PreQ1 Riboswitch
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The PreQ1-I riboswitch is a
cis-acting element ''Cis''-regulatory elements (CREs) or ''cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphog ...
identified in
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
which regulates expression of genes involved in
biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
of the
nucleoside Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotid ...
queuosine Queuosine is a modified nucleoside that is present in certain tRNAs in bacteria and eukaryotes. It contains the nucleobase queuine. Originally identified in ''E. coli'', queuosine was found to occupy the first anticodon position of tRNAs for his ...
(Q) from GTP. PreQ1 (pre-queuosine1) is an intermediate in the queuosine pathway, and preQ1 riboswitch, as a type of
riboswitch In molecular biology, a riboswitch is a regulatory segment of a messenger RNA molecule that binds a small molecule, resulting in a change in Translation (biology), production of the proteins encoded by the mRNA. Thus, an mRNA that contains a ribo ...
, is an RNA element that binds preQ1. The preQ1 riboswitch is distinguished by its unusually small aptamer, compared to other riboswitches. Its atomic-resolution three-dimensional structure has been determined, with th
PDB ID 2L1V


PreQ1 classification

Three subcategories of the PreQ1 riboswitch exist: preQ1-I, preQ1-II, and preQ1-III. PreQ1-I has a distinctly small aptamer, ranging from 25 to 45 nucleotides long, compared to the structures of PreQ1-II riboswitch and preQ1-III riboswitch. PreQ1-II riboswitch, only found in ''
Lactobacillales Lactobacillales are an order of gram-positive, low-GC, acid-tolerant, generally nonsporulating, nonrespiring, either rod-shaped (bacilli) or spherical ( cocci) bacteria that share common metabolic and physiological characteristics. These bac ...
'', has a larger and more complex
consensus sequence In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated sequence of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It represents the result ...
and structure than preQ1-I riboswitch, with an average of 58 nucleotides composing its aptamer, which forms as many as five base-paired substructures. PreQ1-III riboswitch has a distinct structure and is also larger in aptamer size than preQ1-I riboswitch, ranging from sizes ranging from 33 to 58 nucleotides. PreQ1-III riboswitch has an atypically organized
pseudoknot __NOTOC__ A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow ...
that does not appear to incorporate its downstream expression platform at its
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 ...
(RBS).


History

While preQ1 was first discovered as an
anticodon Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...
sequence of tRNAs from
E.coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...
in 1972, preQ1 riboswitch was not first found until 2004 and recognized even later. The first reported preQ1 riboswitch was located in the leader of the Bacillus subtilis ykvJKLM (queCDEF) operon which encodes four genes necessary for queuosine production. In this organism, PreQ1 binding to the riboswitch
aptamer Aptamers are oligomers of artificial ssDNA, RNA, Xeno nucleic acid, XNA, or peptide that ligand, bind a specific target molecule, or family of target molecules. They exhibit a range of affinities (Dissociation constant, KD in the pM to μM rang ...
is thought to induce premature
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, often th ...
termination within the leader to down-regulate expression of these genes. Later on, preQ1 riboswitch was identified as a conserved sequence on the
5' UTR The 5′ untranslated region (also known as 5′ UTR, leader sequence, transcript leader, or leader RNA) is the region of a messenger RNA (mRNA) that is directly Upstream and downstream (DNA), upstream from the initiation codon. This region is im ...
of genes in many gram-positive bacteria and was proved to be associated with synthesis of preQ1. In 2008, a second class of preQ1 riboswitch (
PreQ1-II riboswitch PreQ1-II riboswitches form a class of riboswitches that specifically bind pre-queuosine1 (PreQ1), a precursor of the modified nucleoside queuosine. They are found in certain species of ''Streptococcus'' and ''Lactococcus'', and were originally i ...
es) was also found as a representative of the COG4708 RNA motif from ''Streptococcus pneumoniae'' R6. Although PreQ1-II riboswitch also works as queuosine biosynthetic intermediate, the structural and molecular recognition characteristics are distinct from preQ1-I riboswitch, indicating that natural aptamers utilizing different structures to bind the same metabolite may be more common than is currently known.


Structure and function

PreQ1 riboswitch has two stems and three loops, and its detailed structure has been shown on the right. The riboswitching action of preQ1 riboswitches in bacteria is regulated by binding of metabolite preQ1 to the aptamer region leading to structural changes in the messenger RNA (mRNA) that governs the downstream genetic regulation. The preQ1 riboswitch structure adopts a compact H-type
pseudoknot __NOTOC__ A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow ...
, which makes it quite different from other
purine Purine is a 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 include substituted puri ...
based riboswitches. The preQ1
ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
is buried in the pseudoknot core and stabilized through intercalation between helical stacks and hydrogen bond interaction with heteroatoms. In absence of preQ1, the P2 tail region is away from the P2 loop region and hence the riboswitch is observed to be in undocked (partially docked) state, whereas on the binding of preQ1 to the riboswitch results the two P2 regions to come closer causing a complete docking of riboswitch. This docking and undocking mechanism of riboswitch with the change in concentration of ligand preQ1 is observed to control the signaling of gene regulation, commonly known as “ON” or “OFF” signaling for gene expression. The docking and undocking mechanism are observed to be affected not only by the ligand, but also with other factors like Mg salt. Like any other riboswitch, the two most common types of gene regulation mediated by preQ1 riboswitch are through
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, often th ...
attenuation or inhibition of
translation Translation is the communication of the semantics, 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 English la ...
initiation.
Ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
binding to the transcriptional riboswitch in bacterial causes modification in the structure of riboswitch unit, which leads to hindrance in the activity of
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template. Using the e ...
causing attenuation of
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, often th ...
. Similarly, binding of the ligand to the translational riboswitch causes modification in the secondary structure of riboswitch unit leading to hindrance for ribosome binding and hence inhibiting translational initiation.


Transcriptional regulation

PreQ1 mediated transcriptional attenuation is controlled by the dynamic switching of anti-terminator and terminator hairpin in the riboswitch. For preQ1 riboswitch from bacteria Bacillus subtilis (Bsu), the anti-terminator is predicted to be less stable than the terminator, as the addition of preQ1 shifts the equilibrium significantly towards the formation of terminator. In presence of preQ1, the 3’ end of the
adenine Adenine (, ) (nucleoside#List of nucleosides and corresponding nucleobases, symbol A or Ade) is a purine nucleotide base that is found in DNA, RNA, and Adenosine triphosphate, ATP. Usually a white crystalline subtance. The shape of adenine is ...
rich tail domain pairs with the center of P1 hairpin loop to form an H-type
pseudoknot __NOTOC__ A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow ...
. In the native mRNA structure, binding of preQ1 to the aptamer region in the riboswitch leads to the formation of a terminator hairpin which causes RNA polymerase to stop transcription, a process which is commonly known as OFF- regulation of genetic expression or transcription termination.


Translation regulation

Translation Translation is the communication of the semantics, 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 English la ...
of protein in
prokaryote A prokaryote (; less commonly spelled procaryote) is a unicellular organism, single-celled organism whose cell (biology), cell lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Gree ...
s is initiated by binding of 30S ribosomal subunit to the Shine-Dalgarno (SD) sequence in
mRNA 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 Protein biosynthesis, synthesizing a protein. mRNA is ...
. PreQ1 mediated inhibition of translational regulation is controlled by blocking the Shine-Dalgarno sequence of
mRNA 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 Protein biosynthesis, synthesizing a protein. mRNA is ...
to prevent binding of
ribosome Ribosomes () are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (messenger RNA translation). Ribosomes link amino acids together in the order s ...
to
mRNA 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 Protein biosynthesis, synthesizing a protein. mRNA is ...
for
translation Translation is the communication of the semantics, 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 English la ...
. Binding of preQ1 to the aptamer domain promotes the sequestration of a part of SD sequence at the 5’ end to the P2 stem of the aptamer domain causing inaccessibility of the SD sequence. The translational riboswitch from bacteria ''Thermoanaerobacter tengcongensis'' (''Tte'') is observed to be transiently closed (pre-docked) in absence of preQ1, whereas in presence of preQ1 a fully docked state is adopted. This docking/undocking equilibrium is not only regulated by the concentration of ligand but also by the concentration of Mg salt. The unavailability of SD sequence due to the formation of
pseudoknot __NOTOC__ A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow ...
in presence of preQ1 shows the OFF-regulation of genetic expression in translational riboswitch or inhibition of translational initiation.


Physiological relevance in bacterial gene regulation

PreQ1 riboswitch activity in ''Tte'' bacteria can be measured by the levels of two proteins that are in the
coding region The coding region of a gene, also known as the coding DNA sequence (CDS), is the portion of a gene's DNA or RNA that codes for a protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared ...
of the ''Tte'' mRNA, which are TTE1564 and TTE1563. Proteins downstream of the preQ1 riboswitch biosynthesize a nucleobase called
queuine Queuine () (Q) is a hypermodified nucleobase found in the first (or wobble) position of the anticodon of tRNAs specific for Asn, Asp, His, and Tyr, in most eukaryotes and prokaryotes. Because it is utilized by all eukaryotes but produced exclusiv ...
and a nucleoside
queuosine Queuosine is a modified nucleoside that is present in certain tRNAs in bacteria and eukaryotes. It contains the nucleobase queuine. Originally identified in ''E. coli'', queuosine was found to occupy the first anticodon position of tRNAs for his ...
are inhibited by the activation of the preQ1 riboswitch. Queuine is involved in the
anticodon Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...
sequence of certain
tRNA Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...
. In bacteria, the hyper-modified nucleobase queuine takes up the first anticodon position, or its
wobble Wobble or wobbles may refer to: * "Wobble" (song), a single by V.I.C. * "Wobble", a song by Flo Rida from his 2015 EP '' My House'' * ''Wobble'' (album), an album by Black Market Karma * Wobbles (equine disorder), a disorder of the nervous syst ...
position in the tRNA of
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
,
aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
,
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
, and
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
. In bacteria the enzyme tRNA-guanine transglycosylase (TGT) catalyzes the swap of a guanine in position 34 of the tRNA with queuine into the first anitcodon position. Eukaryae incorporate queuine into RNA, whereas eubacteria incorporate preQ1, which then undergoes modification to yield queuine. Since queuosine is exclusively produced in bacteria, eukaryotic organisms must obtain their supply of queuosine or its nucleobase queuine from their diet or bacteria from their gut microflora. The implication of a deficiency of queuine or queuosine is an inability to make queuosine-modified tRNA, and furthermore, the inability of the cell to convert
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the chemical formula, formula . It can be viewed as a benzyl group substituent, substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of ...
to
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
.


See also

*
PreQ1-II riboswitch PreQ1-II riboswitches form a class of riboswitches that specifically bind pre-queuosine1 (PreQ1), a precursor of the modified nucleoside queuosine. They are found in certain species of ''Streptococcus'' and ''Lactococcus'', and were originally i ...
*
PreQ1-III riboswitch PreQ1-III riboswitches are a class of riboswitches that bind pre-queuosine1 (PreQ1), a precursor to the modified nucleoside queuosine. PreQ1-III riboswitches are the third class of riboswitches to be discovered that sense this ligand, and are struc ...


References


External links

* {{Rfam, id=RF00522, name=PreQ1 riboswitch Cis-regulatory RNA elements Riboswitch