Physical Chemistry of a Single tRNA-Modified Nucleoside Regulates Decoding of the Synonymous Lysine Wobble Codon and Affects Type 2 Diabetes
Sweta Vangaveti, S. Ranganathan, Paul F. Agris
Abstract
The 2-methylthio-modification (ms2-) of N6-threonylcarbonyladenosine (t6A37) at position-37 (ms2t6A37) in tRNAUUULys3 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 tRNAUUULys3, correlate with type 2 diabetes mellitus. Without the ms2-modification, tRNAUUULys3 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 tRNAUUULys3-t6A37, facilitates the decoding of the AAG codon and enables human pancreatic islets to correctly translate insulin mRNA.