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

Sebastian Kirchner, Zhiwei Cai, Robert Rauscher, Nicolai Kastelic, Melanie Anding, Andreas Czech, Bertrand Kleizen, Lynda Ostegaard, Ineke Braakman, David Sheppard, Zoya Ignatova

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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.
Original languageEnglish
Article numbere2000779
Number of pages29
JournalPLoS Biology
Volume15
Issue number5
DOIs
Publication statusPublished - 16 May 2017

Bibliographical note

13-Apr-17

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    Kirchner, S., Cai, Z., Rauscher, R., Kastelic, N., Anding, M., Czech, A., Kleizen, B., Ostegaard, L., Braakman, I., Sheppard, D., & Ignatova, Z. (2017). Alteration of protein function by a silent polymorphism linked to tRNA abundance. PLoS Biology, 15(5), [e2000779]. https://doi.org/10.1371/journal.pbio.2000779