9D9Z

Structure of human UBR4-KCMF1-CaM E3 ligase complex (Silencing Factor of the Integrated stress response, SiFI)

9D9Z の概要

• エントリーDOI: 10.2210/pdb9d9z/pdb
• 関連するPDBエントリー: 9NWD 9NWE
• EMDBエントリー: 46686 46742
• 分子名称: UBR4 (endogenously FLAG-tagged at the N-terminus),E3 ubiquitin-protein ligase UBR4,E3 ubiquitin-protein ligase UBR4,E3 ubiquitin-protein ligase UBR4, Calmodulin-1, E3 ubiquitin-protein ligase KCMF1, ... (5 entities in total)
• 機能のキーワード: e3 liase, ubr4, sifi, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 1273520.15

構造登録者

Yang, Z.,Rape, M. (登録日: 2024-08-21, 公開日: 2025-06-11, 最終更新日: 2025-08-06)

主引用文献

Yang, Z.,Haakonsen, D.L.,Heider, M.,Witus, S.R.,Zelter, A.,Beschauner, T.,MacCoss, M.J.,Rape, M.
Molecular basis of SIFI activity in the integrated stress response.
Nature, 643:1117-1126, 2025

PubMed Abstract: Chronic stress response activation impairs cell survival and causes devastating degenerative diseases. Organisms accordingly deploy silencing factors, such as the E3 ubiquitin ligase silencing factor of the integrated stress response (SIFI), to terminate stress response signalling and ensure cellular homeostasis. How a silencing factor can sense stress across cellular scales to elicit timely stress response inactivation is poorly understood. Here we combine cryo-electron microscopy analysis of endogenous SIFI with AlphaFold modelling and biochemical studies to report the structural and mechanistic basis of the silencing of the integrated stress response. SIFI detects both stress indicators and stress response components through flexible domains within an easily accessible scaffold, before building linkage-specific ubiquitin chains at separate, sterically restricted elongation modules. Ubiquitin handover by a ubiquitin-like domain couples versatile substrate modification to linkage-specific ubiquitin polymer formation. Stress response silencing therefore exploits a catalytic mechanism that is geared towards processing many diverse proteins and therefore allows a single enzyme to monitor and, if needed, modulate a complex cellular state.

PubMed: 40328314
DOI: 10.1038/s41586-025-09074-z

実験手法

ELECTRON MICROSCOPY (3.4 Å)