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<p>The recognition mechanism of Kozak mRNA, typically comprising purines in the −3 and +4 positions flanking the AUG start codon, has remained enigmatic for decades. To address this fundamental function in eukaryotes during translation initiation, we analysed several cryo-EM structures of human 48S preinitiation complexes with mRNA sequences differing in Kozak activity revealing distinct modes of recognition. The pre-codon triplet forms a fan-like intercalation into the 18S ribosomal RNA (rRNA), while a −3 pyrimidine destabilizes ternary complex positioning. Specificity towards the +4 purine is achieved beyond a single residue recognition by mutual conformational adaptations of eIF1A, mRNA and rRNA that involve the insertion of a reading head in which decoding residue A1825 (rRNA) stacks with the A-site codon to stabilize the fully accommodated state. Hence, instead of relying on base pairing as in bacteria, the specific recognition of the Kozak sequence on eukaryotic ribosomes is based on an induced-fit mechanism that triggers a conformational readout of the mRNA.</p>

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Translation initiation by the Kozak mRNA sequence is based on a conformational readout on the ribosome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Ottilie von Loeffelholz,
  • Charles Barchet,
  • Samuel Holvec,
  • Aida Abou Ramadan,
  • Cristina Protuc,
  • Anne Maglott-Roth,
  • S. Nimali T. de Silva,
  • Isabelle Hazemann,
  • Bruno P. Klaholz

摘要

The recognition mechanism of Kozak mRNA, typically comprising purines in the −3 and +4 positions flanking the AUG start codon, has remained enigmatic for decades. To address this fundamental function in eukaryotes during translation initiation, we analysed several cryo-EM structures of human 48S preinitiation complexes with mRNA sequences differing in Kozak activity revealing distinct modes of recognition. The pre-codon triplet forms a fan-like intercalation into the 18S ribosomal RNA (rRNA), while a −3 pyrimidine destabilizes ternary complex positioning. Specificity towards the +4 purine is achieved beyond a single residue recognition by mutual conformational adaptations of eIF1A, mRNA and rRNA that involve the insertion of a reading head in which decoding residue A1825 (rRNA) stacks with the A-site codon to stabilize the fully accommodated state. Hence, instead of relying on base pairing as in bacteria, the specific recognition of the Kozak sequence on eukaryotic ribosomes is based on an induced-fit mechanism that triggers a conformational readout of the mRNA.