The central dogma of gene expression (DNA to RNA to protein) is universal, but in different domains of life there are fundamental mechanistic differences within this pathway. For example, the canonical molecular signals used to initiate protein synthesis in bacteria and eukaryotes are mutually exclusive1. However, the core structures and conformational dynamics of ribosomes that are responsible for the translation steps that take place after initiation are ancient and conserved across the domains of life2. We wanted to explore whether an undiscovered RNA-based signal might be able to use these conserved features, bypassing mechanisms specific to each domain of life, and initiate protein synthesis in both bacteria and eukaryotes. Although structured internal ribosome entry site (IRES) RNAs can manipulate ribosomes to initiate translation in eukaryotic cells, an analogous RNA structure-based mechanism has not been observed in bacteria. Here we report our discovery that a eukaryotic viral IRES can initiate translation in live bacteria. We solved the crystal structure of this IRES bound to a bacterial ribosome to 3.8 Å resolution, revealing that despite differences between bacterial and eukaryotic ribosomes this IRES binds directly to both and occupies the space normally used by transfer RNAs. Initiation in both bacteria and eukaryotes depends on the structure of the IRES RNA, but in bacteria this RNA uses a different mechanism that includes a form of ribosome repositioning after initial recruitment. This IRES RNA bridges billions of years of evolutionary divergence and provides an example of an RNA structure-based translation initiation signal capable of operating in two domains of life.
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Protein Data Bank
Atomic coordinates and structure factor amplitudes have been deposited in the Protein Data Bank under accession number 4XEJ.
We thank the members of the Kieft laboratory for insight and discussion and the staff at the Advanced Photon Source for their support. The original PSIV IGR IRES-containing plasmid was from N. Nakashima and the source of the luciferase genes was a plasmid from A. Willis. This work was supported by grants GM-17129 and GM-59140 from the National Institutes of Health (NIH) and MCB-723300 from the National Science Foundation (to H.F.N.), grant GM-103105 from the NIH (to A.A.K.), and grants GM-97333 and GM-81346 from the NIH (to J.S.K.). J.S.K. is an Early Career Scientist of the Howard Hughes Medical Institute. T.-D.M.P. was an American Heart Association Predoctoral Scholar (10PRE260143).
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Biotechnology and Genetic Engineering Reviews (2018)