“…Unlike other RNA thermometers studied so far (12,17), which respond in a sigmoidal fashion to changes in temperature, the CssA thermometer responds in a graded manner within a narrow range corresponding to differences in the nasal cavity and central body temperature. According to mfold (36), the CssA thermometer forms a long imperfect stem-loop structure flanked by unfolded tails and capped by a 13 nucleotides large apical loop (Figure 1A).…”
Section: Resultsmentioning
confidence: 84%
“…This prevents ribosomes accessing the mRNA, thereby preventing protein translation. As the temperature increases, the secondary structure is lost, allowing translation to proceed (12,13). Unlike other RNA thermometers studied so far (12), however, the css thermometer precisely regulates a single biochemical pathway, rather than affecting global responses to temperature.…”
Section: Introductionmentioning
confidence: 99%
“…As the temperature increases, the secondary structure is lost, allowing translation to proceed (12,13). Unlike other RNA thermometers studied so far (12), however, the css thermometer precisely regulates a single biochemical pathway, rather than affecting global responses to temperature. Furthermore, it responds to relatively small changes in temperature associated with the nasal cavity (14,15) and the host response (7,16), raising the mechanistic question of how this activity is structurally encoded within this RNA element.…”
Neisseria meningitidis causes bacterial meningitis and septicemia. It evades the host complement system by upregulating expression of immune evasion factors in response to changes in temperature. RNA thermometers within mRNAs control expression of bacterial immune evasion factors, including CssA, in the 5′-untranslated region of the operon for capsule biosynthesis. We dissect the molecular mechanisms of thermoregulation and report the structure of the CssA thermometer. We show that the RNA thermometer acts as a rheostat, whose stability is optimized to respond in a small temperature range around 37°C as occur within the upper airways during infection. Small increases in temperature gradually open up the structure to allow progressively increased access to the ribosome binding site. Even small changes in stability induced by mutations of imperfect base pairs, as in naturally occurring polymorphisms, shift the thermometer response outside of the desired temperature range, suggesting that its activity could be modulated by pharmacological intervention.
“…Unlike other RNA thermometers studied so far (12,17), which respond in a sigmoidal fashion to changes in temperature, the CssA thermometer responds in a graded manner within a narrow range corresponding to differences in the nasal cavity and central body temperature. According to mfold (36), the CssA thermometer forms a long imperfect stem-loop structure flanked by unfolded tails and capped by a 13 nucleotides large apical loop (Figure 1A).…”
Section: Resultsmentioning
confidence: 84%
“…This prevents ribosomes accessing the mRNA, thereby preventing protein translation. As the temperature increases, the secondary structure is lost, allowing translation to proceed (12,13). Unlike other RNA thermometers studied so far (12), however, the css thermometer precisely regulates a single biochemical pathway, rather than affecting global responses to temperature.…”
Section: Introductionmentioning
confidence: 99%
“…As the temperature increases, the secondary structure is lost, allowing translation to proceed (12,13). Unlike other RNA thermometers studied so far (12), however, the css thermometer precisely regulates a single biochemical pathway, rather than affecting global responses to temperature. Furthermore, it responds to relatively small changes in temperature associated with the nasal cavity (14,15) and the host response (7,16), raising the mechanistic question of how this activity is structurally encoded within this RNA element.…”
Neisseria meningitidis causes bacterial meningitis and septicemia. It evades the host complement system by upregulating expression of immune evasion factors in response to changes in temperature. RNA thermometers within mRNAs control expression of bacterial immune evasion factors, including CssA, in the 5′-untranslated region of the operon for capsule biosynthesis. We dissect the molecular mechanisms of thermoregulation and report the structure of the CssA thermometer. We show that the RNA thermometer acts as a rheostat, whose stability is optimized to respond in a small temperature range around 37°C as occur within the upper airways during infection. Small increases in temperature gradually open up the structure to allow progressively increased access to the ribosome binding site. Even small changes in stability induced by mutations of imperfect base pairs, as in naturally occurring polymorphisms, shift the thermometer response outside of the desired temperature range, suggesting that its activity could be modulated by pharmacological intervention.
“…All of the above has important consequences for infectious diseases, as the cell membrane is one of the first contact sensing changes down to 1ºC (69). They importantly control virulence factors in bacteria (70,71).…”
Section: Molecular Consequences During Fever: a Theorymentioning
“…RNA thermometers are structural elements that affect expression of the mRNAs in which they reside in direct response to temperature change (Kortmann and Narberhaus 2012;Shapiro and Cowen 2012;Grosso-Becera et al 2015). These elements do not appear to require protein cofactors for proper function, and they can control expression of reporter genes in heterologous systems.…”
RNA thermometers regulate expression of some genes involved in virulence of pathogenic bacteria such as ,, and They often function through temperature-dependent conformational changes that alter accessibility of the ribosome-binding site. The 5'-untranslated region (UTR) of the mRNA from contains a very short RNA thermometer. We have systematically characterized the structure and dynamics of this thermometer at single-nucleotide resolution using SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) assays. Our results confirm that the thermometer adopts the predicted hairpin conformation at low temperatures, with conformational change occurring over a physiological temperature regime. Detailed SHAPE melting curves for individual nucleotides suggest that the thermometer unfolds in a cooperative fashion, with nucleotides from both upper and lower portions of the stem gaining flexibility at a common transition temperature. Intriguingly, analysis of an extended 5' UTR sequence revealed not only the presence of the RNA thermometer, but also an additional, stable upstream structure. We generated and analyzed point mutants of the thermometer, revealing elements that modulate its stability, allowing the hairpin to melt under the slightly elevated temperatures experienced during the infection of a warm-blooded host. This work sheds light on structure-function relationships in and related thermometers, and it also illustrates the utility of SHAPE assays for detailed study of RNA thermometer systems.
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