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Alteration of protein function by a silent polymorphism linked to tRNA abundance
- 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.
Author details: | Sebastian Kirchner, Zhiwei Cai, Robert Rauscher, Nicolai Kastelic, Melanie Anding, Andreas Czech, Bertrand Kleizen, Lynda S. Ostedgaard, Ineke BraakmanORCiD, David N. Sheppard, Zoya Ignatova |
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DOI: | https://doi.org/10.1371/journal.pbio.2000779 |
ISSN: | 1545-7885 |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/28510592 |
Title of parent work (English): | PLoS biology |
Publisher: | PLoS |
Place of publishing: | San Fransisco |
Publication type: | Article |
Language: | English |
Year of first publication: | 2017 |
Publication year: | 2017 |
Release date: | 2020/04/20 |
Volume: | 15 |
Number of pages: | 29 |
Funding institution: | CF Trust [PJ554, SRC 005]; CF Foundation [BRAAKM08XX0, BRAAKM14XX0, SHEPPA14XX0]; NIH [HL091842, HL51670]; CF Foundation, Research Development program [OSTEDG1410]; University of Pittsburgh Cancer Institute (UPCI) Health Sciences Tissue bank [P30CA047904]; DFG [SFB 740, FOR 1805]; Mukoviscidose e.V. [1603] |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
Peer review: | Referiert |