MUTATIONS IN THE ALPHA-SUBUNIT OF EUKARYOTIC TRANSLATION INITIATION FACTOR-II (EIF-2-ALPHA) THAT OVERCOME THE INHIBITORY EFFECT OF EIF-2-ALPHA PHOSPHORYLATION ON TRANSLATION INITIATION

Phosphorylation of eIF-2alpha in Saccharomyces cerevisiae by the prote in kinase GCN2 leads to inhibition of general translation initiation a nd a specific increase in translation of GCN4 mRNA. We isolated mutati ons in the eIF-2alpha structural gene that do not affect the growth ra te of wild-type yeast but which suppress the toxic effects of eIF-2alp ha hyperphosphorylation catalyzed by mutationally activated forms of G CN2. These eIF-2alpha mutations also impair translational derepression of GCN4 in strains expressing wild-type GCN2 protein. All four mutati ons alter single amino acids within 40 residues of the phosphorylation site in eIF-2alpha; however, three alleles do not decrease the level of eIF-2alpha phosphorylation. We propose that these mutations alter t he interaction between eIF-2 and its recycling factor eukaryotic trans lation initiation factor 2B (eIF-2B) in a way that diminishes the inhi bitory effect of phosphorylated eIF-2 on the essential function of eIF -2B-in translation initiation. These mutations may identify a region m eIF-2alpha that participates directly in a physical interaction with the GCN3 subunit of eIF-2B.