eIF4F: a retrospective

Abstract

The original purification of the heterotrimeric eIF4F was published over 30 years ago (Grifo, J. A., Tahara, S. M., Morgan, M. A., Shatkin, A. J., and Merrick, W. C. (1983) J. Biol. Chem. 258, 5804-5810). Since that time, numerous studies have been performed with the three proteins specifically required for the translation initiation of natural mRNAs, eIF4A, eIF4B, and eIF4F. These have involved enzymatic and structural studies of the proteins and a number of site-directed mutagenesis studies. The regulation of translation exhibited through the mammalian target of rapamycin (mTOR) pathway is predominately seen as the phosphorylation of 4E-BP, an inhibitor of protein synthesis that functions by binding to the cap binding subunit of eIF4F (eIF4E). A hypothesis that requires the disassembly of eIF4F during translation initiation to yield free subunits (eIF4A, eIF4E, and eIF4G) is presented.

Keywords: 4E-BP; RNA helicase; eIF4F; eukaryotic initiation factor 4A (eIF4A); eukaryotic initiation factor 4B (eIF4B); eukaryotic translation initiation; initiation factor recycling; mRNA; protein assembly; translation initiation.

FIGURE 1.

Actions of eIF4F in translation initiation. Shown in this figure are the eIF4F steps in translation, the activation of mRNA, which converts an mRNP to an activated mRNA with bound eIF4F and scanning, and the movement in a 5′ to 3′ direction of the mRNA to the initiation codon AUG. Both of the steps are ATP-dependent. The degree wo which free eIF4A, eIF4B, or other RNA helicases may play a role in this process is not pictured. This figure is adapted from Merrick, W. C. (2010) J. Biol. Chem. 285, 21197–21201 (90).

FIGURE 2.

High resolutions structures of eIF4F components. A, a graphic representation of the interactive domains of eIF4F and the two-domain structure of eIF4A. PAM, PABP-interacting motif. B, clockwise, a selection of a few high resolution structures that represent eIF4A·AMP·eIF4FG HEAT domain in the open confirmation (Protein Data Bank (PDB): 2VSO (40)), the closed confirmation of eIF4AIII as it exists in the exon junction complex with ADPNP (PDB: 2HYI (86)), the structure of the C-terminal HEAT-2 and HEAT-3 domains in eIF4G (PDB: 1UG3 39)), the N-terminal PABP binding domain of eIF4G with PABP·poly(A) (PDB 4F02 (87)), and a solution structure of m⁷GTP·eIF4E bound to eIF4G (PDB: 1RF8 (88)). Note that the colors of the domains in the structures are coded to those as seen in the graphic in panel A. This figure is used with the generous permission of Dr. Christopher Fraser, University of California at Davis, and with permission from Elsevier Publishing. This figure can be found in Ref. .