Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
The importance of being modified: Tautomeric forms of pyrimidines provide expanded use of the genetic code
Tautomeric shifts of 5-modified uridines have been established in E. coli tRNAValcmo5UAC as well as in the human cytoplasmic tRNALys3mcm5s2UUU. These shifts enable the recognition of multiple codons with the wobble base pair in the Watson-Crick geometry suggesting an energetic preference for, and perhaps enhanced efficiency with, this conformation. Thus, modifications at the 5-position of wobble position uridines appear to be a common mechanism for expanding tRNA’s codon recognition. One deviation from the universal code that is particularly interesting is the reading of AUG and the universal isoleucine codon AUA as methionine in both the A- and P-sites of the mitochondrial ribosome of most metazoans. We have discovered a mechanism by which 5-formylcytidine (f 5C) at the wobble position of human mitochondrial tRNAMet (hmtRNAMetf5CAU) expands the decoding ability of this tRNA enabling it to read AUA as methionine. We have also found that another modified cytidine can restrict wobble base formation. This underscores the ability of cytidines, as well as uridine, modifications within the anticodon loop to modulate the decoding ability of the tRNA, providing insight into decoding mechanisms and evolution of the genetic code.
This research is supported by: NIH 2RO1 GM23037-25; NSF MCB 0548602; NSF MCB 1101859
Vendeix, F.A.P. and Murphy, F.V. IV, Cantara, W.A., Leszczynska, G., Gustilo, E.M., Sproat, B., Malkiewicz, A. & Agris, P.F. (2012) Human tRNALys3UUU is pre-structured by natural modifications for cognate and wobble codon binding through keto-enol tautomerism. J. Mol. Biol. 416:467-85.
William A. Cantara
The RNA Institute