Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation

Chaomin Sun, Jordi Querol-Audí, Stefanie A. Mortimer, Ernesto Arias-Palomo, Jennifer A. Doudna, Eva Nogales, Jamie H.D. Cate

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7512-7521
Number of pages10
JournalNucleic acids research
Volume41
Issue number15
DOIs
StatePublished - Aug 1 2013

ASJC Scopus subject areas

  • Genetics

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    Sun, C., Querol-Audí, J., Mortimer, S. A., Arias-Palomo, E., Doudna, J. A., Nogales, E., & Cate, J. H. D. (2013). Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation. Nucleic acids research, 41(15), 7512-7521. https://doi.org/10.1093/nar/gkt510