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

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.

Bacillus subtilis exhibits MnmC-like tRNA modification activities

“…Transfer RNAs (tRNAs) are by far the most extensively modified RNAs [1,2]. Modifications are post-transcriptionally introduced at precise positions by specific enzymes, and play important roles in folding, stability, identity, and translational and signaling functions of tRNAs [2,3].…”

“…Modifications are post-transcriptionally introduced at precise positions by specific enzymes, and play important roles in folding, stability, identity, and translational and signaling functions of tRNAs [2,3]. In particular, modified nucleosides of the anticodon loop transform the loop architecture and dynamics to meet the requirements that the ribosome places on all tRNAs [2,4,5].…”

“…Modifications are post-transcriptionally introduced at precise positions by specific enzymes, and play important roles in folding, stability, identity, and translational and signaling functions of tRNAs [2,3]. In particular, modified nucleosides of the anticodon loop transform the loop architecture and dynamics to meet the requirements that the ribosome places on all tRNAs [2,4,5]. In Escherichia coli , the MnmEG complex, formed by the dimeric proteins MnmE and MnmG [6], modifies the wobble uridine (U34) of tRNA Lys UUU , tRNA Glu UUC , tRNA Gln UUG , tRNA Leu UAA , tRNA Arg UCU , and tRNA Gly UCC [7,8].…”

Celebrating wobble decoding: Half a century and still much is new

“…9,25-30 Each of the modified nucleosides contribute distinct chemistries, nucleoside conformations and dynamics, and their contributions to decoding have been studied extensively over decades and most recently reviewed. 20,22,24,28,31-38 However, there is significant evidence that a combination of two or three anticodon domain modifications play a synergistic role in tRNA function where modification of a wobble position U is crucial. 9,20,24,39-46 Today, we know that certain modifications of U 34 enable expansion of codon from NNA/G recognition to synonymous codons ending in pyrimidines, N1-N2-Pyr, where N is any of the 4 nucleosides and Pyr is either U or C. 29 Yet, the anticodon domain of some tRNA species lack modification and can be totally devoid of modified nucleosides.…”

“…28 The nature of the C5 modification affects the tautomerism of the uridine and 2-thio modified uridine 125 producing either an expanded codon recognition, or one which is restricted. Restriction of codon recognition is a common mechanism for fidelity when a tRNA anticodon can mistakably base pair with a near-cognate codon in a shared codon box.…”