![Lys ribosw 1](https://upload.wikimedia.org/wikipedia/commons/f/f3/Lys_ribosw_1.jpg)
In
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, a riboswitch is a regulatory segment of a
messenger RNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the p ...
molecule that binds a
small molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
, resulting in a change in
production
Production may refer to:
Economics and business
* Production (economics)
* Production, the act of manufacturing goods
* Production, in the outline of industrial organization, the act of making products (goods and services)
* Production as a stati ...
of the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s encoded by the mRNA.
Thus, an mRNA that contains a riboswitch is directly involved in regulating its own activity, in response to the concentrations of its
effector
Effector may refer to:
*Effector (biology), a molecule that binds to a protein and thereby alters the activity of that protein
* ''Effector'' (album), a music album by the Experimental Techno group Download
* ''EFFector'', a publication of the El ...
molecule. The discovery that modern organisms use RNA to bind small molecules, and discriminate against closely related analogs, expanded the known natural capabilities of RNA beyond its ability to code for
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s,
catalyze reactions, or to bind other RNA or protein
macromolecules.
The original definition of the term "riboswitch" specified that they directly sense small-molecule
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
concentrations.
Although this definition remains in common use, some biologists have used a broader definition that includes other
cis-regulatory RNAs. However, this article will discuss only metabolite-binding riboswitches.
Most known riboswitches occur in
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, but functional riboswitches of one type (the
TPP riboswitch
The TPP riboswitch, also known as the THI element and Thi-box riboswitch, is a highly conserved RNA secondary structure. It serves as a riboswitch that binds thiamine pyrophosphate (TPP) directly and modulates gene expression through a variety ...
) have been discovered in archaea,
plant
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...
s and certain
fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
. TPP riboswitches have also been predicted in
archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
,
but have not been experimentally tested.
History and discovery
Prior to the discovery of riboswitches, the mechanism by which some genes involved in multiple metabolic pathways were regulated remained mysterious. Accumulating evidence increasingly suggested the then-unprecedented idea that the mRNAs involved might bind metabolites directly, to affect their own regulation. These data included conserved RNA
secondary structure
Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
s often found in the untranslated regions (
UTRs) of the relevant genes and the success of procedures to create artificial small molecule-binding RNAs called
aptamer
Aptamers are short sequences of artificial DNA, RNA, XNA, or peptide that bind a specific target molecule, or family of target molecules. They exhibit a range of affinities ( KD in the pM to μM range), with little or no off-target bindin ...
s.
In 2002, the first comprehensive proofs of multiple classes of riboswitches were published, including protein-free binding assays, and metabolite-binding riboswitches were established as a new mechanism of gene regulation.
Many of the earliest riboswitches to be discovered corresponded to conserved sequence "motifs" (patterns) in
5' UTRs that appeared to correspond to a structured RNA. For example, comparative analysis of upstream regions of several genes expected to be co-regulated led to the description of the S-box
(now the SAM-I riboswitch), the THI-box
(a region within the TPP riboswitch), the RFN element
(now the FMN riboswitch) and the B
12-box (a part of the cobalamin riboswitch), and in some cases experimental demonstrations that they were involved in gene regulation via an unknown mechanism.
Bioinformatics
Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combi ...
has played a role in more recent discoveries, with increasing automation of the basic
comparative genomics strategy. Barrick ''et al.'' (2004)
used
BLAST
Blast or The Blast may refer to:
*Explosion, a rapid increase in volume and release of energy in an extreme manner
*Detonation, an exothermic front accelerating through a medium that eventually drives a shock front
Film
* ''Blast'' (1997 film), ...
to find UTRs
homologous to all UTRs in ''
Bacillus subtilis
''Bacillus subtilis'', known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacillus ...
''. Some of these homologous sets were inspected for conserved structure, resulting in 10 RNA-like motifs. Three of these were later experimentally confirmed as the glmS, glycine and PreQ1-I riboswitches (see below). Subsequent comparative genomics efforts using additional taxa of bacteria and improved computer algorithms have identified further riboswitches that are experimentally confirmed, as well as conserved RNA structures that are hypothesized to function as riboswitches.
Mechanisms
Riboswitches are often conceptually divided into two parts: an
aptamer
Aptamers are short sequences of artificial DNA, RNA, XNA, or peptide that bind a specific target molecule, or family of target molecules. They exhibit a range of affinities ( KD in the pM to μM range), with little or no off-target bindin ...
and an expression platform. The aptamer directly binds the small molecule, and the expression platform undergoes structural changes in response to the changes in the aptamer. The expression platform is what regulates gene expression.
Expression platforms typically turn off gene expression in response to the small molecule, but some turn it on. The following riboswitch mechanisms have been experimentally demonstrated.
* Riboswitch-controlled formation of
rho-independent transcription termination
Intrinsic, or rho-independent termination, is a process in prokaryotes to signal the end of transcription and release the newly constructed RNA molecule. In prokaryotes such as E. coli, transcription is terminated either by a rho-dependent proc ...
hairpins leads to premature transcription termination.
* Riboswitch-mediated folding sequesters the
ribosome-binding site A ribosome binding site, or ribosomal binding site (RBS), is a sequence of nucleotides upstream of the start codon of an mRNA transcript that is responsible for the recruitment of a ribosome during the initiation of translation. Mostly, RBS refers ...
, thereby inhibiting
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
.
* The riboswitch is a
ribozyme
Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonst ...
that cleaves itself in the presence of sufficient concentrations of its metabolite.
* Riboswitch alternate structures affect the
splicing of the pre-mRNA.
** A TPP riboswitch in ''
Neurospora crassa
''Neurospora crassa'' is a type of red bread mold of the phylum Ascomycota. The genus name, meaning "nerve spore" in Greek, refers to the characteristic striations on the spores. The first published account of this fungus was from an infestation ...
'' (a fungus) controls alternative splicing to conditionally produce an
Upstream Open Reading Frame (uORF), thereby affecting the expression of downstream genes
** A TPP riboswitch in plants modifies splicing and alternative 3'-end processing
* A riboswitch in ''
Clostridium acetobutylicum
''Clostridium acetobutylicum'', ATCC 824, is a commercially valuable bacterium sometimes called the "Weizmann Organism", after Jewish Russian-born biochemist Chaim Weizmann. A senior lecturer at the University of Manchester, England, he used th ...
'' regulates an adjacent gene that is not part of the same mRNA transcript. In this regulation, the riboswitch interferes with transcription of the gene. The mechanism is uncertain but may be caused by clashes between two RNA polymerase units as they simultaneously transcribe the same DNA.
* A riboswitch in ''
Listeria monocytogenes
''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the host' ...
'' regulates the expression of its downstream gene. However, riboswitch transcripts subsequently modulate the expression of a gene located elsewhere in the genome. This ''trans'' regulation occurs via base-pairing to the mRNA of the distal gene. As the temperature of the bacterium increases, the riboswitch melts, allowing transcription. Unpublished undergraduate research created a similar riboswitch or 'thermosensor' via random mutagenesis of the Listeria monocytogenes sequence.
Types
![RF00167](https://upload.wikimedia.org/wikipedia/commons/3/3a/RF00167.jpg)
The following is a list of experimentally validated riboswitches, organized by ligand.
* ''
Cobalamin riboswitch'' (also ''B
12-element''), which binds either
adenosylcobalamin
Adenosylcobalamin (AdoCbl), also known as coenzyme B12, cobamamide, and dibencozide, is, along with methylcobalamin (MeCbl), one of the biologically active forms of vitamin B12.
Adenosylcobalamin participates as a cofactor in radical-mediated 1,2 ...
(the coenzyme form of
vitamin B12) or
aquocobalamin to regulate
cobalamin
Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is required by animals, which use it as a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. ...
biosynthesis and transport of cobalamin and similar metabolites, and other genes.
* ''
cyclic AMP-GMP riboswitches'' bind the signaling molecule
cyclic AMP-GMP. These riboswitches are structurally related to
cyclic di-GMP-I riboswitch
Cyclic di-GMP-I riboswitches are a class of riboswitch that specifically bind cyclic di-GMP, which is a second messenger that is used in a variety of microbial processes including virulence, motility and biofilm formation. Cyclic di-GMP-I ribo ...
es (see also "cyclic di-GMP" below).
* ''
cyclic di-AMP riboswitches'' (also called ''ydaO/yuaA'') bind the signaling molecule
cyclic di-AMP.
* ''cyclic di-GMP riboswitches'' bind the signaling molecule
cyclic di-GMP
Cyclic di-GMP (also called cyclic diguanylate and c-di-GMP) is a second messenger used in signal transduction in a wide variety of bacteria. Cyclic di-GMP is not known to be used by archaea, and has only been observed in eukaryotes in ''Dictyos ...
in order to regulate a variety of genes controlled by this second messenger. Two classes of cyclic di-GMP riboswitches are known:
cyclic di-GMP-I riboswitch
Cyclic di-GMP-I riboswitches are a class of riboswitch that specifically bind cyclic di-GMP, which is a second messenger that is used in a variety of microbial processes including virulence, motility and biofilm formation. Cyclic di-GMP-I ribo ...
es and
cyclic di-GMP-II riboswitches. These classes do not appear to be structurally related.
* ''
fluoride riboswitches'' sense fluoride ions, and function in surviving high levels of
fluoride.
* ''
FMN riboswitch'' (also ''RFN-element'') binds
flavin mononucleotide
Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as ...
(FMN) to regulate
riboflavin
Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in ...
biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
and transport.
* ''
glmS riboswitch'', which is a ribozyme that cleaves itself when there is a sufficient concentration of
glucosamine-6-phosphate.
* ''Glutamine riboswitches'' bind
glutamine
Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...
to regulate genes involved in glutamine and
nitrogen
Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
metabolism, as well as short peptides of unknown function. Two classes of glutamine riboswitches are known: the ''
glnA RNA motif'' and ''
Downstream-peptide motif''. These classes are believed to be structurally related (see discussions in those articles).
* ''
Glycine riboswitch
The bacterial glycine riboswitch is an Cis-regulatory element, RNA element that can bind the amino acid glycine. Glycine riboswitches usually consist of two metabolite-binding aptamer domains with similar structures in tandem. The aptamers were o ...
'' binds glycine to regulate glycine metabolism genes, including the use of glycine as an energy source. Previous to 2012, this riboswitch was thought to be the only that exhibits
cooperative binding
Molecular binding is an interaction between molecules that results in a stable physical association between those molecules. Cooperative binding occurs in binding systems containing more than one type, or species, of molecule and in which one of th ...
, as it contains contiguous dual aptamers. Though no longer shown to be cooperative, the cause of dual aptamers still remains ambiguous.
* ''
Lysine riboswitch'' (also ''L-box'') binds
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
to regulate lysine biosynthesis,
catabolism and transport.
* ''
manganese riboswitches'' bind
manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
s.
* ''
NiCo riboswitches'' bind the metal ions
nickel
Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow to ...
and
cobalt
Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, pr ...
.
* ''PreQ1 riboswitches'' bind pre-queuosine
1, to regulate genes involved in the synthesis or transport of this precursor to
queuosine
Queuosine is a modified nucleoside that is present in certain tRNAs in bacteria and eukaryotes. It contains the nucleobase queuine. Originally identified in ''Escherichia coli, E. coli'', queuosine was found to occupy the first anticodon position ...
. Three entirely distinct classes of PreQ1 riboswitches are known:
PreQ1-I riboswitches,
PreQ1-II riboswitches and
PreQ1-III riboswitches. The binding domain of PreQ1-I riboswitches are unusually small among naturally occurring riboswitches. PreQ1-II riboswitches, which are only found in certain species in the genera ''Streptococcus'' and ''Lactococcus'', have a completely different structure, and are larger, as are PreQ1-III riboswitches.
* ''
Purine riboswitches'' binds
purine
Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
s to regulate purine metabolism and transport. Different forms of the purine riboswitch bind
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
(a form originally known as the ''G-box'') or
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
. The specificity for either guanine or adenine depends completely upon Watson-Crick interactions with a single
pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The other ...
in the riboswitch at position Y74. In the guanine riboswitch this residue is always a
cytosine
Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...
(i.e. C74), in the adenine residue it is always a
uracil
Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
(i.e. U74). Homologous types of purine riboswitches bind
deoxyguanosine
Deoxyguanosine is composed of the purine nucleobase guanine linked by its N9 nitrogen to the C1 carbon of deoxyribose. It is similar to guanosine, but with one hydroxyl group removed from the 2' position of the ribose sugar (making it deoxyribo ...
, but have more significant differences than a single nucleotide mutation.
* ''
SAH riboswitches'' bind
S-adenosylhomocysteine to regulate genes involved in recycling this metabolite that is produced when
S-adenosylmethionine
''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
is used in methylation reactions.
* ''SAM riboswitches'' bind
S-adenosyl methionine
''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
(SAM) to regulate
methionine
Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
and SAM biosynthesis and transport. Three distinct SAM riboswitches are known: ''
SAM-I'' (originally called ''S-box''), ''
SAM-II'' and the ''
SMK box riboswitch''. SAM-I is widespread in bacteria, but SAM-II is found only in
Alpha
Alpha (uppercase , lowercase ; grc, ἄλφα, ''álpha'', or ell, άλφα, álfa) is the first letter of the Greek alphabet. In the system of Greek numerals, it has a value of one. Alpha is derived from the Phoenician letter aleph , whic ...
-,
Beta
Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labiod ...
-, and a few
Gammaproteobacteria. The S
MK box riboswitch is found only in the order
Lactobacillales
Lactobacillales are an order of gram-positive, GC-content, low-GC, acid-tolerant, generally nonsporulating, Aerotolerant anaerobe, nonrespiring, either rod-shaped (bacillus (shape), bacilli) or spherical (cocci) bacteria that share common metabo ...
. These three varieties of riboswitch have no obvious similarities in terms of sequence or structure. A fourth variety,
SAM-IV riboswitch
SAM-IV riboswitches are a kind of riboswitch that specifically binds S-adenosylmethionine (SAM), a cofactor used in many methylation reactions. Originally identified by bioinformatics, SAM-IV riboswitches are largely confined to the Actinomyce ...
es, appears to have a similar ligand-binding core to that of SAM-I riboswitches, but in the context of a distinct scaffold.
* ''
SAM-SAH riboswitches'' bind both SAM and SAH with similar affinities. Since they are always found in a position to regulate genes encoding
methionine adenosyltransferase, it was proposed that only their binding to SAM is physiologically relevant.
* ''
Tetrahydrofolate riboswitches'' bind
tetrahydrofolate
Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.
Metabolism
Human synthesis
Tetrahydrofolic acid is produced from dihydrofolic acid by dihydrofolate reductase. This reaction is inhibited by methotrexate.
It is co ...
to regulate synthesis and transport genes.
* ''
TPP riboswitch
The TPP riboswitch, also known as the THI element and Thi-box riboswitch, is a highly conserved RNA secondary structure. It serves as a riboswitch that binds thiamine pyrophosphate (TPP) directly and modulates gene expression through a variety ...
es'' (also THI-box) binds
thiamin pyrophosphate (TPP) to regulate
thiamin
Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of t ...
biosynthesis and transport, as well as transport of similar metabolites. It is the only riboswitch found so far in eukaryotes.
* ''
ZMP/ZTP riboswitches'' sense
ZMP and
ZTP, which are by-products of de novo purine metabolism when levels of
10-Formyltetrahydrofolate are low.
Presumed riboswitches:
* ''
Moco RNA motif'' is presumed to bind
molybdenum cofactor
A molybdenum cofactor is a biochemical cofactor that contains molybdenum.
Examples include:
* Molybdopterin (or, strictly speaking, the molybdopterin-molybdenum-complex), the organophosphate-dithiolate ligand that binds molybdenum and tungsten ...
, to regulate genes involved in biosynthesis and transport of this coenzyme, as well as enzymes that use it or its derivatives as a cofactor.
Candidate metabolite-binding riboswitches have been identified using bioinformatics, and have moderately complex
secondary structure
Protein secondary structure is the three dimensional conformational isomerism, form of ''local segments'' of proteins. The two most common Protein structure#Secondary structure, secondary structural elements are alpha helix, alpha helices and beta ...
s and several highly conserved
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
positions, as these features are typical of riboswitches that must specifically bind a small molecule. Riboswitch candidates are also consistently located in the 5' UTRs of protein-coding genes, and these genes are suggestive of metabolite binding, as these are also features of most known riboswitches. Hypothesized riboswitch candidates highly consistent with the preceding criteria are as follows:
crcB RNA Motif,
manA RNA motif
The ''manA'' RNA motif (also called manA) refers to a conserved RNA structure that was identified by bioinformatics. Instances of the ''manA'' RNA motif were detected in bacteria in the genus ''Photobacterium'' and phages that infect certain ki ...
,
pfl RNA motif
The ''pfl'' RNA motif (now called the ZMP/ZTP riboswitch) refers to a conserved RNA structure present in some bacteria and originally discovered using bioinformatics. ''pfl'' RNAs are consistently present in genomic locations that likely corr ...
,
ydaO/yuaA leader,
yjdF RNA motif
The ''yjdF'' RNA motif is a conserved RNA structure identified using bioinformatics. Most ''yjdF'' RNAs are located in bacteria classified within the phylum Bacillota. A ''yjdF'' RNA is found in the presumed 5' untranslated region (5' UTR) of ...
,
ykkC-yxkD leader
The ykkC/yxkD leader is a conserved RNA structure found upstream of the ykkC and yxkD genes in ''Bacillus subtilis'' and related genes in other bacteria. The function of this family is unclear for many years although it has been suggested that i ...
(and related ykkC-III RNA motif) and the
yybP-ykoY leader. The functions of these hypothetical riboswitches remain unknown.
Computational models
Riboswitches have been also investigated using in-silico approaches.
In particular, solutions for riboswitch prediction can be divided into two wide categories:
* ''riboswitch gene finders'', i.e. systems aimed at uncovering riboswitches by genomic inspections, mostly based on motif-searching mechanisms. This group contains Infernal, the founding component of the
Rfam
Rfam is a database containing information about non-coding RNA (ncRNA) families and other structured RNA elements. It is an annotated, open access database originally developed at the Wellcome Trust Sanger Institute in collaboration with Jane ...
database,
and more specific tools such as RibEx
or RiboSW.
* ''conformational switch predictors'', i.e. methods based on a structural classification of alternative structures, such as paRNAss,
RNAshapes
and RNAbor.
Moreover, family-specific approaches for ON/OFF structure prediction have been proposed as well.
The SwiSpot tool
somehow covers both the groups, as it uses conformational predictions to assess the presence of riboswitches.
The RNA world hypothesis
Riboswitches demonstrate that naturally occurring
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
can bind small molecules specifically, a capability that many previously believed was the domain of
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s or artificially constructed RNAs called
aptamer
Aptamers are short sequences of artificial DNA, RNA, XNA, or peptide that bind a specific target molecule, or family of target molecules. They exhibit a range of affinities ( KD in the pM to μM range), with little or no off-target bindin ...
s. The existence of riboswitches in all domains of life therefore adds some support to the
RNA world hypothesis
The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existence ...
, which holds that life originally existed using only RNA, and proteins came later; this hypothesis requires that all critical functions performed by proteins (including small molecule binding) could be performed by RNA. It has been suggested that some riboswitches might represent ancient regulatory systems, or even remnants of RNA-world
ribozyme
Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonst ...
s whose bindings domains are conserved.
As antibiotic targets
Riboswitches could be a target for novel
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s. Indeed, some antibiotics whose mechanism of action was unknown for decades have been shown to operate by targeting riboswitches.
For example, when the antibiotic
pyrithiamine enters the cell, it is metabolized into pyrithiamine pyrophosphate. Pyrithiamine pyrophosphate has been shown to bind and activate the TPP riboswitch, causing the cell to cease the synthesis and import of TPP. Because pyrithiamine pyrophosphate does not substitute for TPP as a coenzyme, the cell dies.
Engineered riboswitches
Since riboswitches are an effective method of controlling gene expression in natural organisms, there has been interest in engineering artificial riboswitches
for industrial and medical applications such as
gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
.
See also
*
RNA thermometer
An RNA thermometer (or RNA thermosensor) is a temperature-sensitive non-coding RNA molecule which regulates gene expression. RNA thermometers often regulate genes required during either a heat shock or cold shock response, but have been implicat ...
- Another class of mRNA regulatory segments which change conformation in response to temperature fluctuations, thereby exposing or occluding the ribosome binding site.
References
Further reading
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{{Authority control
RNA
Cis-regulatory RNA elements