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 S Ostedgaard; Ineke Braakman; David N Sheppard; Zoya Ignatova

doi:10.1371/journal.pbio.2000779

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

Journal article

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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 S Ostedgaard, Ineke Braakman, David N Sheppard, …

PLoS biology, Vol.15(5), pp.e2000779-e2000779

05/2017

DOI: 10.1371/journal.pbio.2000779

PMCID: PMC5433685

PMID: 28510592

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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.

Silent Mutation

RNA, Transfer - metabolism

Humans

HEK293 Cells

Cystic Fibrosis Transmembrane Conductance Regulator - genetics

Cystic Fibrosis Transmembrane Conductance Regulator - metabolism

Polymorphism, Single Nucleotide

Structure-Activity Relationship

HeLa Cells

Protein Stability

Details

Title: Subtitle: Alteration of protein function by a silent polymorphism linked to tRNA abundance
Creators: Sebastian Kirchner - Biochemistry, Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany
Zhiwei Cai - School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
Robert Rauscher - Institute for Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, Hamburg, Germany
Nicolai Kastelic - Biochemistry, Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany
Melanie Anding - Biochemistry, Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany
Andreas Czech - Institute for Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, Hamburg, Germany
Bertrand Kleizen - Cellular Protein Chemistry, Department of Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands
Lynda S Ostedgaard - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States of America
Ineke Braakman - Cellular Protein Chemistry, Department of Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands
David N Sheppard - School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom
Zoya Ignatova - Institute for Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, Hamburg, Germany
Resource Type: Journal article
Publication Details: PLoS biology, Vol.15(5), pp.e2000779-e2000779
DOI: 10.1371/journal.pbio.2000779
PMID: 28510592
PMCID: PMC5433685
NLM abbreviation: PLoS Biol
ISSN: 1544-9173
eISSN: 1545-7885
Language: English
Date published: 05/2017
Academic Unit: Internal Medicine
Record Identifier: 9984094383102771

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