Riboswitches, metabolite-sensing RNA elements found in untranslated regions of the transcripts they regulate, possess extensive tertiary structure to couple metabolite binding to genetic control. Herein, we discuss recently published structures from four riboswitch classes and compare these natural RNA structures to those of in vitro selected RNA aptamers, which bind similar ligands to those of the riboswitches. Additionally, we examine the glmS riboswitch, the first example of a ribozyme-based riboswitch. This RNA provides the latest twist in the riboswitch field and portends exciting advances in the coming years. Our knowledge of the mechanisms of genetic regulation by riboswitches has increased mightily in recent years and will continue to grow as new riboswitch classes and ligands are discovered and structurally characterized.
KeywordsRNA structure; riboswitch; ribozyme; transcription attenuation; noncoding RNAs; posttranscriptional regulation; crystallography; NMR
Riboswitches: Remnants of an ancient mode of genetic regulation?The "central dogma" states that information is stored as DNA, transcribed into RNA, and translated into proteins, which are traditionally thought to satisfy most cellular structural and catalytic requirements. Genetic control of these steps is believed to occur primarily through the action of regulatory proteins; however, the importance of noncoding RNAs in these processes has become increasingly appreciated in recent years [1]. In eubacterial organisms, regulatory RNAs can elicit control of gene expression through regulation of transcription attenuation, translation initiation [reviewed in 2,3], or mRNA stability [4]. These eubacterial regulatory RNAs function via diverse intermolecular (trans) or intramolecular (cis) mechanisms to regulate the target mRNA. Trans-acting regulatory RNAs interact with target mRNAs to control translation, mRNA stability, or transcription termination [reviewed in 5,6, 7], whereas others regulate gene expression through specific sequestration of RNA-binding proteins [8]. Cis-acting RNAs, which are the focus of this review, are located within untranslated regions (UTRs) of the mRNA transcript that they regulate. Genetic control by the latter RNA elements can be accomplished either through the sole action of the RNA molecule or in conjunction with recruited protein factors.A classic example of a cis-acting regulatory RNA is the transcription attenuation control of tryptophan biosynthesis genes in certain Gram-negative bacteria [9]. For this mechanism, the kinetics of translation of a short leader peptide dictates the conformational state of the overall 5′-UTR. Under tryptophan-depleted conditions the translating ribosome stalls at tryptophan codons within the leader peptide thereby allowing for formation of an antiterminator helix and [24-26; reviewed in 27,12]. Given their ability to function as sensitive sentinels for intracellular metabolites in a protein-independent manner, these RNAs are likely to require exquisite structural sophistication....