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Review
, 7 (1)

Chemical and Conformational Diversity of Modified Nucleosides Affects tRNA Structure and Function

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Review

Chemical and Conformational Diversity of Modified Nucleosides Affects tRNA Structure and Function

Ville Y P Väre et al. Biomolecules.

Abstract

RNAs are central to all gene expression through the control of protein synthesis. Four major nucleosides, adenosine, guanosine, cytidine and uridine, compose RNAs and provide sequence variation, but are limited in contributions to structural variation as well as distinct chemical properties. The ability of RNAs to play multiple roles in cellular metabolism is made possible by extensive variation in length, conformational dynamics, and the over 100 post-transcriptional modifications. There are several reviews of the biochemical pathways leading to RNA modification, but the physicochemical nature of modified nucleosides and how they facilitate RNA function is of keen interest, particularly with regard to the contributions of modified nucleosides. Transfer RNAs (tRNAs) are the most extensively modified RNAs. The diversity of modifications provide versatility to the chemical and structural environments. The added chemistry, conformation and dynamics of modified nucleosides occurring at the termini of stems in tRNA's cloverleaf secondary structure affect the global three-dimensional conformation, produce unique recognition determinants for macromolecules to recognize tRNAs, and affect the accurate and efficient decoding ability of tRNAs. This review will discuss the impact of specific chemical moieties on the structure, stability, electrochemical properties, and function of tRNAs.

Keywords: RNA modified nucleoside contributions to function; chemical biology of RNA modifications; physicochemical properties of RNA modifications; tRNA modifications.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Transfer RNA (tRNA) secondary and tertiary structure. Yeast initiator tRNA cloverleaf structure (Left) and three-dimensional L-shape structure (Right) are shown with selected modification sites labeled. The colors correspond to the acceptor stem (orange), D stem and loop (DSL) domain (gray), T stem and loop (TSL) domain (red), anticodon stem and loop (ASL) domain (blue), and variable loop (V-Loop) domain (green). Three-dimensional figure adopted from Protein Data Bank (PDB) file 1YFG [16]. Weakly binding Mg2+ ions are key to the folding of tRNA, as they are to all RNAs. They are shown in Figure 3. One Mg2+ binding site is in the loop of the ASL and often found in the vicinity of ASL modifications.
Figure 2
Figure 2
Nucleoside Modifications and Conformations. Some 90 modified nucleosides appear in tRNAs. The modifications, nucleobase and ribose conformations addressed in this review are (a) Adenosine and its modifications (R = ribose); (b) Uridine and its modifications (R = ribose); (c) Guanosine and its modifications (R = ribose); (d) Cytidine and its modifications (R = ribose); (e) 2’-O-methylated nucleosides; (f) C3’-endo versus C2’-endo (R = OH or phosphate; B = nucleobase); (g) anti adenosine versus syn adenosine.
Figure 2
Figure 2
Nucleoside Modifications and Conformations. Some 90 modified nucleosides appear in tRNAs. The modifications, nucleobase and ribose conformations addressed in this review are (a) Adenosine and its modifications (R = ribose); (b) Uridine and its modifications (R = ribose); (c) Guanosine and its modifications (R = ribose); (d) Cytidine and its modifications (R = ribose); (e) 2’-O-methylated nucleosides; (f) C3’-endo versus C2’-endo (R = OH or phosphate; B = nucleobase); (g) anti adenosine versus syn adenosine.
Figure 3
Figure 3
tRNA core structure and Levitt base pair model. (a) A three-dimensional model of the tRNAPhe tertiary structure, adapted from PDB File 1EHZ [46]. Nucleoside 15 in the variable loop forms a non-canonical base pair known as the ‘Levitt pair’ with the nucleoside 48 in the loop of the D stem and loop. The Levitt base pairing between nucleosides G15 and C48 is shown along with the U8:A14 stacked bases below the G○C base pair. The open circle denotes a non-canonical base pair. Magnesium ions, found at sites at which modifications also occur, are shown as dark yellow. Other modified nucleosides discussed as important to the tRNA core stability and functions are listed. VL: variable loop. (b) The canonical Watson–Crick (W–C) base pairing between G15○C48 pairs and the Levitt base pair with the reverse W–C (RWC) geometry is formed between two antiparallel strands, by rotation of one base to the syn orientation. (c) The G15○G48 tertiary H-bonding in Escherichia coli tRNACys. The trans orientation of the glycosidic bonds in G15 and G48 (left) allows a W–C base pairing like the G15○C48 in yeast tRNAPhe. The proposed base pairing on the right is stabilized by hydrogen bonding between the exocyclic N-2 with the ring N3 of the base.
Figure 3
Figure 3
tRNA core structure and Levitt base pair model. (a) A three-dimensional model of the tRNAPhe tertiary structure, adapted from PDB File 1EHZ [46]. Nucleoside 15 in the variable loop forms a non-canonical base pair known as the ‘Levitt pair’ with the nucleoside 48 in the loop of the D stem and loop. The Levitt base pairing between nucleosides G15 and C48 is shown along with the U8:A14 stacked bases below the G○C base pair. The open circle denotes a non-canonical base pair. Magnesium ions, found at sites at which modifications also occur, are shown as dark yellow. Other modified nucleosides discussed as important to the tRNA core stability and functions are listed. VL: variable loop. (b) The canonical Watson–Crick (W–C) base pairing between G15○C48 pairs and the Levitt base pair with the reverse W–C (RWC) geometry is formed between two antiparallel strands, by rotation of one base to the syn orientation. (c) The G15○G48 tertiary H-bonding in Escherichia coli tRNACys. The trans orientation of the glycosidic bonds in G15 and G48 (left) allows a W–C base pairing like the G15○C48 in yeast tRNAPhe. The proposed base pairing on the right is stabilized by hydrogen bonding between the exocyclic N-2 with the ring N3 of the base.
Figure 4
Figure 4
Modification-induced tautomerism allows the wobble residue to base pair with a non-cognate residue in the third codon position. (a) The keto form (Upper) of mcm5s2U34 encounters steric hindrance when forming a Watson–Crick base pair with adenosine; while the enol form (Lower) allows for favorable hydrogen bonding; (b) The common amino-oxo form (Upper) of f5C34 is sterically prohibited from forming a Watson–Crick base pair with adenosine; while the imino-oxo form (Lower) hydrogen bonds favorably.

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