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A pseudoknot is a
nucleic acid secondary structure containing at least two
stem-loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence wh ...
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 mosaic virus in 1982.
Pseudoknots fold into knot-shaped three-dimensional conformations but are not true
topological knots.
Prediction and identification
The structural configuration of pseudoknots does not lend itself well to bio-computational detection due to its context-sensitivity or "overlapping" nature. The
base pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both D ...
ing in pseudoknots is not well nested; that is, base pairs occur that "overlap" one another in sequence position. This makes the presence of pseudoknots in RNA sequences more difficult to
predict by the standard method of
dynamic programming
Dynamic programming is both a mathematical optimization method and a computer programming method. The method was developed by Richard Bellman in the 1950s and has found applications in numerous fields, from aerospace engineering to economics.
...
, which use a recursive scoring system to identify paired stems and consequently, most cannot detect non-nested base pairs. The newer method of
stochastic context-free grammar Grammar theory to model symbol strings originated from work in computational linguistics aiming to understand the structure of natural languages. Probabilistic context free grammars (PCFGs) have been applied in probabilistic modeling of RNA stru ...
s suffers from the same problem. Thus, popular secondary structure prediction methods lik
Mfoldan
Pfoldwill not predict pseudoknot structures present in a query sequence; they will only identify the more stable of the two pseudoknot stems.
It is possible to identify a limited class of pseudoknots using dynamic programming, but these methods are not exhaustive and scale worse as a function of sequence length than non-pseudoknotted algorithms.
[Rivas E, Eddy S. (1999). "A dynamic programming algorithm for RNA structure prediction including pseudoknots". ''J Mol Biol'' 285(5): 2053–2068.][Dirks, R.M. Pierce N.A. (2004) An algorithm for computing nucleic acid base-pairing probabilities including pseudoknots. "J Computation Chemistry". 25:1295-1304, 2004.] The general problem of predicting lowest free energy structures with pseudoknots has been shown to be
NP-complete
In computational complexity theory, a problem is NP-complete when:
# it is a problem for which the correctness of each solution can be verified quickly (namely, in polynomial time) and a brute-force search algorithm can find a solution by trying ...
.
[Lyngsø RB, Pedersen CN. (2000). "RNA pseudoknot prediction in energy-based models". ''J Comput Biol'' 7(3–4): 409–427.][Lyngsø, R. B. (2004). Complexity of pseudoknot prediction in simple models. Paper presented at the ICALP.]
Biological significance
Several important biological processes rely on RNA molecules that form pseudoknots, which are often RNAs with extensive
tertiary structure
Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may i ...
. For example, the pseudoknot region of
RNase P is one of the most conserved elements in all of evolution. The
telomerase RNA component
Telomerase RNA component, also known as TR, TER or TERC, is an ncRNA found in eukaryotes that is a component of telomerase, the enzyme used to extend telomeres. TERC serves as a template for telomere replication (reverse transcription) by t ...
contains a pseudoknot that is critical for activity,
and several viruses use a pseudoknot structure to form a tRNA-like motif to infiltrate the host cell.
Representing pseudoknots
Many types of pseudoknots exist, differing by how they cross and how many times they cross. To reflect this difference, pseudoknots are classed into H-, K-, L-, M-types, with each successive type adding a layer of step intercalation. The simple telomerase P2b-P3 example in the article, for example, is an H-type pseudoknot.
RNA secondary structure is usually represented by the dot-bracket notation, with pairing round brackets
() indicating basepairs in a stem and dots representing loops. The interrupted stems of pseudoknots mean that such notation must be extended with extra brackets, or even letters, so that different sets of stems can be represented. One such extension uses, in nesting order,
([]) for closing. The structure for the two (slightly varying) telomerase examples, in this notation, is:
(((.(((((........))))).))). .... .
drawing 1 CGCGCGCUGUUUUUCUCGCUGACUUUCAGCGGGCGA---AAAAAAUGUCAGCU 50
ALIGN , ., , , , , , , , , , , , , , , , , , , , , , , , , ., ., , , , , , , , , , , , , .
1ymo 1 ---GGGCUGUUUUUCUCGCUGACUUUCAGC--CCCAAACAAAAAA-GUCAGCA 47
((((((........
)))) ))......... .
Note that U bulge at the end is normally present in telomerase RNA. It was removed in the 1ymo solution model for enhanced stability of the pseudoknot.
See also
*
Long range pseudoknots
A long range pseudoknot is a pseudoknot containing a long loop region, and may be a mechanism of translational control.
A long range pseudoknot is thought to negatively regulate the translation of the IF3-L35-L20 operon in '' E. coli''. This oper ...
References
External links
Rfam entry for PK-HAV pseudoknot
{{Use dmy dates, date=November 2020
RNA