Knotty is nice: Metabolite binding and RNA-mediated gene regulation by the preQ riboswitch family.

Riboswitches sense specific cellular metabolites, leading to messenger RNA conformational changes that regulate downstream genes. Here, we review the three known prequeosine (preQ) riboswitch classes, which encompass five gene-regulatory motifs derived from distinct consensus models of folded RNA pseudoknots. Structural and functional analyses reveal multiple gene-regulation strategies ranging from partial occlusion of the ribosome-binding Shine-Dalgarno sequence (SDS), SDS sequestration driven by kinetic or thermodynamic folding pathways, direct preQ recognition by the SDS, and complete SDS burial with in the riboswitch architecture. Family members can also induce elemental transcriptional pausing, which depends on ligand-mediated pseudoknot formation. Accordingly, preQ family members provide insight into a wide range of gene-regulatory tactics as well as a diverse repertoire of chemical approaches used to recognize the preQ metabolite. From a broader perspective, future challenges for the field will include the identification of new riboswitches in mRNAs that do not possess an SDS or those that induce ligand-dependent transcriptional pausing. When choosing an antibacterial target, the field must also consider how well a riboswitch accommodates mutations. Investigation of riboswitches in their natural context will also be critical to elucidate how RNA-mediated gene regulation influences organism fitness, thus providing a firm foundation for antibiotic development.