The Biochemical Landscape of Riboswitch Ligands

Abstract

More than 55 distinct classes of riboswitches that respond to small metabolites or elemental ions have been experimentally validated to date. The ligands sensed by these riboswitches are biased in favor of fundamental compounds or ions that are likely to have been relevant to ancient forms of life, including those that might have populated the "RNA World", which is a proposed biochemical era that predates the evolutionary emergence of DNA and proteins. In the following text, I discuss the various types of ligands sensed by some of the most common riboswitches present in modern bacterial cells and consider implications for ancient biological processes centered on the proven capabilities of these RNA-based sensors. Although most major biochemical aspects of metabolism are represented by known riboswitch classes, there are striking sensory gaps in some key areas. These gaps could reveal weaknesses in the performance capabilities of RNA that might have hampered RNA World evolution, or these could highlight opportunities to discover additional riboswitch classes that sense essential metabolites.

Figure 1.

General features of bacterial riboswitches. (A) The predominant architectural features and gene control mechanisms of bacterial riboswitches. Most riboswitches carry a single ligand-binding aptamer domain that precedes and partially overlaps an expression platform structure capable of preventing or promoting gene expression. The two most common expression platform mechanisms exploit ligand-modulated hairpin substructures that terminate transcription (left) or that block ribosome access to the ribosome binding site (RBS) (right), although other mechanisms also exist^–. (B) Riboswitches are classified and named based on distinct ligand binding specificities and distinct aptamer structures. The “-II” notation identifies the second class for a given ligand.

Figure 2.

The list of riboswitch classes with strong experimental support validating their function. Each riboswitch class is named for the ligand sensed, where roman numerals designate distinct riboswitch classes for the same ligand. Black and gray ovals, respectively, indicate that the riboswitch ligand is strongly or weakly associated with the category named for each column. Biochemical categories evaluated include the common biological elements (blue), atomistic components: electrons, energy or elemental ions (green), RNA-based molecules (orange), or various other compounds (purple). Values below each column indicate how many riboswitch classes are known to sense ligands whose primary role (black oval) is linked to the named category. Values highlighted in red appear underrepresented with riboswitch classes. Notes: (i) Some riboswitch classes (SAM-I and SAM-IV; SAM-II and SAM-V) are listed on one line because their architectures are highly similar. (ii) Some riboswitch classes are designated as relevant to more than one category. (iii) It seems likely that many group I self-splicing ribozymes function as riboswitches for guanosine or any of its 5′ phosphorylated derivatives^,, however these are not included as a riboswitch class on the current list due to ambiguity with their function as selfish genetic elements. (iv) Several additional proposed riboswitch classes have been reported in the literature, but these are excluded from the list due to insufficient experimental evidence.

Figure 3.

Many riboswitch classes have been discovered for the most widely distributed enzyme cofactors (A) and nucleotide-based signaling molecules (B).