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Alteration of protein function by a silent polymorphism linked to tRNA abundance
- Source :
- PLoS Biology, 15(5). Public Library of Science, PLoS Biology, PLoS Biology, Vol 15, Iss 5, p e2000779 (2017), 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, vol. 15, no. 5, e2000779 . https://doi.org/10.1371/journal.pbio.2000779
- Publication Year :
- 2017
-
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.<br />Author summary Synonymous single nucleotide polymorphisms (sSNPs) occur at high frequency in the human genome and are associated with ~50 diseases in humans; the responsible molecular mechanisms remain enigmatic. Here, we investigate the impact of the common sSNP, T2562G, on cystic fibrosis transmembrane conductance regulator (CFTR). Although this sSNP, by itself, does not cause cystic fibrosis (CF), it is prevalent in patients with CFTR-related disorders. T2562G sSNP modifies the local translation speed at the Thr854 codon, leading to changes in CFTR stability and channel function. This sSNP introduces a codon pairing to a low-abundance tRNA, which is particularly rare in human bronchial epithelia, but not in other human tissues, suggesting a tissue-specific effect of this sSNP. Enhancement of the cellular concentration of the tRNA cognate to the mutant ACG codon rescues the stability and conduction defects of T2562G-CFTR. These findings reveal an unanticipated mechanism—inverting the programmed local speed of mRNA translation in a tRNA-dependent manner—for sSNP-associated diseases.
- Subjects :
- 0301 basic medicine
Cystic Fibrosis
Pulmonology
Cultured tumor cells
Gene Expression
Cystic Fibrosis Transmembrane Conductance Regulator
Ribosome
Biochemistry
0302 clinical medicine
Protein structure
Single Channel Recording
RNA, Transfer
Medicine and Health Sciences
Biology (General)
Membrane Electrophysiology
Genetics
Protein Stability
General Neuroscience
Messenger RNA
Translation (biology)
Cystic fibrosis transmembrane conductance regulator
Nucleic acids
Bioassays and Physiological Analysis
Genetic Diseases
Transfer RNA
Cell lines
Cellular Structures and Organelles
General Agricultural and Biological Sciences
Biological cultures
Research Article
Silent mutation
QH301-705.5
Biology
Research and Analysis Methods
Transfection
Polymorphism, Single Nucleotide
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Structure-Activity Relationship
Autosomal Recessive Diseases
Humans
HeLa cells
Non-coding RNA
Molecular Biology Techniques
Molecular Biology
Institut für Biochemie und Biologie
Silent Mutation
Clinical Genetics
General Immunology and Microbiology
Biology and life sciences
Electrophysiological Techniques
RNA
Cell Biology
Cell cultures
Fibrosis
030104 developmental biology
HEK293 Cells
biology.protein
Protein Translation
Ribosomes
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 15449173
- Database :
- OpenAIRE
- Journal :
- PLoS Biology, 15(5). Public Library of Science, PLoS Biology, PLoS Biology, Vol 15, Iss 5, p e2000779 (2017), 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, vol. 15, no. 5, e2000779 . https://doi.org/10.1371/journal.pbio.2000779
- Accession number :
- edsair.doi.dedup.....04c87fd721c083034c2c6f0e47cd3467