Riboswitches: the oldest mechanism for the regulation of gene expression?

Abstract

Riboswitches are structures that form in mRNA and regulate gene expression in bacteria. Unlike other known RNA regulatory structures, they are directly bound by small ligands. The mechanism by which gene expression is regulated involves the formation of alternative structures that, in the repressing conformation, cause premature termination of transcription or inhibition of translation initiation. Riboswitches regulate several metabolic pathways including the biosynthesis of vitamins (e.g. riboflavin, thiamin and cobalamin) and the metabolism of methionine, lysine and purines. Candidate riboswitches have also been observed in archaea and eukaryotes. The taxonomic diversity of genomes containing riboswitches and the diversity of molecular mechanisms of regulation, in addition to the fact that direct interaction of riboswitches with their effectors does not require additional factors, suggest that riboswitches represent one of the oldest regulatory systems.The regulation of gene expression in bacteria involving a choice between two alternative structures in the RNA transcript is a well-known phenomenon [1,2]. In most cases one of the alternative structures (i.e. the repressing conformation) contains a terminator of transcription or a paired region covering the translation initiation site, whereas in the second alternative structure (i.e. the nonrepressing conformation) this regulatory element of the secondary structure is destroyed and the gene(s) are expressed. Which one of these structures will fold depends on the concentration of the target metabolite (e.g. a product of the regulated pathway or a compound to be catabolized) sensed via an intermediate molecule [3]. For example, a regulator protein might bind to one of the structures in the presence of an effector (e.g. TRAP protein [4] or antiterminators of the BglG/SacY family [5]) or uncharged tRNA might stabilize one of the conformations (e.g. T-boxes [6]). In classic attenuators of Escherichia coli, the formation of alternative structures depends on the relative rate of translation by the ribosome (as determined by the concentration of charged tRNAs in attenuators of amino acid operons [1]) and transcription by the RNA polymerase (correlated with the concentration of available nucleotide triphosphates, for example, in the pyrBI operon [7]).However, recently it was demonstrated that small molecules can bind directly regulatory mRNA structures, called riboswitches [8]. Riboswitches were shown to regulate several metabolic pathways involved in the biosynthesis of vitamins, amino acids and purines. Although the history behind these findings is diverse, common patterns are emerging in all systems that have been studied. Regulation by riboswitchesRepression of the riboflavin operon of Bacillus subtilis was initially thought to be due to a regulator protein. However, two candidates for this role, RibC and RibR, which were identified genetically, were later shown to regulate the rib operon indirectly. Both proteins have flavokinase activity and thus decrease the con...

Construct of DNA glucose sensor yeast plasmid for early detection of diabetes

“…The genes for transcribed proteins are fused to genes for a protein that fluoresces according to its expression, which correlates directly with glucose concentrations in blood plasma samples. Other authors have suggested repression of the operon containing genes for ribosomal proteins when the amount of free proteins exceeds the amount of ribosomal proteins, thus creating an on/off switch system [36,37]. A riboswitch has also been identified as a signaling mechanism in response to extreme environmental conditions such as oxidative stress [38].…”

Folding Kinetics of Large RNAs

“…the size of mitochondrial SSU mRNAs. The sequences are listed in Table 4 This range covers most of the important regulatory RNA elements that are dependent on refolding effects such as naturally occurring riboswitches (35), self-induced RNA switches as the hok family mRNAs (36) or the fine-tuned system of retarded cloverleaf formation in the case of bacteriophage MS2 (37), and makes them accessible to computational prediction.…”

Evolutionary patterns of non-coding RNAs

“…The best known example of such behavior are the riboswitches [423]. These are autonomous structural elements primarily found within the 5'-UTRs of bacterial mRNAs, which, upon direct binding of small organic molecules, can trigger conformational changes, leading to an alteration of the expression for the downstream located gene.…”