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Translational activation of uncapped mRNAs by the central part of human eIF4G is 5′ end-dependent

  • ENNIO DE GREGORIO (a1), THOMAS PREISS (a1) and MATTHIAS W. HENTZE (a1)

Abstract

Translation initiation factor (eIF) 4G represents a critical link between mRNAs and 40S ribosomal subunits during translation initiation. It interacts directly with the cap-binding protein eIF4E through its N-terminal part, and binds eIF3 and eIF4A through the central and C-terminal region. We expressed and purified recombinant variants of human eIF4G lacking the N-terminal domain as GST-fusion proteins, and studied their function in cell-free translation reactions. Both eIF4G lacking its N-terminal part (aa 486–1404) and the central part alone (aa 486–935) exert a dominant negative effect on the translation of capped mRNAs. Furthermore, these polypeptides potently stimulate the translation of uncapped mRNAs. Although this stimulation is cap-independent, it is shown to be dependent on the accessibility of the mRNA 5′ end. These results reveal two unexpected features of eIF4G-mediated translation. First, the C-terminal eIF4A binding site is dispensable for activation of uncapped mRNA translation. Second, translation of uncapped mRNA still requires 5′ end-dependent ribosome binding. These new findings are incorporated into existing models of mammalian translation initiation.

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Reprint requests to: Matthias W. Hentze, Gene Expression Programme, European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany; e-mail: hentze@embl-heidelberg.de.

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Translational activation of uncapped mRNAs by the central part of human eIF4G is 5′ end-dependent

  • ENNIO DE GREGORIO (a1), THOMAS PREISS (a1) and MATTHIAS W. HENTZE (a1)

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