eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining

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. Fernández () and Joseph D. Puglisi ()
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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

Nature, 2022, vol. 607, issue 7917, 185-190

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04858-z

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