Physical Chemistry of a Single tRNA-Modified Nucleoside Regulates Decoding of the Synonymous Lysine Wobble Codon and Affects Type 2 Diabetes

Abstract

The 2-methylthio-modification (ms²-) of N⁶-threonylcarbonyladenosine (t⁶A₃₇) at position-37 (ms²t⁶A₃₇) in tRNA_UUU^Lys3 provides the needed stability between the tRNA anticodon and the human insulin mRNA codon AAG during translation, as determined by molecular dynamics simulation. Single-nucleoside polymorphisms of the human gene for the enzyme, Cdkal1 that post-transcriptionally modifies t⁶A₃₇ to ms²t⁶A₃₇ in tRNA_UUU^Lys3, correlate with type 2 diabetes mellitus. Without the ms²-modification, tRNA_UUU^Lys3 is incapable of correctly translating the insulin mRNA AAG codon for lysine at the site of protease cleavage between the A-chain and the C-peptide. By enhancing anticodon/codon cross-strand stacking, the ms²-modification adds stability through van der Waals interactions and dehydration of the ASL loop and cavity of the anticodon/codon minihelix but does not add hydrogen bonding of any consequence. Thus, the modifying enzyme Cdkal1, by adding a crucial ms²-group to tRNA_UUU^Lys3-t⁶A₃₇, facilitates the decoding of the AAG codon and enables human pancreatic islets to correctly translate insulin mRNA.