Human protein synthesis requires aminoacyl-tRNA pivoting during proofreading

Divya Sapkota, Karissa Y. Sanbonmatsu and Dylan Girodat ()
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Divya Sapkota: University of Arkansas
Karissa Y. Sanbonmatsu: Los Alamos National Laboratory
Dylan Girodat: University of Arkansas

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Rigorous studies have characterized the aa-tRNA selection mechanism in bacteria, which is essential for maintaining translational fidelity. Recent investigations have identified critical distinctions in humans, such as the requirement of subunit rolling and a tenfold slower proofreading step. Although these studies captured key intermediates involved in tRNA selection, they did not elucidate the transitions of aa-tRNA between intermediates. Through diverse structure-based simulations, we simulated 1856 aa-tRNA accommodation events into the human ribosomal A site. Here we show the requirement for a distinct ~30° pivoting of aa-tRNA about the anticodon stem within the accommodation corridor. This pivoting is crucial for navigating the crowded accommodation corridor, which becomes more constrained due to subunit rolling. Subunit rolling-dependent crowding increases the steric contributions of the accommodation corridor during aa-tRNA accommodation, consistent with the tenfold reduction in the rate of proofreading. Furthermore, we show that eEF1A interacts with the accommodating aa-tRNA through conserved basic residues, limiting premature aa-tRNA dissociation from the A site. These findings provide a structural description of the human aa-tRNA selection process and demonstrate that the aa-tRNA alignment relative to the ribosomal catalytic sites is a critical determinant of translational fidelity.

Date: 2025
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DOI: 10.1038/s41467-025-63617-6

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