Modomics - A Database of RNA Modifications

Published on Oct. 12, 2015 in J Mol Biol volume None.

PubMed ID: 26470919


Human tRNA3Lys is the primer for reverse transcription of HIV; the 3' end is complementary to the primer-binding site on HIV RNA. The complementarity ends at the 18th base, A58, which in tRNA3Lys is modified to remove Watson-Crick pairing. Motivated to test the role of the modification in terminating the primer-binding sequence and so limiting run-on transcription, we asked how the modification of RNA could be accomplished. tRNA m1A58 methyltransferase methylates N1 of A58, which is buried in the TPsiC-loop of tRNA, from cofactor S-adenosyl-L-methionine. This conserved tRNA modification is essential for stability of initiator tRNA in Saccharomyces cerevisiae. Reported here, three structures of human tRNA m1A58 methyltransferase in complex with human tRNA3Lys and the product S-adenosyl-L-homocysteine show a dimer of heterodimers in which each heterodimer comprises a catalytic chain, Trm61, and a homologous, but non-catalytic chain, Trm6, repurposed as a tRNA-binding subunit that acts in trans; tRNAs bind across the dimer interface such that Trm6 from the opposing heterodimer brings A58 in to the active site of Trm61. T-loop and D-loop are splayed apart showing how A58, normally buried in tRNA, becomes accessible for modification. This result has broad impact on our understanding of the mechanisms of modifying internal sites in folded tRNA. The structures serve as templates for design of inhibitors that could be used to test tRNA m1A58 methyltransferase's impact on retroviral priming and transcription.

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