ArticleThe EMBO journal2001
The tRNA-binding moiety in GCN2 contains a dimerization domain that interacts with the kinase domain and is required for tRNA binding and kinase activation.
Article in The EMBO journal, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 117 citations in OpenAlex.
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- 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
- GCN2 regulates paclitaxel-induced neuropathic pain.British journal of pharmacology · 2025Article
- Article
- Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.Nature cell biology · 2025Article
- 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
- GCN2-Mediated eIF2α Phosphorylation Is Required for Central Nervous System Remyelination.International journal of molecular sciences · 2025Article
- Purification and Analysis of eIF2α Phosphorylation by Stress-Activated Protein Kinase Gcn2 from S. cerevisiae.Methods in molecular biology (Clifton, N.J.) · 2025Article
- GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension.JCI insight · 2024Article
- 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
- Evidence that Xrn1 is in complex with Gcn1, and is required for full levels of eIF2α phosphorylation.The Biochemical journal · 2024Article
- General control nonderepressible 2 (GCN2) as a therapeutic target in age-related diseases.Frontiers in aging · 2024Review
- Cells use multiple mechanisms for cell-cycle arrest upon withdrawal of individual amino acids.Cell reports · 2023Article
- Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice.Biomedicines · 2023Article
- L-serine: Neurological Implications and Therapeutic Potential.Biomedicines · 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
- The Role of GCN2 Kinase in Mediating the Effects of Amino Acids on Longevity and Feeding Behaviour inFrontiers in aging · 2022Article
- Ribosome quality control antagonizes the activation of the integrated stress response on colliding ribosomes.Molecular cell · 2021Article
- Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis.Frontiers in immunology · 2020Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
GCN2 stimulates translation of GCN4 mRNA in amino acid-starved cells by phosphorylating translation initiation factor 2. GCN2 is activated by binding of uncharged tRNA to a domain related to histidyl-tRNA synthetase (HisRS). The HisRS-like region contains two dimerization domains (HisRS-N and HisRS-C) required for GCN2 function in vivo but dispensable for dimerization by full-length GCN2. Residues corresponding to amino acids at the dimer interface of Escherichia coli HisRS were required for dimerization of recombinant HisRS-N and for tRNA binding by full-length GCN2, suggesting that HisRS-N dimerization promotes tRNA binding and kinase activation. HisRS-N also interacted with the protein kinase (PK) domain, and a deletion impairing this interaction destroyed GCN2 function without reducing tRNA binding; thus, HisRS-N-PK interaction appears to stimulate PK function. The C-terminal domain of GCN2 (C-term) interacted with the PK domain in a manner disrupted by an activating PK mutation (E803V). These results suggest that the C-term is an autoinhibitory domain, counteracted by tRNA binding. We conclude that multiple domain interactions, positive and negative, mediate the activation of GCN2 by uncharged tRNA.
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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.