Translation initiation factor 2gamma mutant alters start codon selection independent of Met-tRNA binding |
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Authors: | Alone Pankaj V Cao Chune Dever Thomas E |
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Institution: | Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA. |
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Abstract: | Selection of the AUG start codon for translation in eukaryotes is governed by codon-anticodon interactions between the initiator Met-tRNAiMet and the mRNA. Translation initiation factor 2 (eIF2) binds Met-tRNAiMet to the 40S ribosomal subunit, and previous studies identified Sui− mutations in eIF2 that enhanced initiation from a noncanonical UUG codon, presumably by impairing Met-tRNAiMet binding. Consistently, an eIF2γ-N135D GTP-binding domain mutation impairs Met-tRNAiMet binding and causes a Sui− phenotype. Intragenic A208V and A382V suppressor mutations restore Met-tRNAiMet binding affinity and cell growth; however, only A208V suppresses the Sui− phenotype associated with the eIF2γ-N135D mutation. An eIF2γ-A219T mutation impairs Met-tRNAiMet binding but unexpectedly enhances the fidelity of initiation, suppressing the Sui− phenotype associated with the eIF2γ-N135D,A382V mutant. Overexpression of eIF1, which is thought to monitor codon-anticodon interactions during translation initiation, likewise suppresses the Sui− phenotype of the eIF2γ mutants. We propose that structural alterations in eIF2γ subtly alter the conformation of Met-tRNAiMet on the 40S subunit and thereby affect the fidelity of start codon recognition independent of Met-tRNAiMet binding affinity. |
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