mRNA decoding in human is kinetically and structurally distinct from bacteria

Mikael Holm, S. Kundhavai Natchiar, Emily J. Rundlet, Alexander G. Myasnikov, Zoe L. Watson, Roger B. Altman, Hao-Yuan Wang, Jack Taunton and Scott C. Blanchard ()
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Mikael Holm: St Jude Children’s Research Hospital
S. Kundhavai Natchiar: St Jude Children’s Research Hospital
Emily J. Rundlet: St Jude Children’s Research Hospital
Alexander G. Myasnikov: St Jude Children’s Research Hospital
Zoe L. Watson: St Jude Children’s Research Hospital
Roger B. Altman: St Jude Children’s Research Hospital
Hao-Yuan Wang: University of California
Jack Taunton: University of California
Scott C. Blanchard: St Jude Children’s Research Hospital

Nature, 2023, vol. 617, issue 7959, 200-207

Abstract: Abstract In all species, ribosomes synthesize proteins by faithfully decoding messenger RNA (mRNA) nucleotide sequences using aminoacyl-tRNA substrates. Current knowledge of the decoding mechanism derives principally from studies on bacterial systems1. Although key features are conserved across evolution2, eukaryotes achieve higher-fidelity mRNA decoding than bacteria3. In human, changes in decoding fidelity are linked to ageing and disease and represent a potential point of therapeutic intervention in both viral and cancer treatment4–6. Here we combine single-molecule imaging and cryogenic electron microscopy methods to examine the molecular basis of human ribosome fidelity to reveal that the decoding mechanism is both kinetically and structurally distinct from that of bacteria. Although decoding is globally analogous in both species, the reaction coordinate of aminoacyl-tRNA movement is altered on the human ribosome and the process is an order of magnitude slower. These distinctions arise from eukaryote-specific structural elements in the human ribosome and in the elongation factor eukaryotic elongation factor 1A (eEF1A) that together coordinate faithful tRNA incorporation at each mRNA codon. The distinct nature and timing of conformational changes within the ribosome and eEF1A rationalize how increased decoding fidelity is achieved and potentially regulated in eukaryotic species.

Date: 2023
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DOI: 10.1038/s41586-023-05908-w

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