9NWD

Human E3 ligase UBR4-KCMF1-calmodulin complex (N-terminal)

Summary for 9NWD

• Entry DOI: 10.2210/pdb9nwd/pdb
• Related: 9D9Z
• EMDB information: 46688
• Descriptor: E3 ubiquitin-protein ligase UBR4 (1 entity in total)
• Functional Keywords: e3 ligase, ligase, ubr4
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 1148924.62

Authors

Yang, Z.,Haakonsen, D.L.,Heider, M.,Witus, S.R.,Zelter, A.,Beschauner, T.,MacCoss, M.J.,Rape, M. (deposition date: 2025-03-22, release date: 2025-06-11, Last modification date: 2025-08-06)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.4 Å)