ArticleNature structural & molecular biology2021
Higher-order phosphatase-substrate contacts terminate the integrated stress response.
Article in Nature structural & molecular biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Pooled it
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- Enhancing Enzymatic Bioconjugation Efficiency via Computer-Based Installation of a Substrate Recruitment Domain.Bioconjugate chemistry · 2026Article
- Termination of the integrated stress response.Science (New York, N.Y.) · 2026Article
- Article
- The Fascinating Intricacy of pSer/Thr-Specific Phosphatases and Their Higher-Order Complexes: Emerging Concepts.Biochemistry · 2025Review
- Combining cryo-electron microscopy (cryo-EM) with orthogonal solution state methods to define the molecular basis of the phosphoprotein phosphatase family regulation and substrate specificity.Current opinion in structural biology · 2025Review
- Article
- Alternating binding and p97-mediated dissociation of SDS22 and I3 recycles active PP1 between holophosphatases.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Functional validation of EIF2AK4 (GCN2) missense variants associated with pulmonary arterial hypertension.Human molecular genetics · 2024Article
- A highly optimized human in vitro translation system.Cell reports methods · 2024Article
- Substrate recruitment via eIF2γ enhances catalytic efficiency of a holophosphatase that terminates the integrated stress response.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B.Molecular cell · 2024Article
- Article
- The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP).International journal of molecular sciences · 2023Review
- The integrated stress response in cancer progression: a force for plasticity and resistance.Frontiers in oncology · 2023Review
- Computational study of the impact of nucleotide variations on highly conserved proteins: In the case of actin.Biophysics and physicobiology · 2022Article
- Substrate recognition determinants of human eIF2α phosphatases.Open biology · 2021Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c-PPP1R15A-G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.