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J. Biol. Chem., Vol. 276, Issue 20, 17591-17596, May 18, 2001

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Budding Yeast GCN1 Binds the GI Domain to Activate the eIF2 Kinase GCN2^*

Hiroyuki Kubota^§, Kazuhisa Ota, Yoshiyuki Sakaki^§, and Takashi Ito^¶

From the  Division of Genome Biology, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-0934, Japan and ^§ Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

When starved for a single amino acid, the budding yeast Saccharomyces cerevisiae activates the eukaryotic initiation factor 2 (eIF2) kinase GCN2 in a GCN1-dependent manner. Phosphorylated eIF2 inhibits general translation but selectively derepresses the synthesis of the transcription factor GCN4, which leads to coordinated induction of genes involved in biosynthesis of various amino acids, a phenomenon called general control response. We recently demonstrated that this response requires binding of GCN1 to the GI domain occurring at the N terminus of GCN2 (Kubota, H., Sakaki, Y., and Ito, T. (2000) J. Biol. Chem. 275, 20243-20246). Here we provide the first evidence for the involvement of GCN1-GCN2 interaction in activation of GCN2 per se. We identified a C-terminal segment of GCN1 sufficient to bind the GI domain and used a novel dual bait two-hybrid method to identify mutations rendering GCN1 incapable of interacting with GCN2. The yeast bearing such an allele, gcn1-F2291L, fails to display derepression of GCN4 translation and hence general control response, as does a GI domain mutant, gcn2-Y74A, defective in association with GCN1. Furthermore, we demonstrated that phosphorylation of eIF2 is impaired in both mutants. Since GCN2 is the sole eIF2 kinase in yeast, these findings indicate a critical role of GCN1-GCN2 interaction in activation of the kinase in vivo.

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