Abstract
Riboswitches are RNAs that specifically sense a small molecule and regulate genes accordingly. The recent discovery of guanidine-binding riboswitches revealed the biological significance of this compound, and uncovered genes related to its biology. For example, certain sugE genes encode guanidine exporters and are activated by the riboswitches to reduce toxic levels of guanidine in the cell. In order to study guanidine biology and riboswitches, we applied a bioinformatics strategy for discovering additional guanidine riboswitches by searching for new candidate motifs associated with sugE genes. Based on in vitro and in vivo experiments, we determined that one of our six best candidates is a new structural class of guanidine riboswitches. The expression of a genetic reporter was induced 80-fold in response to addition of 5 mM guanidine in Staphylococcus aureus. This new class, called the guanidine-IV riboswitch, reveals additional guanidine-associated protein domains that are extremely rarely or never associated with previously established guanidine riboswitches. Among these protein domains are two transporter families that are structurally distinct from SugE, and could represent novel types of guanidine exporters. These results establish a new metabolite-binding RNA, further validate a bioinformatics method for finding riboswitches and suggest substrate specificities for as-yet uncharacterized transporter proteins.
Highlights
Riboswitches are structured, non-coding regions in the 5 untranslated regions (UTRs) of mRNAs that regulate the downstream gene [1,2,3,4]
Since nucleotides are highly conserved, despite the RNAs being highly diverged across phyla, the RNA appears to be subject to strong biochemical constraints, which is expected of an RNA that binds a small molecule
Our results show that Guanidine-Gene-Associated Motifs (GGAM)-1 RNAs bind guanidine, discriminate it from other, similar compounds, and efficiently regulate genes in vivo
Summary
Riboswitches are structured, non-coding regions in the 5 untranslated regions (UTRs) of mRNAs that regulate the downstream gene [1,2,3,4]. They sense metabolites or ions to control gene expression and thereby maintain cellular homeostasis of the cognate ligand, respond to signaling molecules, or detoxify xenobiotics or ions. Binding usually induces a structural rearrangement in the expression platform leading to modulation of downstream events [6]. This conformational change either represses (OFF-switches) or activates (ON-switches) gene expression. The discovery of additional riboswitch classes and their associated regulatory networks will help to understand functions of associated genes and their encoded proteins [2], and enables investigations into RNA structure and biochemistry [14]
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