9HVF

Native human PPP1R15B-P-eIF2-eIF2B complex

Summary for 9HVF

• Entry DOI: 10.2210/pdb9hvf/pdb
• EMDB information: 52434
• Descriptor: Translation initiation factor eIF-2B subunit gamma, Protein phosphatase 1 regulatory subunit 15B, Eukaryotic translation initiation factor 2 subunit 2, ... (5 entities in total)
• Functional Keywords: translation, phosphorylation, eukaryotic initiation factor-2b, eukaryotic initiation factor-2
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 188025.61

Authors

De Miguel, C.,Thorkelsson, S.R.,Wang, C.,Bertolotti, A. (deposition date: 2024-12-27, release date: 2025-11-19, Last modification date: 2025-11-26)

Primary citation

De Miguel, C.,Thorkelsson, S.R.,Fatalska, A.,Hodgson, G.,Wang, C.,Bertolotti, A.
Termination of the integrated stress response.
Science, :eadw5137-eadw5137, 2025

PubMed Abstract: Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by phosphorylation of translation initiation factor eIF2, which traps and inhibits rate-limiting translation factor eIF2B thereby attenuating translation initiation. Termination of this pathway thus requires relieving eIF2B from P-eIF2 inhibition. Here, we found that eIF2 phosphatase subunits PPP1R15A and PPP1R15B (R15B) bound P-eIF2 in complex with eIF2B. Biochemical investigations guided by cryo-EM structures of native eIF2-eIF2B and P-eIF2-eIF2B complexes bound to R15B demonstrated that R15B enabled dephosphorylation of otherwise dephosphorylation-incompetent P-eIF2 on eIF2B. This sheds light on ISR termination, revealing that R15B rescues eIF2B from P-eIF2 inhibition, thereby safeguarding translation and cell fitness.

PubMed: 41231936
DOI: 10.1126/science.adw5137

Experimental method

ELECTRON MICROSCOPY (3.8 Å)