Mn2+-Sensing Mechanisms of yybP-ykoY Orphan Riboswitches

Price, Ian R.; Gaballa, Ahmed; Ding, Fang; Helmann, John D.; Ke, Ailong

doi:10.1016/j.molcel.2015.02.016

Cited by 111 publications

(222 citation statements)

References 56 publications

(74 reference statements)

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“…Furthermore, each discovery links the riboswitch ligand to the protein products of the genes under regulation. Recent riboswitch findings have exposed unique facets of biology, such as the widespread molecular mechanisms that confer fluoride (5) or guanidine (6) resistance, that maintain metal ion homeostasis (7)(8)(9), and that control important bacterial processes such as sporulation, biofilm formation, and chemotaxis (10)(11)(12)(13)(14). Thus, the identification of additional riboswitch classes promises to offer insights into otherwise hidden biological processes and their regulation.…”

mentioning

confidence: 99%

Bioinformatic analysis of riboswitch structures uncovers variant classes with altered ligand specificity

Weinberg

Nelson

Lünse

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Riboswitches are RNAs that form complex, folded structures that selectively bind small molecules or ions. As with certain groups of protein enzymes and receptors, some riboswitch classes have evolved to change their ligand specificity. We developed a procedure to systematically analyze known riboswitch classes to find additional variants that have altered their ligand specificity. This approach uses multiple-sequence alignments, atomic-resolution structural information, and riboswitch gene associations. Among the discoveries are unique variants of the guanine riboswitch class that most tightly bind the nucleoside 2′-deoxyguanosine. In addition, we identified variants of the glycine riboswitch class that no longer recognize this amino acid, additional members of a rare flavin mononucleotide (FMN) variant class, and also variants of c-di-GMP-I and -II riboswitches that might recognize different bacterial signaling molecules. These findings further reveal the diverse molecular sensing capabilities of RNA, which highlights the potential for discovering a large number of additional natural riboswitch classes.iboswitches are structured noncoding RNA domains that regulate gene expression in response to the selective binding of small-molecule or ion ligands. The discovery of numerous classes of riboswitches has helped reveal how RNAs can form exquisitely precise ligand-binding pockets using only the four common RNA nucleotides (1-4). Furthermore, each discovery links the riboswitch ligand to the protein products of the genes under regulation. Recent riboswitch findings have exposed unique facets of biology, such as the widespread molecular mechanisms that confer fluoride (5) or guanidine (6) resistance, that maintain metal ion homeostasis (7-9), and that control important bacterial processes such as sporulation, biofilm formation, and chemotaxis (10-14). Thus, the identification of additional riboswitch classes promises to offer insights into otherwise hidden biological processes and their regulation.Riboswitch variants have been reported previously, wherein the ligand-binding "aptamer" domain has mutated to accommodate a different metabolite or signaling compound. The identification of such RNAs provides rare opportunities to study how small changes in RNA sequence can lead to major changes in smallmolecule ligand affinity. There have been seven examples, either experimentally validated or suspected, of ligand specificity changes reported to date. These include guanine aptamer variations present in riboswitches for adenine (15) and 2′-deoxyguanosine (2′-dG) (16), c-di-GMP-I aptamer variations that result in riboswitches that bind the recently discovered bacterial signaling molecule c-AMP-GMP (13, 14), and coenzyme B 12 aptamer changes (17, 18) that yield riboswitches selective for aquocobalamin (19). Three additional ligand specificity changes are suspected. Namely, some molybdenum cofactor riboswitches appear to exploit an altered aptamer structure to selectively recognize tungsten cofactor (20), certain flavin mononu...

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mentioning

confidence: 99%

Bioinformatic analysis of riboswitch structures uncovers variant classes with altered ligand specificity

Weinberg

Nelson

Lünse

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…One of the longest-unresolved orphan riboswitch candidates was the yybP motif RNA . After many years of uncertainty (Meyer et al 2011), both genetic (Dambach et al 2015) and structural (Price et al 2015) data eventually confirmed the hypothesis (Waters et al 2011) that members of this orphan riboswitch candidate naturally respond to Mn 2+ ions. A total of 4383 representatives of this riboswitch class have been identified in species from 18 divisions of bacteria, indicating that this riboswitch and its natural ligand are broadly important for bacteria.…”

Section: Five Distinct Riboswitch Classes Sense Atomic Ionsmentioning

confidence: 67%

Riboswitch diversity and distribution

McCown

Corbino

Stav

et al. 2017

RNA

400

516

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Riboswitches are commonly used by bacteria to detect a variety of metabolites and ions to regulate gene expression. To date, nearly 40 different classes of riboswitches have been discovered, experimentally validated, and modeled at atomic resolution in complex with their cognate ligands. The research findings produced since the first riboswitch validation reports in 2002 reveal that these noncoding RNA domains exploit many different structural features to create binding pockets that are extremely selective for their target ligands. Some riboswitch classes are very common and are present in bacteria from nearly all lineages, whereas others are exceedingly rare and appear in only a few species whose DNA has been sequenced. Presented herein are the consensus sequences, structural models, and phylogenetic distributions for all validated riboswitch classes. Based on our findings, we predict that there are potentially many thousands of distinct bacterial riboswitch classes remaining to be discovered, but that the rarity of individual undiscovered classes will make it increasingly difficult to find additional examples of this RNA-based sensory and gene control mechanism.

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“…These four families all possessed transmembrane regions with conserved charged amino acids, suggesting these could be manganese exporters. Of these, a previous study had suggested that the P-type ATPase might have a role in export of manganese in firmicutes (32). Both UPF0016 and TerC belong to the same higher-order clade of the LysE superfamily as MntP and share the conserved acidic residue in each of the core three-helical TM units (Fig 2).…”

Section: The Upf0016 Family Proteins Are Predicted To Be Novel Manganmentioning

confidence: 98%

“…In E. coli, the mntP gene has been shown to be transcriptionally and post-transcriptionally regulated by manganese levels through the MntR transcription factor and the yybP-ykoY riboswitch (20,31). The yybP-ykoY riboswitch directly and specifically binds manganese and regulates gene expression by ribosomebinding site sequestration or termination/antitermination mechanism in different organisms (31,32). Intriguingly, the yybP-ykoY riboswitch is very broadly conserved across bacteria, suggesting an important role for manganese homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Structure–function analysis of manganese exporter proteins across bacteria

Zeinert

Martinez

Schmitz

et al. 2018

Journal of Biological Chemistry

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Manganese is an essential trace nutrient for organisms, because of its role in cofactoring enzymes and providing protection against reactive oxygen species (ROS). Many bacteria require manganese to form pathogenic or symbiotic interactions with eukaryotic host cells. However, excess manganese is toxic, requiring cells to have manganese export mechanisms. Bacteria are currently known to possess two widely-distributed classes of manganese export proteins, MntP and MntE, but other types of transporters likely exist. Moreover, the structure and function of MntP is not well understood. Here, we characterized the role of three structurally related proteins known or predicted to be involved in manganese transport in bacteria from the MntP, UPF0016 and TerC families. These studies used computational analysis to analyze phylogeny and structure, physiological assays to test sensitivity to high levels of manganese and ROS, and ICP-MS to measure metal levels. We found that MntP alters cellular resistance to ROS. Moreover, we used extensive computational analyses and phenotypic assays to identify amino acids required for MntP activity. These negativelycharged residues likely serve to directly bind manganese and transport it from the cytoplasm through the membrane. We further characterized two other potential manganese transporters associated with a Mn-sensing riboswitch, and found that the UPF0016 family of proteins has manganese export activity. We provide the first phenotypic and biochemical evidence for the role of Alx, a member of the TerC family, in manganese homeostasis. It does not appear to export manganese, rather it intriguingly facilitates an increase in intracellular manganese concentration. These findings expand knowledge about the identity and mechanisms of manganese homeostasis proteins across bacteria and show that proximity to a Mnresponsive riboswitch can be used to identify new components of the manganese homeostasis machinery. INTRODUCTIONTransition metals are essential for life as they play important roles as enzyme cofactors and structural components of proteins and RNAs. Reflecting this, one third of the proteomes of organisms from bacteria to humans consist of metalloproteins (1,2). In bacteria, metal availability is intimately involved in pathogenesis. Bacteria unable to maintain proper metal homeostasis are less virulent, and mammalian hosts actively seek to withhold essential metals from invading bacteria (3,4). Yet in excess, metals are toxic to cells. This toxicity typically results from metaldependent oxidative damage (e.g., the Fenton reaction) and/or the displacement of cognate metals from their binding sites by the metal that is in excess (3,(5)(6)(7)(8). Thus, cells have a battery of metal importers, exporters, sequestration factors, and regulators to carefully control the intracellular level of each metal (1,2,9,10).

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Mn2+-Sensing Mechanisms of yybP-ykoY Orphan Riboswitches

Cited by 111 publications

References 56 publications

Bioinformatic analysis of riboswitch structures uncovers variant classes with altered ligand specificity

Bioinformatic analysis of riboswitch structures uncovers variant classes with altered ligand specificity

Riboswitch diversity and distribution

Structure–function analysis of manganese exporter proteins across bacteria

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