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

PLoS Biology
Sebastian KirchnerZoya Ignatova

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.

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Datasets Mentioned

BETA
GSE53991
GSE74365

Methods Mentioned

BETA
protein folding
PCR
transfection
phosphotransferase
electrophoresis
ubiquitination
biopsies
Chips
deamination
Chip

Software Mentioned

Prism
cutadapt
Bowtie
fastx
GraphPad
GenPix Pro
- toolkit
pCLAMP
SigmaPlot

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