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Molecular and Cellular Biology, November 2008, p. 6877-6888, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01147-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Translation Initiation Factor 2{gamma} Mutant Alters Start Codon Selection Independent of Met-tRNA Binding {triangledown} ,{dagger}

Pankaj V. Alone, Chune Cao, and Thomas E. Dever*

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

Received 21 July 2008/ Accepted 3 September 2008

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 eIF2{gamma}-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 eIF2{gamma}-N135D mutation. An eIF2{gamma}-A219T mutation impairs Met-tRNAiMet binding but unexpectedly enhances the fidelity of initiation, suppressing the Sui– phenotype associated with the eIF2{gamma}-N135D,A382V mutant. Overexpression of eIF1, which is thought to monitor codon-anticodon interactions during translation initiation, likewise suppresses the Sui– phenotype of the eIF2{gamma} mutants. We propose that structural alterations in eIF2{gamma} 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.

* Corresponding author. Mailing address: NIH, Bldg. 6A/Rm. B1A-03, 6 Center Dr., Bethesda, MD 20892. Phone: (301) 496-4519. Fax: (301) 496-8576. E-mail: tdever{at}nih.gov

{triangledown} Published ahead of print on 15 September 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2008, p. 6877-6888, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01147-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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