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On the role of mRNA secondary structure in bacterial translation

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Abstract Messenger RNA (mRNA) is no longer considered as a mere informational molecule whose sole function is to convey the genetic information specified by DNA to the ribosome. Beyond this primary function, mRNA also contains additional instructions that influence the way and the extent to which this message is translated by the ribosome into protein(s). Indeed, owing to its intrinsic propensity to quickly and dynamically fold and form higher order structures, mRNA exhibits a second layer of structural information specified by the sequence itself. Besides influencing transcription and mRNA stability, this additional information also affects translation, and more precisely the frequency of translation initiation, the choice of open reading frame by recoding, the elongation speed, and the folding of the nascent protein. Many studies in bacteria have shown that mRNA secondary structure participates to the rapid adaptation of these versatile organisms to changing environmental conditions by efficiently tuning translation in response to diverse signals, such as the presence of ligands, regulatory proteins, or small RNAs. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems Translation > Translation Regulation
Control of translation initiation via rearrangement of mRNA secondary structure induced by ribosomes stalling on an upstream ORF (uORF). (Left and top left) In the absence of inducer, the 30S ribosomal subunit binds to RBS1, promoting synthesis of a leader peptide (in orange) from uORF by the ribosome. Stem‐loop 1/2 is transiently unwound, while RBS2 is occluded within stem 3/4 and is not accessible to 30S ribosomal subunit (translation “off”). (Top right) Stem‐loop 1/2 reforms once the ribosome has passed through, while RBS2 remains occluded within stem‐loop 3/4 (translation“off”). (Bottom left) In the presence of inducer, the inducer‐bound ribosome stalls on uORF, triggering a structural switch by which disruption of stem‐loop 1/2 leads to formation of alternative stem‐loop 2/3 and consecutive unmasking of RBS2. (Bottom right) Binding of the 30S ribosomal subunit to RBS2 allows translation of the ORF to proceed (translation “on”). mRNA, messenger RNA; ORF, open reading frame
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Mechanism of translation initiation activation by translational coupling. (a) Coupling by a translating ribosome. When ORF 1 is not translated by ribosomes (left), the RBS of ORF2 is masked within a stem‐loop structure by base pairing with an anti‐RBS sequence located within ORF1. As a result, 30S ribosomal subunit access to the mRNA is blocked (translation “off”). When ORF1 is translated (middle and right), the translating ribosome progressively opens the inhibitory secondary structure. As a result, the RBS of ORF2 becomes accessible to an incoming 30S ribosomal subunit (translation “on”). (b) Translational coupling of secM and secA expression by ribosome stalling on secM mRNA. When secM is not translated (upper left), the secA SD sequence is occluded in a stem‐loop structure formed by the 3′‐terminus of secM and the secM‐secA intergenic region, leading to low initiation frequency of secA translation. When secM is translated, a ribosome stalls transiently at Pro166, located 12 nucleotides upstream of the stop codon (upper middle). During the time window of ribosome stalling, the stem‐loop is disrupted and the secA SD sequence becomes accessible to incoming 30S ribosomal subunit. SRP binds to the peptide signal of SecM and cotranslationally conveys the translating complex formed by the mRNA and the stalled ribosome tethered to the nascent SecM polypeptide to the membrane (lower right). As a result, SecA is synthesized close to the membrane where it assembles to the SecYEG channel to form the translocon. The secM translation arrest due to ribosome stalling is relieved by the mechanical “pulling force” provided by the SecA‐driven export of SecM from the cytoplasm to the periplasm through the translocon. As a result, SecM is dislodged from the translating complex (lower left) which in turn dissociates thus allowing reformation of the inhibitory stem‐loop as the mRNA detaches from the ribosome (upper left). Consequently, duration of ribosome stalling, and thus induction of SecA synthesis, increases when SecM export is inhibited. mRNA, messenger RNA; ORF, open reading frame; RBS, ribosome binding site
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Mechanism of translation initiation control by environmental cues. An RNA thermometer (RNAT) is depicted in equilibrium between closed and open state. (Left) At low temperature, RNAT is closed and the RBS is masked, thus precluding 30S ribosomal subunit (in light gray) access to the mRNA (translation “off”). (Middle and right) As temperature increases, RNAT gradually melts and opens, making the RBS more accessible to the subunit (translation “on”) thus allowing translation to proceed upon binding of the 50S ribosomal subunit (in deep gray). mRNA, messenger RNA; RBS, ribosome binding site
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Schematic representation of a loop–loop interaction (“kissing)” between a sRNA and its target‐mRNA. A loop–loop interaction (here two GC base pairs) between the sRNA (in red) and its target‐mRNA (in blue) initiates the formation of a helix nucleus. The nascent helix grows by addition of base pairs in both directions
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Schematic view of the two binding sites for repressor ribosomal protein L20 in the polycistronic infC‐rpmI‐rplT mRNA of E. coli. (Top) Schematic drawing of the mRNA. The infC, rpmI, and rplT sequences are indicated by blue, green, and purple arrows, respectively. Untranslated and intergenic sequences are colored in black. The sequences required for L20 binding are colored in orange for stem S1, red for stem S2, and cyan for L20‐binding site 2. Double‐headed arrows indicate base‐pairing interactions. (Bottom left) Schematic drawing of the secondary structure of the mRNA region containing the sequences forming the two L20‐binding sites. Stems S1 and S2 and L20‐binding site 2 are colored as indicated above. Sequences forming the pseudoknotted L20‐binding site 1 are boxed in gray. (Bottom middle) L20‐binding site 1 is formed by stacking of stem S2 on stem S1. (Bottom right) Scheme of L20‐bound site 1 complex. mRNA, messenger RNA
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Modulation of mRNA recoding by specific secondary structures. (a) Models of the slippery sites of E. coli dnaX and copA genes, based on Larsen, Wills, Gesteland, and Atkins () and Meydan et al. ()), respectively. Frameshift sites and downstream stop codons in the −1 frame are boxed in green and red, respectively. The upstream SD‐like sequence present on dnaX mRNA is boxed in gray and is shown in base pairing interaction with the 3′‐terminus of 16S rRNA (in blue). The numbers indicate the number of nucleotides separating the indicated sites. (b) Consensus bacterial SECIS element based on Y. Zhang and Gladyshev (). The start codon (AUG or GUG) of the gene subjected to recoding is boxed in purple while the recoded UGA stop codon and the UAA, UAG, and UGA stop codons specifying arrest of translation following recoding are boxed in red and orange, respectively. The numbers are as in (a). mRNA, messenger RNA; SD, Shine‐Dalgarno; SECIS, selenocysteine insertion sequence
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Activation of translation initiation of the E. coli fepA mRNA by a secondary structure located in the mRNA coding sequence. The activating stem‐loop (ASL) located at position +19 of the coding sequence is shown in a model where it restricts the 30S ribosomal subunit (in light gray) to the appropriate position to initiate translation. mRNA, messenger RNA
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Control of translation initiation via rearrangement of mRNA secondary structure by a regulatory protein. (a) Binding of a regulatory protein to the mRNA induces a structural rearrangement that increases the SD accessibility and thereby activates translation initiation (translation “on”). (b) Binding of a regulatory protein to the mRNA induces a structural rearrangement that decreases the SD accessibility and thereby inhibits translation initiation (translation “off”). mRNA, messenger RNA; SD, Shine‐Dalgarno
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Regulation of translation initiation via rearrangement of mRNA structure by a regulatory small RNA. (a) Pairing of an sRNA (in brown) to an anti‐RBS sequence (in blue) unmasks the RBS (in green) and promotes translation initiation of the ORF (translation “on”). (b) Pairing of an sRNA to an anti‐anti‐RBS sequence (in orange) can also induce a structural rearrangement leading to RBS occlusion by an anti‐RBS sequence and thereby translation inhibition of the ORF (translation “off”). mRNA, messenger RNA; ORF, open reading frame; RBS, ribosome binding site
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Mechanism of riboswitch‐mediated control of translation initiation. A riboswitch is composed of an aptamer domain (outlined in black) that binds a small ligand and an expression platform (outlined in green) that controls gene expression. (a) (Left) In the absence of the ligand, an anti‐RBS sequence (in red) is trapped in a secondary structure by pairing with an anti‐anti‐RBS sequence (in blue). (Middle) In this configuration, the RBS is accessible to the 30S ribosomal subunit (in light gray) and translation is allowed to proceed (translation “on”) upon binding of the 50S ribosomal subunit (in deep gray). (Right) When bound to the aptamer domain, the ligand promotes and stabilizes the formation of an alternative structure where the anti‐RBS sequence pairs with the RBS thus preventing the binding of the 30S ribosomal subunit (translation “off”). (b) (Left and middle) When the ligand is not bound to the aptamer domain, the RBS (in green) is trapped in a stem‐loop by pairing with an anti‐RBS sequence (in red), which prevents 30S ribosomal subunit binding (translation “off”). (Right) Binding of the ligand induces a conformational switch by which the anti‐RBS sequence is trapped by an anti‐anti‐RBS sequence (in blue). The RBS becomes accessible to 30S ribosomal subunit, thus leading to activation of translation initiation (translation “on”). ORF, open reading frame; RBS, ribosome binding site
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Translation > Translation Regulation
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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