1, 1,2-ETHANEDIOL, BETA-MERCAPTOETHANOL, ... (5 entities in total)
• 機能のキーワード: nadase, sam domain, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 641812.70

構造登録者

Sporny, M.,Guez-Haddad, J.,Khazma, T.,Yaron, A.,Dessau, M.,Mim, C.,Isupov, M.N.,Zalk, R.,Hons, M.,Opatowsky, Y. (登録日: 2020-06-18, 公開日: 2020-11-11, 最終更新日: 2020-12-09)

主引用文献

Sporny, M.,Guez-Haddad, J.,Khazma, T.,Yaron, A.,Dessau, M.,Shkolnisky, Y.,Mim, C.,Isupov, M.N.,Zalk, R.,Hons, M.,Opatowsky, Y.
Structural basis for SARM1 inhibition and activation under energetic stress.
Elife, 9:-, 2020

PubMed 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.

PubMed: 33185189
DOI: 10.7554/eLife.62021

実験手法

ELECTRON MICROSCOPY (7.7 Å)