Key result
Mutations in the RNA-binding motifs of eIF3a and eIF3c weaken eIF3 binding to the HCV IRES and the 40S ribosomal subunit, suppressing start codon recognition and downstream translation steps.
Identifies two highly conserved RNA-binding motifs in eIF3 that direct translation initiation from the HCV IRES RNA, providing structural insights into translation initiation.
Should not change HCV care; leaves open eIF3 motifs as antiviral research targets.
The initiation of protein synthesis plays an essential regulatory role in human biology. At the center of the initiation pathway, the 13-subunit eukaryotic translation initiation factor 3 (eIF3) controls access of other initiation factors and mRNA to the ribosome by unknown mechanisms. Using electron microscopy (EM), bioinformatics and biochemical experiments, we identify two highly conserved RNA-binding motifs in eIF3 that direct translation initiation from the hepatitis C virus internal ribosome entry site (HCV IRES) RNA. Mutations in the RNA-binding motif of subunit eIF3a weaken eIF3 binding to the HCV IRES and the 40S ribosomal subunit, thereby suppressing eIF2-dependent recognition of the start codon. Mutations in the eIF3c RNA-binding motif also reduce 40S ribosomal subunit binding to eIF3, and inhibit eIF5B-dependent steps downstream of start codon recognition. These results provide the first connection between the structure of the central translation initiation factor eIF3 and recognition of the HCV genomic RNA start codon, molecular interactions that likely extend to the human transcriptome.
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Sun et al. (2013) studied Hepatitis C virus (HCV) translation initiation. Mutations in eIF3a and eIF3c RNA-binding motifs vs. Wild-type eIF3 was evaluated on eIF3 binding to the HCV IRES and 40S ribosomal subunit. Mutations in the RNA-binding motifs of eIF3a and eIF3c weaken eIF3 binding to the HCV IRES and the 40S ribosomal subunit, suppressing start codon recognition and downstream translation steps.
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