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    Mol Cell Biol. 2008 Nov;28(22):6877-88. Epub 2008 Sep 15.

    Translation initiation factor 2gamma mutant alters start codon selection independent of Met-tRNA binding.

    Alone PV, Cao C, Dever TE.

    Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

    Selection of the AUG start codon for translation in eukaryotes is governed by codon-anticodon interactions between the initiator Met-tRNA(i)(Met) and the mRNA. Translation initiation factor 2 (eIF2) binds Met-tRNA(i)(Met) 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-tRNA(i)(Met) binding. Consistently, an eIF2gamma-N135D GTP-binding domain mutation impairs Met-tRNA(i)(Met) binding and causes a Sui(-) phenotype. Intragenic A208V and A382V suppressor mutations restore Met-tRNA(i)(Met) binding affinity and cell growth; however, only A208V suppresses the Sui(-) phenotype associated with the eIF2gamma-N135D mutation. An eIF2gamma-A219T mutation impairs Met-tRNA(i)(Met) binding but unexpectedly enhances the fidelity of initiation, suppressing the Sui(-) phenotype associated with the eIF2gamma-N135D,A382V mutant. Overexpression of eIF1, which is thought to monitor codon-anticodon interactions during translation initiation, likewise suppresses the Sui(-) phenotype of the eIF2gamma mutants. We propose that structural alterations in eIF2gamma subtly alter the conformation of Met-tRNA(i)(Met) on the 40S subunit and thereby affect the fidelity of start codon recognition independent of Met-tRNA(i)(Met) binding affinity.

    PMID: 18794367 [PubMed - indexed for MEDLINE]

    PMCID: PMC2573310

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