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Molecular and Cellular Biology, August 2000, p. 6019-6029, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Physical Association of Eukaryotic Initiation Factor 4G (eIF4G) with eIF4A Strongly Enhances Binding of eIF4G to the Internal Ribosomal Entry Site of Encephalomyocarditis Virus and Is Required for Internal Initiation of Translation

Ivan B. Lomakin,1 Christopher U. T. Hellen,1 and Tatyana V. Pestova1,2,*

Department of Microbiology and Immunology, State University of New York Health Science Center at Brooklyn, Brooklyn, New York 11203,1 and A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119899 Moscow, Russia2

Received 14 February 2000/Returned for modification 29 March 2000/Accepted 22 May 2000

Mammalian eukaryotic initiation factor 4GI (eIF4GI) may be divided into three similarly sized regions. The central region (amino acids [aa] 613 to 1090) binds eIF3, eIF4A, and the encephalomyocarditis virus (EMCV) internal ribosomal entry site (IRES) and mediates initiation on this RNA. We identified the regions of eIF4GI that are responsible for its specific interaction with the IRES and that are required to mediate 48S complex formation on the IRES in vitro. Mutational analysis demarcated the IRES binding fragment of eIF4GI (aa 746 to 949) and indicated that it does not resemble an RNA recognition motif (RRM)-like domain. An additional amino-terminal sequence (aa 722 to 746) was required for binding eIF4A and for 48S complex formation. eIF4GI bound the EMCV IRES and beta -globin mRNA with similar affinities, but association with eIF4A increased its affinity for the EMCV IRES (but not beta -globin RNA) by 2 orders of magnitude. On the other hand, eIF4GI mutants with defects in binding eIF4A were defective in mediating 48S complex formation even if they bound the IRES normally. These data indicate that the eIF4G-eIF4A complex, rather than eIF4G alone, is required for specific high-affinity binding to the EMCV IRES and for internal ribosomal entry on this RNA.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, State University of New York Health Science Center at Brooklyn, 450 Clarkson Ave., Box 44, Brooklyn, NY 11203. Phone: (718) 270-1034. Fax: (718) 270-2656. E-mail: tpestova{at}netmail.hscbklyn.edu.

Molecular and Cellular Biology, August 2000, p. 6019-6029, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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