Functional Roles of Chelated Magnesium Ions in RNA Folding and Function

RNA regulates myriad cellular events such as transcription, translation, and splicing. To perform these essential functions, RNA often folds into complex tertiary structures in which its negatively charged ribose-phosphate backbone interacts with metal ions. Magnesium, the most abundant divalent metal ion in cells, neutralizes the backbone, thereby playing essential roles in RNA folding and function. This has been known for more than 50 years, and there are now thousands of in vitro studies, most of which have used ≥10 mM free Mg²⁺ ions to achieve optimal RNA folding and function. In the cell, however, concentrations of free Mg²⁺ ions are much lower, with most Mg²⁺ ions chelated by metabolites. In this Perspective, we curate data from a number of sources to provide extensive summaries of cellular concentrations of metabolites that bind Mg²⁺ and to estimate cellular concentrations of metabolite-chelated Mg²⁺ species, in the representative prokaryotic and eukaryotic systems Escherichia coli, Saccharomyces cerevisiae, and iBMK cells. Recent research from our lab and others has uncovered the fact that such weakly chelated Mg²⁺ ions can enhance RNA function, including its thermodynamic stability, chemical stability, and catalysis. We also discuss how metabolite-chelated Mg²⁺ complexes may have played roles in the origins of life. It is clear from this analysis that bound Mg²⁺ should not be simply considered non-RNA-interacting and that future RNA research, as well as protein research, could benefit from considering chelated magnesium.