Multiple prebiotic metals mediate translation

ABSTRACT Today, Mg 2+ is an essential cofactor with diverse structural and functional roles in life’s oldest macromolecular machine, the translation system. We tested whether ancient Earth conditions (low O 2 , high Fe 2+ , high Mn 2+ ) can revert the ribosome to a functional ancestral state. First, SHAPE (Selective 2’ H ydroxyl A cylation analyzed by P rimer E xtension) was used to compare the effect of Mg 2+ , Fe 2+ , and Mn 2+ on the tertiary structure of rRNA. Then, we used in vitro translation reactions to test whether Fe 2+ or Mn 2+ could mediate protein production, and quantified ribosomal metal content. We found that: (i) Mg 2+ , Fe 2+ , and Mn 2+ had strikingly similar effects on rRNA folding; (ii) Fe 2+ and Mn 2+ can replace Mg 2+ as the dominant divalent cation during translation of mRNA to functional protein; (iii) Fe and Mn associate extensively with the ribosome. Given that the translation system originated and matured when Fe 2+ and Mn 2+ were abundant, these findings suggest that Fe 2+ and Mn 2+ played a role in early ribosomal evolution. SIGNIFICANCE Ribosomes are found in every living organism where they are responsible for the translation of messenger RNA into protein. The ribosome’s centrality to cell function is underscored by its evolutionary conservation; the core structure has changed little since its inception ~4 billion years ago when ecosystems were anoxic and metal-rich. The ribosome is a model system for the study of bioinorganic chemistry, owing to the many highly coordinated divalent metal cations that are essential to its function. We studied the structure, function, and cation content of the ribosome under early Earth conditions (low O 2 , high Fe 2+ , high Mn 2+ ). Our results expand the roles of Fe 2+ and Mn 2+ in ancient and extant biochemistry as cofactors for ribosomal structure and function.