Idiosyncratic recognition of UUG/UUA codons by modified nucleoside 5-taurinomethyluridine, τm5U present at ‘wobble’ position in anticodon loop of tRNALeu: A molecular modeling approach

Abstract

Lack of naturally occurring modified nucleoside 5-taurinomethyluridine (τm5U) at the ‘wobble’ 34th position in tRNALeu causes mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The τm5U34 specifically recognizes UUG and UUA codons. Structural consequences of τm5U34 to read cognate codons have not been studied so far in detail at the atomic level. Hence, 50ns multiple molecular dynamics (MD) simulations of various anticodon stem loop (ASL) models of tRNALeu in presence and absence of τm5U34 along with UUG and UUA codons were performed to explore the dynamic behaviour of τm5U34 during codon recognition process. The MD simulation results revealed that τm5U34 recognizes G/A ending codons by ‘wobble’ as well as a novel ‘single’ hydrogen bonding interactions. RMSD and RMSF values indicate the comparative stability of the ASL models containing τm5U34 modification over the other models, lacking τm5U34. Another MD simulation study of 55S mammalian mitochondrial rRNA with tRNALeu showed crucial interactions between the A-site residues, A918, A919, G256 and codon-anticodon bases. Thus, these results could improve our understanding about the decoding efficiency of human mt tRNALeu with τm5U34 to recognize UUG and UUA codons.

Phytophthora capsici infection causes dynamic alterations in tRNA modifications and their associated gene candidates in black pepper

“…The presence of tm(5)U modification was reported at the 34th wobble position of tRNA Leu, tRNA Trp and tRNA Lys, tRNA Gln, tRNA Glu [50] . In humans, the lack of tm5U modification in 34th wobble position leads to MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes) disease [29] , [30] . However, the enzymes involved in the formation of tm5U modification are not reported yet [20] , [47] .…”

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets

“…Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Myoclonic Epilepsy with Ragged Red Fibers (MERRF) [166] are a group of mitochondrial diseases caused by the lack of taurine modification at the first anticodon nucleotide of mt-tRNA Leu(UUR) [167]. Due to the absence of naturally occurring modified nucleoside 5-taurinomethyluridine (τm 5 U) at the wobble position (C34) of tRNA Leu , resulting in errors in codon translation [168]. High dose of taurine can improve mitochondrial tRNA Leu (UUR) modification defect in peripheral blood leukocytes and inhibit stroke in MELAS patients [169].…”

Role of Wybutosine and Mg2+ Ions in Modulating the Structure and Function of tRNAPhe: A Molecular Dynamics Study

“…tRNA is unique in its base composition as it encompasses a variety of modified nucleic acid bases in addition to the usual RNA bases, A, U, G, and C . Various studies have reported that these modified bases are crucial elements contributing to various properties of the molecule. − Some studies also show that the absence of a specific modified nucleoside in tRNA causes structural deformities, which in turn cause considerable damage to native functions of the molecule. − …”