Transfer RNA
Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA
Overview
While the specific nucleotide sequence of an mRNA specifies which
On the other end of the tRNA is a covalent attachment to the amino acid that corresponds to the anticodon sequence. Each type of tRNA molecule can be attached to only one type of amino acid, so each organism has many types of tRNA. Because the genetic code contains multiple codons that specify the same amino acid, there are several tRNA molecules bearing different anticodons which carry the same amino acid.
The covalent attachment to the tRNA
Structure
The structure of tRNA can be decomposed into its
- The acceptor stem is a 7- to 9-base pair (bp) stem made by the base pairing of the 5′-terminal nucleotide with the 3′-terminal nucleotide (which contains the CCA tail used to attach the amino acid). The acceptor stem may contain non-Watson-Crick base pairs.[6][8]
- The CCA tail is a cytosine-cytosine-adenine sequence at the 3′ end of the tRNA molecule. The amino acid loaded onto the tRNA by aminoacyl tRNA synthetases, to form aminoacyl-tRNA, is covalently bonded to the 3′-hydroxyl group on the CCA tail.[9] This sequence is important for the recognition of tRNA by enzymes and critical in translation.[10][11] In prokaryotes, the CCA sequence is transcribed in some tRNA sequences. In most prokaryotic tRNAs and eukaryotic tRNAs, the CCA sequence is added during processing and therefore does not appear in the tRNA gene.[12]
- The D loop is a 4- to 6-bp stem ending in a loop that often contains dihydrouridine.[6]
- The anticodon loop is a 5-bp stem whose loop contains the anticodon.[6]
- The ribothymidine, m5U) and A forming a base pair.[13]
- The variable loop or V loop sits between the anticodon loop and the ΨU loop and, as its name implies, varies in size from 3 to 21 bases. In some tRNAs, the "loop" is long enough to form a rigid stem, the variable arm.[14] tRNAs with a V loop more than 10 bases long is classified as "class II" and the rest is called "class I".[15]
Anticodon
An anticodon
Nomenclature
A tRNA is commonly named by its intended amino acid (e.g. tRNA-Asn), by its anticodon sequence (e.g. tRNA(GUU)), or by both (e.g. tRNA-Asn(GUU) or tRNAAsn
GUU).[19] These two features describe the main function of the tRNA, but do not actually cover the whole diversity of tRNA variation; as a result, numerical suffixes are added to differentiate.[20] tRNAs intended for the same amino acid are called "isotypes"; these with the same anticodon sequence are called "isoacceptors"; and these with both being the same but differing in other places are called "isodecoders".[21]
Aminoacylation
Aminoacylation is the process of adding an aminoacyl group to a compound. It covalently links an amino acid to the CCA 3′ end of a tRNA molecule. Each tRNA is aminoacylated (or charged) with a specific amino acid by an aminoacyl tRNA synthetase. There is normally a single aminoacyl tRNA synthetase for each amino acid, despite the fact that there can be more than one tRNA, and more than one anticodon for an amino acid. Recognition of the appropriate tRNA by the synthetases is not mediated solely by the anticodon, and the acceptor stem often plays a prominent role.[22] Reaction:
Certain organisms can have one or more aminophosphate-tRNA synthetases missing. This leads to charging of the tRNA by a chemically related amino acid, and by use of an enzyme or enzymes, the tRNA is modified to be correctly charged. For example,
Binding to ribosome
The
Once translation initiation is complete, the first aminoacyl tRNA is located in the P/P site, ready for the elongation cycle described below. During translation elongation, tRNA first binds to the ribosome as part of a complex with elongation factor Tu (
The P/I site is actually the first to bind to aminoacyl tRNA, which is delivered by an initiation factor called
has not yet been confirmed. The P-site protein L27 has been determined by affinity labeling by E. Collatz and A. P. Czernilofsky (FEBS Lett., Vol. 63, pp. 283–286, 1976).tRNA genes
Organisms vary in the number of tRNA
In the human genome, which, according to January 2013 estimates, has about 20,848 protein coding genes suggesting the possibility that the lookalikes are functional.
Cytoplasmic tRNA genes can be grouped into 49 families according to their anticodon features. These genes are found on all chromosomes, except the 22 and Y chromosome. High clustering on 6p is observed (140 tRNA genes), as well as on chromosome 1.[33]
The HGNC, in collaboration with the Genomic tRNA Database (GtRNAdb) and experts in the field, has approved unique names for human genes that encode tRNAs.
Typically, tRNAs genes from Bacteria are shorter (mean = 77.6 bp) than tRNAs from Archaea (mean = 83.1 bp) and eukaryotes (mean = 84.7 bp).[31] The mature tRNA follows an opposite pattern with tRNAs from Bacteria being usually longer (median = 77.6 nt) than tRNAs from Archaea (median = 76.8 nt), with eukaryotes exhibiting the shortest mature tRNAs (median = 74.5 nt).[31]
Evolution
Genomic tRNA content is a differentiating feature of genomes among biological domains of life: Archaea present the simplest situation in terms of genomic tRNA content with a uniform number of gene copies, Bacteria have an intermediate situation and Eukarya present the most complex situation.[39] Eukarya present not only more tRNA gene content than the other two kingdoms but also a high variation in gene copy number among different isoacceptors, and this complexity seem to be due to duplications of tRNA genes and changes in anticodon specificity[citation needed].
Evolution of the tRNA gene copy number across different species has been linked to the appearance of specific tRNA modification enzymes (uridine methyltransferases in Bacteria, and adenosine deaminases in Eukarya), which increase the decoding capacity of a given tRNA.[39] As an example, tRNAAla encodes four different tRNA isoacceptors (AGC, UGC, GGC and CGC). In Eukarya, AGC isoacceptors are extremely enriched in gene copy number in comparison to the rest of isoacceptors, and this has been correlated with its A-to-I modification of its wobble base. This same trend has been shown for most amino acids of eukaryal species. Indeed, the effect of these two tRNA modifications is also seen in codon usage bias. Highly expressed genes seem to be enriched in codons that are exclusively using codons that will be decoded by these modified tRNAs, which suggests a possible role of these codons—and consequently of these tRNA modifications—in translation efficiency.[39]
It is important to note that many species have lost specific tRNAs during evolution. For instance, both mammals and birds lack the same 14 out of the possible 64 tRNA genes, but other life forms contain these tRNAs.[40] For translating codons for which an exactly pairing tRNA is missing, organisms resort to a strategy called wobbling, in which imperfectly matched tRNA/mRNA pairs still give rise to translation, although this strategy also increases to propensity for translation errors.[41] The reasons why tRNA genes have been lost during evolution remains under debate but may relate improving resistance to viral infection.[42] Because nucleotide triplets can present more combinations than there are amino acids and associated tRNAs, there is redundancy in the genetic code, and several different 3-nucleotide codons can express the same amino acid. This codon bias is what necessitates codon optimization.
Hypothetical origin
The top half of tRNA (consisting of the T arm and the acceptor stem with 5′-terminal phosphate group and 3′-terminal CCA group) and the bottom half (consisting of the D arm and the anticodon arm) are independent units in structure as well as in function. The top half may have evolved first including the 3′-terminal genomic tag which originally may have marked tRNA-like molecules for replication in early
tRNA-derived fragments
tRNA-derived fragments (or tRFs) are short molecules that emerge after cleavage of the mature tRNAs or the precursor transcript.
tRFs have multiple dependencies and roles; such as exhibiting significant changes between sexes, among races and disease status.[50][54][55] Functionally, they can be loaded on Ago and act through RNAi pathways,[48][51][56] participate in the formation of stress granules,[57] displace mRNAs from RNA-binding proteins[58] or inhibit translation.[59] At the system or the organismal level, the four types of tRFs have a diverse spectrum of activities. Functionally, tRFs are associated with viral infection,[60] cancer,[51] cell proliferation [52] and also with epigenetic transgenerational regulation of metabolism.[61]
tRFs are not restricted to humans and have been shown to exist in multiple organisms.[51][62][63][64]
Two online tools are available for those wishing to learn more about tRFs: the framework for the interactive exploration of mitochondrial and nuclear tRNA fragments (MINTbase)[65][66] and the relational database of Transfer RNA related Fragments (tRFdb).[67] MINTbase also provides a naming scheme for the naming of tRFs called tRF-license plates (or MINTcodes) that is genome independent; the scheme compresses an RNA sequence into a shorter string.
Engineered tRNAs
tRNAs with modified anticodons and/or acceptor stems can be used to modify the genetic code. Scientists have successfully repurposed codons (sense and stop) to accept amino acids (natural and novel), for both initiation (see: start codon) and elongation.
In 1990, tRNAfMet2
CUA (modified from the tRNAfMet2
CAU gene metY) was inserted into E. coli, causing it to initiate protein synthesis at the UAG stop codon, as long as it is preceded by a strong
tRNA biogenesis
In
Pre-tRNAs undergo extensive modifications inside the nucleus. Some pre-tRNAs contain
History
The existence of tRNA was first hypothesized by
Clinical relevance
Interference with aminoacylation may be useful as an approach to treating some diseases: cancerous cells may be relatively vulnerable to disturbed aminoacylation compared to healthy cells. The protein synthesis associated with cancer and viral biology is often very dependent on specific tRNA molecules. For instance, for liver cancer charging tRNA-Lys-CUU with lysine sustains liver cancer cell growth and metastasis, whereas healthy cells have a much lower dependence on this tRNA to support cellular physiology.[95] Similarly, hepatitis E virus requires a tRNA landscape that substantially differs from that associated with uninfected cells.[96] Hence, inhibition of aminoacylation of specific tRNA species is considered a promising novel avenue for the rational treatment of a plethora of diseases.
See also
- Cloverleaf model of tRNA
- Kim Sung-Hou
- Kissing stem-loop
- mRNA
- non-coding RNA and introns
- Slippery sequence
- tmRNA
- Transfer RNA-like structures
- Translation
- tRNADB
- Wobble hypothesis
- Aminoacyl-tRNA
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External links
- tRNAdb (updated and completely restructured version of Spritzls tRNA compilation)
- tRNA surprising role in breast cancer growth
- tRNA link to heart disease and stroke
- GtRNAdb: Collection of tRNAs identified from complete genomes
- HGNC: Gene nomenclature of human tRNAs
- Molecule of the Month © RCSB Protein Data Bank:
- Rfam entry for tRNA