Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant
Autor: | Nikolay V. Dokholyan, Josee Gauthier, Douglas Tsao, S. Shabalina, Luda Diatchenko |
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Jazyk: | angličtina |
Rok vydání: | 2011 |
Předmět: |
Nonsynonymous substitution
Translational efficiency Population Molecular Sequence Data Codon Initiator Biology Molecular Dynamics Simulation Catechol O-Methyltransferase Polymorphism Single Nucleotide Cell Line 03 medical and health sciences 0302 clinical medicine Eukaryotic translation Start codon 030202 anesthesiology Genetics Medicine Animals Humans RNA Messenger education Peptide Chain Initiation Translational 030304 developmental biology 0303 health sciences Messenger RNA education.field_of_study Catechol-O-methyl transferase Base Sequence business.industry Molecular biology Cell biology Folding (chemistry) Anesthesiology and Pain Medicine Neurology Haplotypes RNA Nucleic Acid Conformation Neurology (clinical) business Synonymous substitution 030217 neurology & neurosurgery |
Zdroj: | Nucleic Acids Research |
ISSN: | 1362-4962 0305-1048 |
Popis: | 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. |
Databáze: | OpenAIRE |
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