Mutations in the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha) that overcome the inhibitory effect of eIF-2 alpha phosphorylation on translation initiation.
Phosphorylation of eIF-2 alpha in Saccharomyces cerevisiae by the protein kinase GCN2 leads to inhibition of general translation initiation and a specific increase in translation of GCN4 mRNA. We isolated mutations in the eIF-2 alpha structural gene that do not affect the growth rate of wild-type yeast but which suppress the toxic effects of eIF-2 alpha hyperphosphorylation catalyzed by mutationally activated forms of GCN2. These eIF-2 alpha mutations also impair translational derepression of GCN4 in strains expressing wild-type GCN2 protein. All four mutations alter single amino acids within 40 residues of the phosphorylation site in eIF-2 alpha; however, three alleles do not decrease the level of eIF-2 alpha phosphorylation. We propose that these mutations alter the interaction between eIF-2 and its recycling factor eukaryotic translation initiation factor 2B (eIF-2B) in a way that diminishes the inhibitory effect of phosphorylated eIF-2 on the essential function of eIF-2B in translation initiation. These mutations may identify a region in eIF-2 alpha that participates directly in a physical interaction with the GCN3 subunit of eIF-2B.
Vazquez de Aldana
C R
CR
Section on Molecular Genetics of Lower Eukaryotes, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Dever
T E
TE
Hinnebusch
A G
AG
D000595:Amino Acid Sequence; D001483:Base Sequence; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D016153:Genes, Suppressor; D020662:Guanine Nucleotide Exchange Factors; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010442:Peptide Chain Initiation, Translational; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D013329:Structure-Activity Relationship; D019892:eIF-2 Kinase
D015852:Eukaryotic Initiation Factor-2; D020662:Guanine Nucleotide Exchange Factors; D009838:Oligodeoxyribonucleotides; D011506:Proteins; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase