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Logo of jbcThe Journal of Biological Chemistry
J Biol Chem. 2011 October 21; 286(42): e99968.
PMCID: PMC3196115

Gettin' Hungry: Regulation of Cellular Starvation Response by Translation Elongation Factor 1A♦

Evidence That Eukaryotic Translation Elongation Factor 1A (eEF1A) Binds the Gcn2 Protein C Terminus and Inhibits Gcn2 Activity

♦ See referenced article, J. Biol. Chem. 2011, 286, 36568–36579

Protein synthesis is highly responsive to environmental signals and requires constant monitoring of amino acid concentration to function properly. However, the interplay and overlap between proteins involved in the multiple feedback mechanisms involved in the process are poorly defined. In their Paper of the Week, Visweswaraiah et al. provide evidence that points to a previously unrecognized role for the translation elongation factor eEF1A in the cellular starvation response. eEF1A is known to be responsible for delivering charged aminoacyl-tRNA molecules to ribosomes. The authors found that eEF1A also interacts with Gcn2, which plays a key role in the amino acid starvation response by detecting uncharged tRNAs and inhibiting the activity of eIF2α, a translation initiation factor. Using co-immunoprecipitation assays, the authors observed that eEF1A and Gcn2 bind each other directly. This interaction requires only the C-terminal domain of Gcn2 and is not dependent on ribosome binding. Inducing amino acid starvation diminished the Gcn2-eEF1A interaction, as did the direct addition of uncharged tRNA molecules, suggesting that eEF1A inhibits Gcn2. Loss of the Gcn2-eEF1A reaction also resulted in an increase in eIF2α phosphorylation, thereby inhibiting its activity. The authors propose a model in which eEF1A binds Gcn2 under normal conditions, keeping Gcn2 inactive and allowing translation to proceed. As the concentration of uncharged tRNAs increases upon starvation, Gcn2 is activated via autophosphorylation, causing dissociation from eEF1A and allowing Gcn2 to phosphorylate eIF2α, halting translation and resulting in the starvation response. This model provides a new context for studying the relationship between protein synthesis and nutrient availability.

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The Gcn2-CTD is sufficient for forming a complex with eEF1A.

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