ArticleProceedings of the National Academy of Sciences of the United States of America2019
Activation of GCN2 by the ribosomal P-stalk.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 141 papers, 1 of them a synthesis that pooled it.
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Who cites it
141 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Systematic Review of Plant Ribosome Heterogeneity and Specialization.Frontiers in plant science · 2020Pooled it
- Review
- Substrate Binding Relieves Autoinhibition of the Mammalian GCN2 Kinase.bioRxiv : the preprint server for biology · 2026Article
- Batch- and Composition-Controlled Reanalysis of Bulk and Single-Nucleus Transcriptomes Reveals Co-Enrichment of Glial Complement and of Translational Signatures in Parkinson's Disease and Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2026Article
- Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.Molecular therapy. Nucleic acids · 2026Article
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- A multilayered stress-response circuit: The mammalian mitochondrial UPR.The FEBS journal · 2026Review
- Regulatory dynamics of monosomes and polysomes in cellular adaptation.Journal of biochemistry · 2026Review
- Allosteric disordering of eIF2B regulates the integrated stress response.Nature chemical biology · 2026Article
- Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.RNA (New York, N.Y.) · 2026Article
- Hydrogen/deuterium exchange mass spectrometry analysis of ribosome-nascent chain complexes to study protein biogenesis at the peptide level.Nature protocols · 2026Article
- A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- tRNA synthetase activity is required for stress granule and P-body assembly.Genes & development · 2026Article
- Nanoscaled, Fully Automated Hydrogen/Deuterium Exchange for Analysis of Macromolecular Assemblies Reaching the MDa Scale.Molecular & cellular proteomics : MCP · 2026Article
- Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Quality control and signaling pathways at stalled ribosomes.Experimental & molecular medicine · 2026Review
- GCN2 in Cancer: Molecular Mechanisms to Therapeutic Potential.Current cancer drug targets · 2026Review
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- GCN2 regulates paclitaxel-induced neuropathic pain.British journal of pharmacology · 2025Article
- Depurination of sarcin/ricin loop 25S rRNA is signaled through the small ribosomal subunit during translation.RNA (New York, N.Y.) · 2025Article
81 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors.
Funding
Abstract
Cells dynamically adjust their protein translation profile to maintain homeostasis in changing environments. During nutrient stress, the kinase general control nonderepressible 2 (GCN2) phosphorylates translation initiation factor eIF2α, initiating the integrated stress response (ISR). To examine the mechanism of GCN2 activation, we have reconstituted this process in vitro, using purified components. We find that recombinant human GCN2 is potently stimulated by ribosomes and, to a lesser extent, by tRNA. Hydrogen/deuterium exchange-mass spectrometry (HDX-MS) mapped GCN2-ribosome interactions to domain II of the uL10 subunit of the ribosomal P-stalk. Using recombinant, purified P-stalk, we showed that this domain of uL10 is the principal component of binding to GCN2; however, the conserved 14-residue C-terminal tails (CTTs) in the P1 and P2 P-stalk proteins are also essential for GCN2 activation. The HisRS-like and kinase domains of GCN2 show conformational changes upon binding recombinant P-stalk complex. Given that the ribosomal P-stalk stimulates the GTPase activity of elongation factors during translation, we propose that the P-stalk could link GCN2 activation to translational stress, leading to initiation of ISR.
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