ArticlePLoS genetics2015
Interaction between the tRNA-binding and C-terminal domains of Yeast Gcn2 regulates kinase activity in vivo.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 56 citations in OpenAlex.
- Leucyl tRNA synthetase ameliorates cholestatic liver injury by inhibiting integrated stress response in mice.Scientific reports · 2026Article
- tRNA synthetase activity is required for stress granule and P-body assembly.Genes & development · 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
- Insights into the role of collided ribosomes during the activation of the integrated stress response.Biochemical Society transactions · 2025Review
- Structure of a Gcn2 dimer in complex with the large 60S ribosomal subunit.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Purification and Analysis of eIF2α Phosphorylation by Stress-Activated Protein Kinase Gcn2 from S. cerevisiae.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Cryo-EM structure of histidyl-tRNA synthetase-like domain reveals activating crossed helices at the core of GCN2.PNAS nexus · 2024Article
- Multifaceted role of GCN2 in tumor adaptation and therapeutic targeting.Translational oncology · 2024Review
- Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response.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
- Emerging Role of GCN1 in Disease and Homeostasis.International journal of molecular sciences · 2024Review
- Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions.Nucleic acids research · 2024Article
- Recognition of the tRNA structure: Everything everywhere but not all at once.Cell chemical biology · 2024Review
- General control nonderepressible 2 (GCN2) as a therapeutic target in age-related diseases.Frontiers in aging · 2024Review
- Cellular Stress: Modulator of Regulated Cell Death.Biology · 2023Review
- Hepatitis E Virus Protease Inhibits the Activity of Eukaryotic Initiation Factor 2-Alpha Kinase 4 and Promotes Virus Survival.Journal of virology · 2023Article
- Differential requirements for P stalk components in activating yeast protein kinase Gcn2 by stalled ribosomes during stress.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Multiple Roles of the Stress Sensor GCN2 in Immune Cells.International journal of molecular sciences · 2023Review
- TORC1 Signaling in Fungi: From Yeasts to Filamentous Fungi.Microorganisms · 2023Review
- Review: Emerging roles of the signaling network of the protein kinase GCN2 in the plant stress response.Plant science : an international journal of experimental plant biology · 2022Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The stress-activated protein kinase Gcn2 regulates protein synthesis by phosphorylation of translation initiation factor eIF2α. Gcn2 is activated in amino acid-deprived cells by binding of uncharged tRNA to the regulatory domain related to histidyl-tRNA synthetase, but the molecular mechanism of activation is unclear. We used a genetic approach to identify a key regulatory surface in Gcn2 that is proximal to the predicted active site of the HisRS domain and likely remodeled by tRNA binding. Mutations leading to amino acid substitutions on this surface were identified that activate Gcn2 at low levels of tRNA binding (Gcd- phenotype), while other substitutions block kinase activation (Gcn- phenotype), in some cases without altering tRNA binding by Gcn2 in vitro. Remarkably, the Gcn- substitutions increase affinity of the HisRS domain for the C-terminal domain (CTD), previously implicated as a kinase autoinhibitory segment, in a manner dampened by HisRS domain Gcd- substitutions and by amino acid starvation in vivo. Moreover, tRNA specifically antagonizes HisRS/CTD association in vitro. These findings support a model wherein HisRS-CTD interaction facilitates the autoinhibitory function of the CTD in nonstarvation conditions, with tRNA binding eliciting kinase activation by weakening HisRS-CTD association with attendant disruption of the autoinhibitory KD-CTD interaction.
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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.