In eukaryotes, a crucial step of translation initiation is the binding of the multifactor complex eIF4F to the 5′ end of the mRNA, a prerequisite to recruitment of the activated small ribosomal 43S particle. Histone H4 mRNAs have short 5′UTRs, which do not conform to the conventional scanning-initiation model. Here we show that the ORF of histone mRNA contains two structural elements critical for translation initiation. One of the two structures binds eIF4E without the need of the cap. Ribosomal 43S particles become tethered to this site and directly loaded in the vicinity of the AUG. The other structure, 19 nucleotides downstream of the initiation codon, forms a three-way helix junction, which sequesters the m7G cap. This element facilitates direct positioning of the ribosome on the cognate start codon. This unusual translation initiation mode might be considered as a hybrid mechanism between the canonical and the IRES-driven translation initiation process.
Graphical Abstract
Highlights
► Two structural elements of histone H4 mRNA drive translation initiation ► Ribosome is tethered by an eIF4E-binding site located in the coding region ► A RNA three-way helix junction element positions ribosome on the start codon ► The m7G cap-binding pocket formed by the mRNA controls histone translation