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eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining
Nature  (IF69.504),  Pub Date : 2022-06-22, DOI: 10.1038/s41586-022-04858-z
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, Joseph D. Puglisi

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.