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Chapter 15 : Riboswitches That Sense Cyclic Di-GMP

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Abstract:

Riboswitches are almost always located in the 5’ untranslated regions (UTRs) of messenger RNAs, where they typically control either transcription elongation or translation initiation of genes whose protein products synthesize or transport the regulatory ligand. GEMM RNAs were very promising candidate riboswitches because, in part, they contain regions of high sequence conservation interspersed with secondary structure elements supported by covariation. The first technique employed to test the candidate riboswitch was an assay called in-line probing, which can be used to assess structural changes in riboswitches in response to ligand binding. The recognition that GEMM RNAs function as cyclic di-GMP (c-di-GMP) riboswitches facilitates the identification of entire regulons of genes that are likely controlled by changing concentrations of second messenger. Regardless of these complications, the association of genes with sequences that appear homologous to validated c-di-GMP riboswitches may help researchers identify and examine processes that are likely to be regulated by the second messenger. carries two elements that conform to the c-di-GMP riboswitch consensus. The identification of c-di-GMP riboswitches will allow researchers to more easily identify processes that are regulated in response to changing concentrations of the second messenger. Furthermore, some of these riboswitches already have proven to function in new hosts and, therefore, may function as useful biosensors that can report the concentrations of c-di-GMP in cells in different genetic backgrounds or under different environmental conditions. Riboswitches that bind to c-di-GMP have been identified that appear to control a great diversity of genes associated with second messenger signaling.

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15

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Figures

Image of Figure 1.
Figure 1.

Consensus sequences and structures of type 1 and type 2 GEMM RNAs. Representatives from both types have been validated as riboswitch aptamers for c-di-GMP. Adapted from reference with permission. nt, nucleotide.

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15
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Image of Figure 2.
Figure 2.

Predicted mechanism of a c-di-GMP riboswitch from located in the 5′ UTR of a putative cytochrome gene. When c-di-GMP concentrations are high (left), ligand binding is predicted to stabilize the tertiary structure involving both stems P1 and P2, which should preclude formation of an intrinsic transcription terminator stem. When c-di-GMP concentrations are low (right), the aptamer will not be bound to ligand and the terminator stem will form rather than the unstable P2 stem. This arrangement of aptamer and expression platform is predicted to function as a genetic on switch, wherein ligand binding prevents premature transcription termination and thus permits expression of the adjoining ORF. Adapted from reference .

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15
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Image of Figure 3.
Figure 3.

Riboswitches for c-di-GMP are widespread in eubacteria. The phylogenetic tree depicts the number of c-di-GMP aptamers found in various bacterial lineages. Types of genes predicted to be controlled by c-di-GMP riboswitches are identified.

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15
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Image of Figure 4.
Figure 4.

A c-di-GMP riboswitch representative from undergoes ligand-induced structural modulation. (A) Mechanism of spontaneous RNA phosphoester transfer and chain cleavage exploited by in-line probing assays. (B) Polyacrylamide gel electrophoresis separation of RNA products generated by in-line probing of 5′ P-labeled 110 Vc2 RNA: NR, no reaction; T1, partial digest with RNase T1; OH, partial digest with alkali. RNA was incubated in the absence (–) or presence (+) of 100 μM c-di-GMP. (C) Sequence and secondary structure model of the Vc2 RNA from chromosome 2 and its proximity to the ORF of VC1722. Bold numbers identify regions of ligand-mediated structure modulation as observed in panel B. Brackets identify the minimal 5′ or 3′ terminus (when the opposing terminus for 110 Vc2 RNA is retained) that exhibits structural modulation when tested with 1 µM c-di-GMP. Adapted from reference with permission. nt, nucleotide.

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15
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Image of Figure 5.
Figure 5.

Vc2 RNA binds c-di-GMP with high affinity and specificity. (A) Plot of the normalized fraction of 110 Vc2 aptamer cleaved versus c-di-GMP concentration. Sites of structural modulation are as depicted in Fig. 4B . (B) Comparison of values exhibited by the 110 Vc2 aptamer for c-di-GMP and various analogs. G, guanosine; pG, pGpG, pGpA, 5′ phosphorylated mono- and dinucleotides; GpGpG, trinucleotide. (C) Plot of the natural logarithm of the fraction of c-di-GMP remaining intact versus incubation time under in-line probing conditions. The negative slope of the line reflects the uncatalyzed rate constant () for cleavage of the second messenger. Adapted from reference with permission.

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15
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Image of Figure 6.
Figure 6.

Representative c-di-GMP aptamers are components of gene control elements. (A) Reporter fusion constructs carry WT or mutant (M1 through M3) riboswitches from (Vc2) or carry the equivalent WT and M3 riboswitches from (Bc1 and Bc2) or (Cd1). (B) β-Galactosidase reporter gene assays for the constructs depicted in panel A when transformed into Maximum Miller units measured for the four representatives were 436, 47, 5, and 51, respectively. (C) Products of single-round transcription of DNA templates coding for the WT and disruption mutant M3 Cd1 riboswitches. The M3 mutant carries a single G-to-U mutation in the c-di-GMP aptamer as noted in panel A. FL and T identify full-length (runoff) transcripts and terminated transcripts, respectively, and % T represents the percentage of transcripts that terminate via riboswitch action. Reactions were conducted in the absence (–) or presence (+) of 100 µM c-di-GMP or in the presence of increasing concentrations of c-di-GMP (last four lanes from left to right: 0.01, 0.1, 1, or 10 µM). (D) β-Galactosidase reporter assays of cells carrying the reporter gene fused to WT or M3 riboswitches as indicated and transformed with plasmids as described for panel A. The normalized gene expression value of 1 for Cd1 represents 102 Miller units. Adapted from reference with permission. nt, nucleotide.

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15
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Image of Figure 7.
Figure 7.

Genomic locations of c-di-GMP riboswitches or aptamers for representative organisms. Genes residing immediately downstream of representatives are depicted where multiple genes indicate predicted operons. An absence of genes indicates that the c-di-GMP aptamer is not located 5′ proximal to any ORF, possibly indicating an association with a noncoding RNA. COG3070 is joined to a pfam04994 domain, which is a protein arrangement similar to TfoX ( ). Chromosomes are represented by shaded lines. ori, origin of replication; chr., chromosome. Adapted from reference with permission.

Citation: Lee E, Sudarsan N, Breaker R. 2010. Riboswitches That Sense Cyclic Di-GMP, p 215-229. In Wolfe A, Visick K (ed), The Second Messenger Cyclic Di-GMP. ASM Press, Washington, DC. doi: 10.1128/9781555816667.ch15
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