Structural basis for nematode eIF4E binding an mG-Cap and its implications for translation initiation

Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Nucleic Acids Research (Impact Factor: 9.11). 09/2011; 39(20):8820-32. DOI: 10.1093/nar/gkr650
Source: PubMed


Metazoan spliced leader (SL) trans-splicing generates mRNAs with an m(2,2,7)G-cap and a common downstream SL RNA sequence. The mechanism for eIF4E binding an m²²⁷G-cap is unknown. Here, we describe the first structure of an eIF4E with an m(2,2,7)G-cap and compare it to the cognate m⁷G-eIF4E complex. These structures and Nuclear Magnetic Resonance (NMR) data indicate that the nematode Ascaris suum eIF4E binds the two different caps in a similar manner except for the loss of a single hydrogen bond on binding the m(2,2,7)G-cap. Nematode and mammalian eIF4E both have a low affinity for m(2,2,7)G-cap compared with the m⁷G-cap. Nematode eIF4E binding to the m⁷G-cap, m(2,2,7)G-cap and the m(2,2,7)G-SL 22-nt RNA leads to distinct eIF4E conformational changes. Additional interactions occur between Ascaris eIF4E and the SL on binding the m(2,2,7)G-SL. We propose interactions between Ascaris eIF4E and the SL impact eIF4G and contribute to translation initiation, whereas these interactions do not occur when only the m(2,2,7)G-cap is present. These data have implications for the contribution of 5'-UTRs in mRNA translation and the function of different eIF4E isoforms.

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    • "PARN recognizes the cap structure by stacking with only one aromatic residue without any substitute that mimics the sandwich stacking as is seen for DcpS Leu206[101,102], or the first transcribed nucleoside for snurportin[96]and viral methyltransferase NS5MTase DV[103]. Despite the apparently similar cap-binding motif of stacking complemented by other intermolecular interactions, the resultant affinity and selectivity can vary among cap-binding proteins to a large extent[41,42,44,45,82,97,104]. PARN thus provides the minimal, necessary and sufficient condition to confer protein specificity to the 5′ cap structure. "
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