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Review
. 2013 Jan 17;152(1-2):17-24.
doi: 10.1016/j.cell.2012.12.024.

A Decade of Riboswitches

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Free PMC article
Review

A Decade of Riboswitches

Alexander Serganov et al. Cell. .
Free PMC article

Abstract

Riboswitches were discovered in 2002 in bacteria as RNA-based intracellular sensors of vitamin derivatives. During the last decade, naturally occurring RNA sensor elements have been found to bind a range of small metabolites and ions and to exert regulatory control of transcription, translation, splicing, and RNA stability. Extensive biochemical, structural, and genetic studies have established the basic principles underpinning riboswitch function in all three kingdoms of life with implications for developing antibiotics, designing new molecular sensors, and integrating riboswitches into synthetic circuits.

Figures

Figure 1
Figure 1. Diversity of Riboswitches and Mechanisms of Gene Control in Bacteria
Mechanisms of modulation of gene expression are highly divergent in prokaryotes and involve control of transcription, translation, splicing, and mRNA stability. (A) Various metabolites (violet, top) present in cells above threshold concentration can be directly sensed and specifically bound by sensor domains of riboswitches (white). Entrapment of a metabolite stabilizes the ligand-bound conformation of the riboswitch sensor and typically induces structural changes in the adjacent region (expression platform) that bears structural elements that stimulate (green) or repress (pink) gene expression. GlnN6P, glucosamine-6-phosphate; 2′-dG, 2′ -deoxyguanosine; preQ1, pre-queuosine-1; c-di-GMP, cyclic di-guanosyl-5′-monophosphate; Moco/Tuco, molybdenum and tungsten cofactors; SAH, S-adenosyl-L-homocysteine. Left: metabolite binding most often prevents formation of the antiterminator hairpin (complementary RNA regions in light blue) and promotes formation of the alternative Rho-independent termination hairpin (middle) or Rho binding site (bottom) that causes premature transcription termination. Center: in some cases, bound metabolites stabilize the antiterminator hairpin that allows RNA polymerase (Pol) to complete transcription of the gene (bottom). Right: expression of open reading frames (ORF) can be repressed by sequestration of the ribosome entry site (RBS or Shine-Dalgarno sequence, SD, dark blue) and blockage of translation initiation (middle). Metabolite binding to some riboswitches facilitates formation of the SD antisequester hairpin that opens up SD for ribosome binding and translation initiation (bottom). (B) In gram-positive bacteria, bound GlcN6P induces cleavage by the glmS riboswitch-ribozyme in the 5′ UTR. The 5′-OH of the resulting fragment stimulates degradation of the message by RNase J. (C) C. difficile exploits an allosteric ribozyme-riboswitch that combines self-splicing and translation activation. Left: in the absence of c-di-GMP, the intron uses GTP cleavage site 2 (black triangle, GTP2), thus yielding RNAs with truncated SDs that are not expressed. Right: binding of c-di-GMP to the riboswitch in the presence of GTP promotes cleavage at site 1 (green triangle, GTP1) and self-excision (green arrows) of the group I self-splicing intron using splicing sites shown in green circles. This self-cleavage brings together two halves of the SD, and the resulting mRNA is efficiently translated. (D) In L. monocytogenes, the SreA and SreB riboswitches form antiterminator hairpins and allow normal transcription in the absence of SAM. Binding of SAM causes transcription termination. The resulting mRNA fragments base pair with the 5′ UTR of the mRNA and functions in trans as an antisense sRNA that destabilizes the target transcript, thus reducing protein production.
Figure 2
Figure 2. TPP-Dependent Riboswitches in Eukaryotes
In some eukaryotes, TPP riboswitches modulate mRNA splicing by controlling accessibility to alternative splice sites. In the absence of TPP, the riboswitch is not folded, and complementary regions (light blue lines) of the riboswitch and the adjacent sequence interact with one another. (A) In fungi, complementary base pairing results in preferential use of the distal set of splicing sites (black open circles) and elimination of the region between black dashed arrowed lines (left). The resulting mRNA is translated to yield full-length product. TPP binding to the riboswitch stabilizes the riboswitch fold, precludes the complementary base pairing, and opens different set(s) of splicing sites (green circles) that are otherwise sequestered. Splicing at the alternative splice sites removes sequences between the green arrowed lines. The resulting mRNAs retain micro ORFs, which preclude translation of the main ORF located downstream of the micro ORF (right). (B) In algae, mRNA splicing in the absence of TPP eliminates a stop codon located within a riboswitch sequence. TPP binding promotes alternative splicing events that introduce a premature termination codon and disrupts translation of the ORF. (C) In higher plants, sequestration of splice sites in the absence of TPP causes retention of the mRNA processing site (polyadenylation signal, yellow rhomb) and yields stable mRNA with a short 3′ UTR. TPP binding to the riboswitch sensor exposes the 5′ splice site, causing the removal of the fragment between the green arrows containing the polydenylation signal. The resulting mRNA contains long and less stable 3′ UTR, which compromises protein production.
Figure 3
Figure 3. Structural Principles of Ligand Recognition by Riboswitches
(A–C) Schematic representations of a “straight” junctional fold (A), observed in type Ia riboswitches; an “inverse” junctional fold (B) from type Ib riboswitches; and a pseudoknot fold (C), which is characteristic for type II riboswitches. Pink and blue shading depict ligand binding sites and long-distance tertiary interactions, respectively. The magenta segment in helix P1 designates regions capable of alternative base pairing. Representative structures in ribbon representation for TPP (Serganov et al., 2006; Thore et al., 2006), THF (Huang et al., 2011; Trausch et al., 2011), and fluoride (Ren et al., 2012) riboswitches are shown under the corresponding fold schematics. Ligands are in red surface representation. Mg2+ cations are depicted by green spheres. 3WJ, three-way junction; PK, pseudoknot. (D) Recognition of TPP by the TPP riboswitch. PP, pyrophosphate; Thi, thiazole; and APy, aminopyrimidine moieties. Mg2+ cations are shown with coordination bonds depicted by green sticks. Water molecules are shown as red spheres.

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