Riboswitch

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In molecular biology, a riboswitch is a part of an mRNA molecule that can directly bind a small target molecule, and whose binding of the target affects the gene's activity. Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, depending on the presence or absence of its target molecule.

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[edit] Mechanics and prevalence of riboswitches

Riboswitches are conceptually divided into two parts: an aptamer and an expression platform. The aptamer directly binds the small molecule, and undergoes structural changes in response. These structural changes also affect the expression platform, which is the mechanism by which gene expression is regulated.

Expression platforms typically (UTC)turn off gene expression in response to the small molecule, but some turn it on. Expression platforms include:

  • The formation of transcription termination hairpins
  • sequestering the ribosome-binding site, thereby blocking translation, and
  • self-cleavage (i.e. the riboswitch contains a ribozyme that cleaves itself in the presence of sufficient concentrations of its metabolite).

Most known riboswitches occur in eubacteria, but functional riboswitches of one type (the TPP riboswitch) have been discovered in eukaryotes. Sequences similar to known TPP riboswitches have also been found in archaea, but are not experimentally verified. A riboswitch that responds to Arginase has also been postulated to occur in Aspergillus nidulans. The mechanism of this riboswitch seems to influence the splicing of the mRNA transcript.

The following riboswitches are known:

  • T-Box The first riboswitch characterized, binds uncharged tRNA to regulate the expression of amino acid related genes (Aminoacyl tRNA synthetase, biosynthetic, and transport) in many Gram-positive and a few Gram-negative bacteria.
  • TPP riboswitch (also THI-element) binds thiamin pyrophosphate to regulate thiamin biosynthesis and transport, as well as transport of similar metabolites
  • FMN riboswitch (also RFN-element) binds flavin mononucleotide to regulate riboflavin biosynthesis and transport.
  • Cobalamin riboswitch (also B12-element), which binds adenosylcobalamin (related to vitamin B12) to regulate cobalamin biosynthesis and transport of cobalamin and similar metabolites, and other genes.
  • SAM riboswitches bind S-adenosyl methionine to regulate methionine biosynthesis and transport. Three distinct SAM riboswitches are known: SAM-I (originally called S-box), SAM-II and the SAM(MK) riboswitch. SAM-I is widespread in bacteria, but SAM-II is found only in alpha-, beta- and a few gamma-proteobacteria. SAM(MK) is found only in the taxon lactobacillales. These three varieties have no obvious similarities in terms of sequence or structure.
  • Purine riboswitch binds purines to regulate purine metabolism and transport. Different forms of the purine riboswitch can bind either guanine (a form originally known as the G-box) or adenine . The specificity for either guanine or adenine depends completely upon Watson-Crick interactions with a single pyrimidine in the riboswitch at position Y74. In the guanine riboswitch this residue is always a cytosine (i.e. C74), in the adenine residue it is always a uracil (i.e. U74).
  • Lysine riboswitch (also L-box) binds lysine to regulate lysine biosynthesis, catabolism and transport.
  • glmS riboswitch, which is a ribozyme that cleaves itself when there is a sufficient concentration of glucosamine-6-phosphate.
  • glycine riboswitch binds glycine to regulate glycine metabolism genes, including the use of glycine as an energy source. As of 2006, this riboswitch is the only known natural RNA that exhibits cooperative binding, it contains two copies of the riboswitch in close proximity.
  • Mg2+ riboswitch senses magnesium ions to regulate transportation of magnesium. As of 2006, this is the only known ion-sensing riboswitch.

Although the genetic pathways in which riboswitches are involved have been studied for decades, the existence of riboswitches has only recently been found. This oversight may relate to an assumption that genes are regulated by proteins, not by the mRNA transcript itself. Now that riboswitches are a known mechanism of genetic control, it is reasonable to speculate that more riboswitches will be found.

[edit] Riboswitches and the RNA World hypothesis

Riboswitches demonstrate that naturally occurring RNA can bind small molecules specifically, a capability that many previously believed was the domain of proteins or artificially constructed RNAs called aptamers. The existence of riboswitches in all domains of life therefore adds some support to the RNA world hypothesis, which holds that life originally existed using only RNA, and proteins came later; this hypothesis requires that all critical functions performed by proteins could be performed by RNA.

[edit] Identification of riboswitches

All known riboswitches were initially discovered by manually inspecting 5' UTRs for a conserved RNA secondary structure. Initially, the set of UTRs to inspect was suggested by the literature. For example, in the case of the purine riboswitch, a protein (PurR) had been found that represses purine biosynthesis genes when adenine levels are high. However, it was known that high levels of guanine also repressed those genes, and no mechanism was found despite significant efforts to identify a protein. This situation suggested to early riboswitch researchers that the genes may be controlled by a riboswitch.

Bioinformatics has played a role in more recent discoveries. Barrick et al. (2004) used BLAST to find UTRs homologous to all UTRs in Bacillus subtilis. Some of these homologous sets were inspected for conserved structure. This method was used to discover the glmS and glycine riboswitches.

Proof that an RNA element is a riboswitch most often includes in vitro evidence that the RNA can bind the putative small molecule ligand, and in vivo genetic evidence that the riboswitch controls binding in the cell.

[edit] Riboswitches as antibiotic targets

At least one antimicrobial compound, pyrithiamine, has been shown to act by targeting riboswitches. In this case, cells metabolize pyrithiamine to pyrithiamine pyrophosphate, which was shown to bind and activate the TPP riboswitch. As a consequence, the cell ceases to make TPP. It has also been shown that S-(2-aminoethyl)L-cysteine binds the lysine riboswitch; this could explain why this compound is antimicrobial.

One potential advantage that riboswitches have as an antibiotic target is that many of the riboswitches have multiple instances per genome, where each instance controls an operon containing many genes, many of which are essential. Therefore, in order for bacteria to evolve resistance to the antibiotic by mutations in the riboswitch, all riboswitches must be mutated. However, of course, other mechanisms for resistance may exist, and some -- such as altering the specificity of an exporter to export the drug -- may require fewer mutations.

[edit] References

  • Grundy, F.J. and T.M. Henkin. (1993) "tRNA as a positive regulator of transcription antitermination in B. subtilis." Cell. 13;74(3):475-82. [1]
  • A.G. Vitreschak, D.A. Rodionov, A.A. Mironov and M.S. Gelfand (2004) "Riboswitches: the oldest mechanism for the regulation of gene expression?", TRENDS in Genetics, 20 (1): 44-50. (A review paper. Not as focussed on the RNA world hypothesis as the title suggests.) article in PubMed
  • N. Sudarsan, J.E. Barrick and R.R. Breaker (2003), "Metabolite-binding RNA domains are present in the genes of eukaryotes", RNA, 9:644-647. (The authors computationally discover a THI element-like sequence in plants and fungi, and show that it binds thiamin pyrophosphate in vitro.) article in PubMed
  • B.J. Tucker and R.R. Breaker (2005) "Riboswitches as Versatile Gene Control Elements," Current Opinion in Structural Biology, 15(3):342-8. (An recent review paper). [2]
  • M.J. Cromie, Y. Shi, T. Latifi and E.A. Groisman (2006) "An RNA sensor for intracellular Mg(2+)", Cell, 125: 71-84.
  • Sudarsan N, Cohen-Chalamish S, Nakamura S, Emilsson GM, Breaker RR (2005) "Thiamine pyrophosphate riboswitches are targets for the antimicrobial compound pyrithiamine". Chem Biol 2005, 12:1325-1335.
  • Barrick JE, Corbino KA, Winkler WC, Nahvi A, Mandal M, Collins J, Lee M, Roth A, Sudarsan N, Jona I, Wickiser JK, Breaker RR. (2004) "New RNA motifs suggest an expanded scope for riboswitches in bacterial genetic control", PNAS, 101(17):6421-6.
  • Borsuk P, Przykorska A, Blachnio K, Koper M, Pawlowicz JM, Pekala M, Weglenski P. (2007) "l-Arginine influences the structure and function of arginase mRNA in Aspergillus nidulans", Biol Chem., 388(2):135-44
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