Guanine riboswitch

From Proteopedia

Guanine Riboswitch

Riboswitches are highly conserved metabolite binding domains that are present in the 5'-untranslated region (5'-UTR) of certain mRNAs in bacteria which can act in the absence of protein cofactors. Riboswitches have been found to be broadly distributed among all forms of life, but all most frequently found in bacteria. These structural elements bind specific metabolites in the aptamer (binding site) domain that results in allosteric rearrangement in the adjacent expression platform that interacts with RNA elements to regulate gene expression associated with biosythesis and transport. In bacteria, riboswitches account for the regulation of 2% of the genes, thus making them attractive for genetic research. Within the bacterium, Bacillus subtilus, the guanine riboswitch is found. The operates by the binding of a guanine, hypoxanthine, or xanthine to the aptamer domain. Through allosteric effects the aptamer then changes the conformation of the expression platform which results in the premature termination of transcription. Thus, the guanine riboswitch has two distinct conformations in which it operates: a metabolite bound and metabolite-free folds, involving the alternative base-pairing of the regulatory RNA region.^[1]

Riboswitch Structure

The guanine riboswitch is comprised of three helices which are labeled P1, P2, and P3 which connect to form a junction. It is within this junction that ligand binding occurs. When the g-riboswitch-guanine complex is formed the kissing interactions of two hairpin loops force P2 and P3 to align in a parallel fashion and form hydrogen bonds. The is bound to the junction within the guanine riboswitch via several hydrogen bonds to nucleotides U22, U47, U51, C74. Due to the compactness of the binding site the ligand must utilize the induced-fit binding mechanism. ^[2]

Regulation Mechanism

Metabolite-binding riboswitches are triggered if a high concentration of the metabolite is present within the cell. Under these conditions, the metabolite will interact with the aptamer domain, with high affinity and selectivity, which will then stabilize the metabolite bound fold in the nascent RNA, and in so doing prevents the formation of the metabolite-free fold. This typically results in the stabilization or disruption of a regulatory hairpin, which prematurely terminates transcription or sequesters the ribosome-binding site, thereby regulating gene expression. In the absence of the metabolite when the 5’-UTR is transcribed the riboswitch folds into the metabolite-free fold which does not interfere with the expression of the adjacent open reading frame. In Bacillus subtilis, the 5'-UTR of xpt-pbuX mRNA binds guanine with high precision to down regulate the expression of genes by forming transcription terminator structures. Due to the mechanism and function of riboswitches, they are an attractive target for drug development. ^[3]

3D structures of riboswitch

Riboswitch

References

1. ↑ Serganov A, Yuan YR, Pikovskaya O, Polonskaia A, Malinina L, Phan AT, Hobartner C, Micura R, Breaker RR, Patel DJ. Structural basis for discriminative regulation of gene expression by adenine- and guanine-sensing mRNAs. Chem Biol. 2004 Dec;11(12):1729-41. PMID:15610857 doi:S1074-5521(04)00343-6
2. ↑ Noeske J, Buck J, Furtig B, Nasiri HR, Schwalbe H, Wohnert J. Interplay of 'induced fit' and preorganization in the ligand induced folding of the aptamer domain of the guanine binding riboswitch. Nucleic Acids Res. 2007;35(2):572-83. Epub 2006 Dec 14. PMID:17175531 doi:10.1093/nar/gkl1094
3. ↑ Serganov A, Yuan YR, Pikovskaya O, Polonskaia A, Malinina L, Phan AT, Hobartner C, Micura R, Breaker RR, Patel DJ. Structural basis for discriminative regulation of gene expression by adenine- and guanine-sensing mRNAs. Chem Biol. 2004 Dec;11(12):1729-41. PMID:15610857 doi:S1074-5521(04)00343-6