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

Publication ,  Journal Article
Tsao, D; Shabalina, SA; Gauthier, J; Dokholyan, NV; Diatchenko, L
Published in: Nucleic Acids Res
August 2011

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.

Duke Scholars

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

August 2011

Volume

39

Issue

14

Start / End Page

6201 / 6212

Location

England

Related Subject Headings

  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Peptide Chain Initiation, Translational
  • Nucleic Acid Conformation
  • Molecular Sequence Data
  • Molecular Dynamics Simulation
  • Humans
  • Haplotypes
  • Developmental Biology
  • Codon, Initiator
 

Citation

APA
Chicago
ICMJE
MLA
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Tsao, D., Shabalina, S. A., Gauthier, J., Dokholyan, N. V., & Diatchenko, L. (2011). Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant. Nucleic Acids Res, 39(14), 6201–6212. https://doi.org/10.1093/nar/gkr165
Tsao, Douglas, Svetlana A. Shabalina, Josée Gauthier, Nikolay V. Dokholyan, and Luda Diatchenko. “Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant.Nucleic Acids Res 39, no. 14 (August 2011): 6201–12. https://doi.org/10.1093/nar/gkr165.
Tsao D, Shabalina SA, Gauthier J, Dokholyan NV, Diatchenko L. Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant. Nucleic Acids Res. 2011 Aug;39(14):6201–12.
Tsao, Douglas, et al. “Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant.Nucleic Acids Res, vol. 39, no. 14, Aug. 2011, pp. 6201–12. Pubmed, doi:10.1093/nar/gkr165.
Tsao D, Shabalina SA, Gauthier J, Dokholyan NV, Diatchenko L. Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant. Nucleic Acids Res. 2011 Aug;39(14):6201–6212.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

August 2011

Volume

39

Issue

14

Start / End Page

6201 / 6212

Location

England

Related Subject Headings

  • RNA, Messenger
  • Polymorphism, Single Nucleotide
  • Peptide Chain Initiation, Translational
  • Nucleic Acid Conformation
  • Molecular Sequence Data
  • Molecular Dynamics Simulation
  • Humans
  • Haplotypes
  • Developmental Biology
  • Codon, Initiator