Douglas Tsao - Disruptive mRNA folding increases translational efficiency of catechol O-methyltransferase variant

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  Publication Details (including relevant citation   information):

  Tsao, D., Shabalina, S. A., Gauthier, J., Dokholyan, N. V., and   Diatchenko, L., Nucleic Acids Research, 39:6201-6212,   (2011)

  Abstract:

  Catechol   O-methyltransferase (COMT) is a major enzyme controlling   catecholamine levels that plays a central role in cognition,   affective mood and pain perception. There are three common COMT   haplotypes in the human population reported to have functional   effects, divergent in two synonymous and one nonsynonymous   position. We demonstrate that one of the haplotypes, carrying the   non-synonymous variation known to code for a less stable protein,   exhibits increased protein expression in vitro. This increased   protein expression, which would compensate for lower protein   stability, is solely produced by a synonymous variation (C(166)T)   situated within the haplotype and located in the 5' region of the   RNA transcript. Based on mRNA secondary structure predictions, we   suggest that structural destabilization near the start codon   caused by the T allele could be related to the observed increase   in COMT expression. Our folding simulations of the tertiary mRNA   structures demonstrate that destabilization by the T allele   lowers the folding transition barrier, thus decreasing the   probability of occupying its native state. These data suggest a   novel structural mechanism whereby functional synonymous   variations near the translation initiation codon affect the   translation efficiency via entropy-driven changes in mRNA   dynamics and present another example of stable compensatory   genetic variations in the human population.

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