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eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining

Author

Listed:
  • Christopher P. Lapointe

    (Stanford University School of Medicine)

  • Rosslyn Grosely

    (Stanford University School of Medicine)

  • Masaaki Sokabe

    (University of California)

  • Carlos Alvarado

    (Stanford University School of Medicine)

  • Jinfan Wang

    (Stanford University School of Medicine)

  • Elizabeth Montabana

    (Stanford University School of Medicine)

  • Nancy Villa

    (University of California)

  • Byung-Sik Shin

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Thomas E. Dever

    (Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health)

  • Christopher S. Fraser

    (University of California)

  • Israel S. Fernández

    (Department of Structural Biology, St Jude Children’s Research Hospital)

  • Joseph D. Puglisi

    (Stanford University School of Medicine)

Abstract

Translation initiation defines the identity and quantity of a synthesized protein. The process is dysregulated in many human diseases1,2. A key commitment step is when the ribosomal subunits join at a translation start site on a messenger RNA to form a functional ribosome. Here, we combined single-molecule spectroscopy and structural methods using an in vitro reconstituted system to examine how the human ribosomal subunits join. Single-molecule fluorescence revealed when the universally conserved eukaryotic initiation factors eIF1A and eIF5B associate with and depart from initiation complexes. Guided by single-molecule dynamics, we visualized initiation complexes that contained both eIF1A and eIF5B using single-particle cryo-electron microscopy. The resulting structure revealed how eukaryote-specific contacts between the two proteins remodel the initiation complex to orient the initiator aminoacyl-tRNA in a conformation compatible with ribosomal subunit joining. Collectively, our findings provide a quantitative and architectural framework for the molecular choreography orchestrated by eIF1A and eIF5B during translation initiation in humans.

Suggested Citation

  • Christopher P. Lapointe & Rosslyn Grosely & Masaaki Sokabe & Carlos Alvarado & Jinfan Wang & Elizabeth Montabana & Nancy Villa & Byung-Sik Shin & Thomas E. Dever & Christopher S. Fraser & Israel S. Fe, 2022. "eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining," Nature, Nature, vol. 607(7917), pages 185-190, July.
    • Handle: RePEc:nat:nature:v:607:y:2022:i:7917:d:10.1038_s41586-022-04858-z
    DOI: 10.1038/s41586-022-04858-z
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    Cited by:

    1. Jailson Brito Querido & Masaaki Sokabe & Irene Díaz-López & Yuliya Gordiyenko & Philipp Zuber & Yifei Du & Lucas Albacete-Albacete & V. Ramakrishnan & Christopher S. Fraser, 2024. "Human tumor suppressor protein Pdcd4 binds at the mRNA entry channel in the 40S small ribosomal subunit," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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