ArticleProceedings of the National Academy of Sciences of the United States of America2021
Structure of Gcn1 bound to stalled and colliding 80S ribosomes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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100 citing papers in PubMed, 161 citations in OpenAlex.
- Genetic dissection reveals distinct contributions of the eS31 N-terminal domain to translational accuracy in Saccharomyces cerevisiae.The FEBS journal · 2026Article
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- eIF5A and polyamines restrict mRNA levels in response to ribosome stalls.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Substrate Binding Relieves Autoinhibition of the Mammalian GCN2 Kinase.bioRxiv : the preprint server for biology · 2026Article
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- Principles of ribosome-associated protein quality control during the synthesis of CFTR.The EMBO journal · 2026Article
- Regulatory dynamics of monosomes and polysomes in cellular adaptation.Journal of biochemistry · 2026Review
- Mechanism of RACK1-dependent ZAKα activation at stalled and collided ribosomes.Molecular cell · 2026Article
- tRNA synthetase activity is required for stress granule and P-body assembly.Genes & development · 2026Article
- 5-Azacytidine incorporation into mRNAs disrupts translation and induces ribosome collisions.bioRxiv : the preprint server for biology · 2026Article
- Ribosome-associated quality control and related mechanisms.Nature structural & molecular biology · 2026Review
- 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
- Differential regulation of translational stress responses by herpesvirus ubiquitin deconjugases.The FEBS journal · 2026Article
- Saccharomyces cerevisiae as a model for mammalian diseases.FEMS yeast research · 2026Review
- Suboptimal codon pairs trigger ribosome collisions and cellular quality control responses in tRNA modification mutants.Nucleic acids research · 2025Article
- Article
- Determining the effects of pseudouridine incorporation on human tRNAs.The EMBO journal · 2025Article
- Mechanisms suppressing noncoding translation.Trends in cell biology · 2025Review
- Insights into the role of collided ribosomes during the activation of the integrated stress response.Biochemical Society transactions · 2025Review
40 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Gcn pathway is conserved in all eukaryotes, including mammals such as humans, where it is a crucial part of the integrated stress response (ISR). Gcn1 serves as an essential effector protein for the kinase Gcn2, which in turn is activated by stalled ribosomes, leading to phosphorylation of eIF2 and a subsequent global repression of translation. The fine-tuning of this adaptive response is performed by the Rbg2/Gir2 complex, a negative regulator of Gcn2. Despite the wealth of available biochemical data, information on structures of Gcn proteins on the ribosome has remained elusive. Here we present a cryo-electron microscopy structure of the yeast Gcn1 protein in complex with stalled and colliding 80S ribosomes. Gcn1 interacts with both 80S ribosomes within the disome, such that the Gcn1 HEAT repeats span from the P-stalk region on the colliding ribosome to the P-stalk and the A-site region of the lead ribosome. The lead ribosome is stalled in a nonrotated state with peptidyl-tRNA in the A-site, uncharged tRNA in the P-site, eIF5A in the E-site, and Rbg2/Gir2 in the A-site factor binding region. By contrast, the colliding ribosome adopts a rotated state with peptidyl-tRNA in a hybrid A/P-site, uncharged-tRNA in the P/E-site, and Mbf1 bound adjacent to the mRNA entry channel on the 40S subunit. Collectively, our findings reveal the interaction mode of the Gcn2-activating protein Gcn1 with colliding ribosomes and provide insight into the regulation of Gcn2 activation. The binding of Gcn1 to a disome has important implications not only for the Gcn2-activated ISR, but also for the general ribosome-associated quality control pathways.
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