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

Department of Chemistry, Center for Neurosensory Disorders, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Nucleic Acids Research (Impact Factor: 9.11). 04/2011; 39(14):6201-12. DOI: 10.1093/nar/gkr165
Source: PubMed


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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    • "Functional importance of alternative protein terminal regions is supported by our transcriptome-scale analysis demonstrating that these regions are subject to purifying selection. Our finding of the elevated RNSP in the 5′ grey areas is in good agreement with the reported selection in favour of mRNA folding pattern in the vicinity of translation start codons (47,50,55,74,75) and elevated occupancy of the first protein-coding exons with TF recognition sites across the human exome (56). Thus, nucleotide-level constraints appear to be a major driver of evolution in the upstream translated gene sequences (55,76). "
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    • "SNPs in the prothrombin 3′UTR affect post-transcriptional processing and 3′-cleavage/polyadenylation and SNPs in SNCA affect polyadenylation [28], [29]; both of which affect expression. Variants in the 5′UTR of the COMT gene are associated with structural destabilization of the COMT mRNA through differential tertiary structures [30]. Thus, it is possible that the SNPs evaluated in this study which correlated with differential luciferase expression may affect mRNA stability through polyadenylation or other differences resulting in changes to mRNA stability which can be addressed in future studies. "
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