Alteration of protein function by a silent polymorphism linked to tRNA abundance

Kirchner, S. et al. (2017) Alteration of protein function by a silent polymorphism linked to tRNA abundance. PLoS Biology, 15(5), e2000779. (doi: 10.1371/journal.pbio.2000779) (PMID:28510592) (PMCID:PMC5433685)

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Abstract

Synonymous single nucleotide polymorphisms (sSNPs) are considered neutral for protein function, as by definition they exchange only codons, not amino acids. We identified an sSNP that modifies the local translation speed of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to detrimental changes to protein stability and function. This sSNP introduces a codon pairing to a low-abundance tRNA that is particularly rare in human bronchial epithelia, but not in other human tissues, suggesting tissue-specific effects of this sSNP. Up-regulation of the tRNA cognate to the mutated codon counteracts the effects of the sSNP and rescues protein conformation and function. Our results highlight the wide-ranging impact of sSNPs, which invert the programmed local speed of mRNA translation and provide direct evidence for the central role of cellular tRNA levels in mediating the actions of sSNPs in a tissue-specific manner.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kirchner, Dr Sebastian
Creator Roles:
Kirchner, S.Conceptualization, Data curation, Formal analysis, Investigation, Validation, Visualization, Writing – original draft, Writing – review and editing
Authors: Kirchner, S., Cai, Z., Rauscher, R., Kastelic, N., Anding, M., Czech, A., Kleizen, B., Ostedgaard, L. S., Braakman, I., Sheppard, D. N., and Ignatova, Z.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN:1544-9173
ISSN (Online):1545-7885
Published Online:16 May 2017
Copyright Holders:This is an open access article distributed under the terms of the CC0 Public Domain Dedication
First Published:First published in PLoS Biology 15(5): e2000779
Publisher Policy:Reproduced under a Creative Commons License

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