Hepatitis delta virus ribozyme

Last updated
Hepatitis delta virus ribozyme
RF00094.jpg
Predicted secondary structure and sequence conservation of HDV ribozyme
Identifiers
SymbolHDV_ribozyme
Rfam RF00094
Other data
RNA type Gene; ribozyme
Domain(s) Viruses
SO SO:0000374
PDB structures PDBe
A representation of the 3D structure of the Hepatitis delta virus ribozyme. PDB 1cx0 EBI.jpg
A representation of the 3D structure of the Hepatitis delta virus ribozyme.

The hepatitis delta virus (HDV) ribozyme is a non-coding RNA found in the hepatitis delta virus that is necessary for viral replication. Hepatitis delta virus is the only known human virus that utilizes ribozyme activity to infect its host. [1] The ribozyme acts to process the RNA transcripts to unit lengths in a self-cleavage reaction during replication of the hepatitis delta virus, which is thought to propagate by a double rolling circle mechanism. [2] [3] The ribozyme is active in vivo in the absence of any protein factors and was the fastest known naturally occurring self-cleaving RNA at the time of its discovery. [4]

Contents

The crystal structure of this ribozyme has been solved using X-ray crystallography and shows five helical segments connected by a double pseudoknot. [1]

In addition to the sense (genomic version), all HDV viruses also have an antigenomic version of the HDV ribozyme. [5] This version is not the exact complementary sequence but adopts the same structure as the sense (genomic) strand. The only "significant" differences between the two are a small bulge in P4 stem and a shorter J4/2 junction. Both the genomic and antigenomic ribozymes are necessary for replication. [2]

HDV-like ribozymes

The HDV ribozyme is structurally and biochemically related to many other self-cleaving ribozymes. These other ribozymes are often referred to as examples of HDV ribozymes, because of these similarities, even though they are not found in hepatitis delta viruses. They can also be referred to as "HDV-like" to indicate this fact. [6]

HDV-like ribozymes include the mammalian CPEB3 ribozyme, theta ribozymes in bacteriophages, retrotransposons members (e.g. in the R2 RNA element in insects and in the L1Tc and probably other retrotransposons in trypanosomatids) and sequences from bacteria. [7] [8] [6] [9] [10] [11] The grouping is probably a result of convergent evolution: Deltavirus found outside of humans also possess a DV ribozyme, and no horizontal gene transfer scenarios proposed can yet explain this. [12] [13] [14]

Mechanism of catalysis

The HDV ribozyme catalyzes cleavage of the phosphodiester bond between the substrate nucleotide or oligonucleotide and the 5′-hydroxyl of the ribozyme. In the hepatitis delta virus, this substrate nucleotide sequence begins with uridine and is known as U(-1), however, the identity of the -1 nucleotide does not significantly change the rate of catalysis. [1] There is only a requirement for its chemical nature, since as shown by Perrotta and Been, substitution of the U(-1) ribose with deoxyribose abolishes the reaction, which is consistent with the prediction that the 2′-hydroxyl is the nucleophile in the chemical reaction. [15] Hence, unlike many other ribozymes, such as the hammerhead ribozyme, the HDV ribozyme has no upstream requirements for catalysis and requires only a single -1 ribonucleotide as a substrate to efficiently react. [1]

Initially, it was believed that the 75th nucleotide in the ribozyme, a cytosine known as C75, was able to act as a general base with the N3 of C75 abstracting a proton from the 2′-hydroxyl of the U(-1) nucleotide to facilitate nucleophilic attack on the phosphodiester bond. [1] However, although it is well established that the N3 of C75 has a pKa perturbed from its normal value of 4.45 and is closer to about 6.15 or 6.40, [16] [17] it is not neutral enough to act as a general base catalyst. Instead, the N3 of C75 is believed to act as a Lewis acid to stabilize the leaving 5′-hydroxyl of the ribozyme; this is supported by its proximity to the 5′-hydroxyl in the crystal structure. [1] [18] Substitution of the C75 nucleotide with any other nucleotide abolishes or substantially impairs ribozyme activity, although this activity can be partially restored with imidazole, further implicating C75 in catalytic activity. [19]

The C75 in the HDV ribozyme has been the subject of several studies because of its peculiar pKa. The typical pKa values for the free nucleosides are around 3.5 to 4.2; these lower pKa values are acidic and it is unlikely that they would become basic. However, it is likely that the structural environment within the ribozyme, which includes a desolvated active site cleft, provides negative electrostatic potential that could perturb the pKa of cytosine enough to act as a Lewis acid. [20] [21] [22] [23]

General acid catalysis by cytosine 75, in which the protonated form of the C donates a proton to the leaving group during catalysis Acid Base Catalysis.png
General acid catalysis by cytosine 75, in which the protonated form of the C donates a proton to the leaving group during catalysis

In addition to Lewis acid stabilization of the 5′-hydroxyl leaving group, it is also now accepted that the HDV ribozyme can use a metal ion to assist in activation of the 2′-hydroxyl for attack on the U(-1) nucleotide. A magnesium ion in the active site of the ribozyme is coordinated to the 2’-hydroxyl nucleophile and an oxygen of the scissile phosphate, and may act as a Lewis acid to activate the 2′-hydroxyl. [19] [18] In addition, it is possible that the phosphate of U23 can act as a Lewis acid to accept a proton from the 2′-hydroxyl with the magnesium serving as a coordinating ion. [24] Because the HDV ribozyme does not require metal ions to have activity, it is not an obligate metalloenzyme, but the presence of magnesium in the active site significantly improves the cleavage reaction. The HDV ribozyme does seem to have a nonspecific requirement for low amounts of divalent cations to fold, being active in Mg2+, Ca2+, Mn2+, and Sr2+. [1] In the absence of metal ions, it seems likely that water can replace the role of magnesium as a Lewis acid.

Regulation by upstream RNA

As limited by the rapid self-cleaving nature of HDV ribozyme, the previous ribonuclease experiments were performed on the 3′ product of self-cleavage rather than the precursor. [25] However, flanking sequence is known to participate in regulating the self-cleavage activity of HDV ribozyme. [26] [27] [28] Therefore, the upstream sequence 5′ to the self-cleavage site has been incorporated to study the resultant self-cleavage activity of the HDV ribozyme. [26] Two alternative structures have been identified.

The first inhibitory structure is folded by an extended transcript (i.e. -30/99 transcript, coordinates are referenced against the self-cleavage site) spanning from 30 nt upstream of the cleavage site to 15 nt downstream of the 3′-end. [26] The flanking sequence sequesters the ribozyme in a kinetic trap during transcription and results in the extremely diminished self-cleavage rate. [26] This self-cleavage-preventing structure includes 3 alternative stems: Alt1, Alt2 and Alt3, which disrupt the active conformation. Alt1 is a 10-bp Long-Range-Interaction formed by an inhibitory upstream stretch (-25/-15 nt) and the downstream stretch (76/86 nt). [26] The Alt1 disrupts the stem P2 in the active conformation wherein P2 is proposed to have an activating role for both genomic and antigenomic ribozyme. [26] [29] [30] Alt2 is an interaction between upstream flanking sequence and the ribozyme, and Alt3 is a nonnative ribozyme-ribozyme interaction. [26]

The secondary structure of this inhibitory conformation is supported by various experimental approaches. [26] First, direct probing via ribonucleases was performed and the subsequent modeling via mfold 3.0 using constraints from the probing results agrees with the proposed structure. [26] Second, a series of DNA oligomer complementary to different regions of AS1/2 were used to rescue the ribozyme activity; the results confirms the inhibitory roles of AS1/2. [26] Third, mutational analysis introduces single/double mutations outside the ribozyme to ensure the observed ribozyme activity is directly associated with the stability of the Alt1. [26] The stability of AS1 is found to be inversely related to the self-cleavage activity. [26]

The second permissive structure enables the HDV ribozyme to self-cleave co-transcriptionally and this structure further includes the -54/-18 nt portion of the RNA transcript. [26] The upstream inhibitory -24/-15 stretch from the aforementioned inhibitory conformation is now sequestered in a hairpin P(-1) located upstream of the cleavage site. [26] [31] [32] The P(-1) motif, however, is only found in the genomic sequence, which may be correlated with the phenomenon that genomic HDV RNA copies are more abundant in the infected liver cells. [26] [5] Experimental evidence also supports this alternative structure. First, structural mapping via ribonuclease is used to probe the -54/-1 fragment instead of the whole precursor transcript due to the fast-cleaving nature of this structure, which agrees with the local hairpin P(-1) (between -54/-40 and -18/-30 nt). [26] Secondly, evolutionary conservation is found in P(-1) and the linking region between P(-1) and P1 among 21 genomic HDV RNA isolates. [26]

Use in RNA transcript preparation

The special properties of the HDV ribozyme's cleavage reaction make it a useful tool to prepare RNA transcripts with homogenous 3′ ends, an alternative to transcription of RNA with T7 RNA polymerase than can often produce heterogenous ends or undesired additions. The cDNA version of the ribozyme may be prepared adjacent to cDNA of the target RNA sequence and RNA prepared from transcription with T7 RNA polymerase. The ribozyme sequence will efficiently cleave itself with no downstream requirements, as the -1 nucleotide is invariant, leaving a 2′–3′ cyclic phosphate that can easily be removed by treatment with a phosphatase or T4 polynucleotide kinase. [33] The target RNA can then be purified with gel purification.

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<span class="mw-page-title-main">Ribozyme</span> Type of RNA molecules

Ribozymes 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 demonstrated that RNA can be both genetic material and a biological catalyst, and contributed to the RNA world hypothesis, which suggests that RNA may have been important in the evolution of prebiotic self-replicating systems.

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Virusoids are circular single-stranded RNA(s) dependent on viruses for replication and encapsidation. The genome of virusoids consists of several hundred (200–400) nucleotides and does not code for any proteins.

<span class="mw-page-title-main">Hammerhead ribozyme</span>

The hammerhead ribozyme is an RNA motif that catalyzes reversible cleavage and ligation reactions at a specific site within an RNA molecule. It is one of several catalytic RNAs (ribozymes) known to occur in nature. It serves as a model system for research on the structure and properties of RNA, and is used for targeted RNA cleavage experiments, some with proposed therapeutic applications. Named for the resemblance of early secondary structure diagrams to a hammerhead shark, hammerhead ribozymes were originally discovered in two classes of plant virus-like RNAs: satellite RNAs and viroids. They are also known in some classes of retrotransposons, including the retrozymes. The hammerhead ribozyme motif has been ubiquitously reported in lineages across the tree of life.

<span class="mw-page-title-main">Hairpin ribozyme</span> Enzymatic section of RNA

The hairpin ribozyme is a small section of RNA that can act as a ribozyme. Like the hammerhead ribozyme it is found in RNA satellites of plant viruses. It was first identified in the minus strand of the tobacco ringspot virus (TRSV) satellite RNA where it catalyzes self-cleavage and joining (ligation) reactions to process the products of rolling circle virus replication into linear and circular satellite RNA molecules. The hairpin ribozyme is similar to the hammerhead ribozyme in that it does not require a metal ion for the reaction.

<span class="mw-page-title-main">Leadzyme</span>

Leadzyme is a small ribozyme (catalytic RNA), which catalyzes the cleavage of a specific phosphodiester bond. It was discovered using an in-vitro evolution study where the researchers were selecting for RNAs that specifically cleaved themselves in the presence of lead. However, since then, it has been discovered in several natural systems. Leadzyme was found to be efficient and dynamic in the presence of micromolar concentrations of lead ions. Unlike in other small self-cleaving ribozymes, other divalent metal ions cannot replace Pb2+ in the leadzyme. Due to obligatory requirement for a lead, the ribozyme is called a metalloribozyme.

<span class="mw-page-title-main">VS ribozyme</span>

The Varkud satellite (VS) ribozyme is an RNA enzyme that carries out the cleavage of a phosphodiester bond.

<span class="mw-page-title-main">R2 RNA element</span>

The R2 RNA element is a non-long terminal repeat (non-LTR) retrotransposable element that inserts at a specific site in the 28S ribosomal RNA (rRNA) genes of most insect genomes. In order to insert itself into the genome, retrotransposon encoded protein (R2) protein makes a specific nick in one of the DNA strands at the insertion site and uses the 3′ hydroxyl group exposed by this nick to prime the reverse transcription process termed target primed reverse transcription (TPRT), where the RNA genome is transcribed into DNA.

<span class="mw-page-title-main">Mammalian CPEB3 ribozyme</span> Ribozyme

The mammalian CPEB3 ribozyme is a self cleaving non-coding RNA located in the second intron of the CPEB3 gene which belongs to a family of genes regulating messenger RNA polyadenylation. This ribozyme is highly conserved and found only in mammals. The CPEB3 ribozyme is structurally and biochemically related to the human hepatitis delta virus ribozyme. Other HDV-like ribozymes have been identified and confirmed to be active in vitro in a number of eukaryotes.

<span class="mw-page-title-main">Cas9</span> Microbial protein found in Streptococcus pyogenes M1 GAS

Cas9 is a 160 kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utilized in genetic engineering applications. Its main function is to cut DNA and thereby alter a cell's genome. The CRISPR-Cas9 genome editing technique was a significant contributor to the Nobel Prize in Chemistry in 2020 being awarded to Emmanuelle Charpentier and Jennifer Doudna.

<span class="mw-page-title-main">Twister ribozyme</span> Ribozyme capable of self-cleavage

The twister ribozyme is a catalytic RNA structure capable of self-cleavage. The nucleolytic activity of this ribozyme has been demonstrated both in vivo and in vitro and has one of the fastest catalytic rates of naturally occurring ribozymes with similar function. The twister ribozyme is considered to be a member of the small self-cleaving ribozyme family which includes the hammerhead, hairpin, hepatitis delta virus (HDV), Varkud satellite (VS), and glmS ribozymes.

<span class="mw-page-title-main">RNA hydrolysis</span>

RNA hydrolysis is a reaction in which a phosphodiester bond in the sugar-phosphate backbone of RNA is broken, cleaving the RNA molecule. RNA is susceptible to this base-catalyzed hydrolysis because the ribose sugar in RNA has a hydroxyl group at the 2’ position. This feature makes RNA chemically unstable compared to DNA, which does not have this 2’ -OH group and thus is not susceptible to base-catalyzed hydrolysis.

<span class="mw-page-title-main">Twister sister ribozyme</span> RNA structure

The twister sister ribozyme (TS) is an RNA structure that catalyzes its own cleavage at a specific site. In other words, it is a self-cleaving ribozyme. The twister sister ribozyme was discovered by a bioinformatics strategy as an RNA Associated with Genes Associated with Twister and Hammerhead ribozymes, or RAGATH.

The pistol ribozyme is an RNA structure that catalyzes its own cleavage at a specific site. In other words, it is a self-cleaving ribozyme. The pistol ribozyme was discovered through comparative genomic analysis. Subsequent biochemical analysis determined further biochemical characteristics of the ribozyme. This understanding was further advanced by an atomic-resolution crystal structure of a pistol ribozyme

<span class="mw-page-title-main">Hatchet ribozyme</span> Self-cleaving ribozyme

Background: The hatchet ribozyme is an RNA structure that catalyzes its own cleavage at a specific site. In other words, it is a self-cleaving ribozyme. Hatchet ribozymes were discovered by a bioinformatics strategy as RNAs Associated with Genes Associated with Twister and Hammerhead ribozymes, or RAGATH.

<span class="mw-page-title-main">RAGATH RNA motifs</span> Bioinformatics strategy

RNAs Associated with Genes Associated with Twister and Hammerhead ribozymes (RAGATH) refers to a bioinformatics strategy that was devised to find self-cleaving ribozymes in bacteria. It also refers to candidate RNAs, or RAGATH RNA motifs, discovered using this strategy.

<span class="mw-page-title-main">Ribozyviria</span> Realm of viruses

Ribozyviria is a realm of satellite nucleic acids — infectious agents that resemble viruses, but cannot replicate without a helper virus. Established in ICTV TaxoProp 2020.012D, the realm is named after the presence of genomic and antigenomic ribozymes of the Deltavirus type. The agents in Ribozyviria are satellite nucleic acids, which are distinct from satellite viruses in that they do not encode all of their own structural proteins but require proteins from their helper viruses in order to assemble. Additional common features include a rod-like structure, an RNA-binding "delta antigen" encoded in the genome, and animal hosts. Furthermore, the size range of the genomes of these viruses is between around 1547–1735nt, they encode a hammerhead ribozyme or a hepatitis delta virus ribozyme, and their coding capacity only involves one conserved protein. Most lineages of this realm are poorly understood, the notable exception being the genus Deltavirus, comprising the causal agents of hepatitis D in humans.

Retrozymes are a family of retrotransposons first discovered in the genomes of plants but now also known in genomes of animals. Retrozymes contain a hammerhead ribozyme (HHR) in their sequences, although they do not possess any coding regions. Retrozymes are nonautonomous retroelements, and so borrow proteins from other elements to move into new regions of a genome. Retrozymes are actively transcribed into covalently closed circular RNAs and are detected in both polarities, which may indicate the use of rolling circle replication in their lifecycle.

References

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