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Molecular and Cellular Biology, August 2003, p. 5431-5445, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5431-5445.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Yeast Eukaryotic Initiation Factor 4G (eIF4G) HEAT Domain Interacts with eIF1 and eIF5 and Is Involved in Stringent AUG Selection

Hui He,1,2, Tobias von der Haar,3 C. Ranjit Singh,1 Miki Ii,1 Bin Li,1 Alan G. Hinnebusch,4 John E. G. McCarthy,3 and Katsura Asano1*

Division of Biology,1 Department of Biochemistry, Kansas State University, Manhattan, Kansas 66506,2 Department of Biomolecular Sciences, UMIST, Manchester M60 1QD, United Kingdom; and Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,3 4

Received 18 March 2003/ Returned for modification 6 May 2003/ Accepted 12 May 2003

Eukaryotic initiation factor 4G (eIF4G) promotes mRNA recruitment to the ribosome by binding to the mRNA cap- and poly(A) tail-binding proteins eIF4E and Pap1p. eIF4G also binds eIF4A at a distinct HEAT domain composed of five stacks of antiparallel {alpha}-helices. The role of eIF4G in the later steps of initiation, such as scanning and AUG recognition, has not been defined. Here we show that the entire HEAT domain and flanking residues of Saccharomyces cerevisiae eIF4G2 are required for the optimal interaction with the AUG recognition factors eIF5 and eIF1. eIF1 binds simultaneously to eIF4G and eIF3c in vitro, as shown previously for the C-terminal domain of eIF5. In vivo, cooverexpression of eIF1 or eIF5 reverses the genetic suppression of an eIF4G HEAT domain Ts- mutation by eIF4A overexpression. In addition, excess eIF1 inhibits growth of a second eIF4G mutant defective in eIF4E binding, which was also reversed by cooverexpression of eIF4A. Interestingly, excess eIF1 carrying the sui1-1 mutation, known to relax the accuracy of start site selection, did not inhibit the growth of the eIF4G mutant, and sui1-1 reduced the interaction between eIF4G and eIF1 in vitro. Moreover, a HEAT domain mutation altering eIF4G moderately enhances translation from a non-AUG codon. These results strongly suggest that the binding of the eIF4G HEAT domain to eIF1 and eIF5 is important for maintaining the integrity of the scanning ribosomal preinitiation complex.

* Corresponding author. Mailing address: Division of Biology, Kansas State University, Manhattan, KS 66506. Phone: (785) 532-0116. Fax: (785) 532-6653. E-mail: kasano{at}ksu.edu.

Molecular and Cellular Biology, August 2003, p. 5431-5445, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5431-5445.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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