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

PLoS Biol. 2017 May 16;15(5):e2000779. doi: 10.1371/journal.pbio.2000779. eCollection 2017 May.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Polymorphism, Single Nucleotide
  • Protein Stability
  • RNA, Transfer / metabolism*
  • Silent Mutation*
  • Structure-Activity Relationship

Substances

  • Cystic Fibrosis Transmembrane Conductance Regulator
  • RNA, Transfer

Grants and funding

CF Trust https://www.cysticfibrosis.org.uk/ (grant number PJ554 and SRC 005). Received by DNS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CF Foundation https://www.cff.org/ (grant number BRAAKM08XX0 and BRAAKM14XX0). Received by IB. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH https://www.nih.gov/ (grant number HL091842 and HL51670). Supported LSO. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CF Foundation, Research Development program https://www.cff.org/ (grant number OSTEDG1410). Received by LSO. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. University of Pittsburgh Cancer Institute (UPCI) Health Sciences Tissue bank service https://www.nih.gov/ (grant number P30CA047904). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. DFG www.dfg.de (grant number SFB 740 and FOR 1805). Received by ZI. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Mukoviscidose e.V. https://muko.info/english/mukoviszidose-ev.html (grant number 1603). Received by ZI. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. CF Foundation https://www.cff.org/ (grant number SHEPPA14XX0). Received by DNS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.