The primary folding defect and rescue of δf508 CFTR emerge during translation of the mutant domain

Hanneke Hoelen, Sbertrand Kleizen, Andre Schmidt, John Richardson, Paraskevi Charitou, Philip J. Thomas, Ineke Braakman

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Abstract

In the vast majority of cystic fibrosis (CF) patients, deletion of residue F508 from CFTR is the cause of disease. F508 resides in the first nucleotide binding domain (NBD1) and its absence leads to CFTR misfolding and degradation. We show here that the primary folding defect arises during synthesis, as soon as NBD1 is translated. Introduction of either the I539T or G550E suppressor mutation in NBD1 partially rescues ΔF508 CFTR to the cell surface, but only I539T repaired ΔF508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length ΔF508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of ΔF508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis.

Original languageEnglish (US)
Article numbere15458
JournalPloS one
Volume5
Issue number11
DOIs
StatePublished - Dec 10 2010

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Hoelen, H., Kleizen, S., Schmidt, A., Richardson, J., Charitou, P., Thomas, P. J., & Braakman, I. (2010). The primary folding defect and rescue of δf508 CFTR emerge during translation of the mutant domain. PloS one, 5(11), [e15458]. https://doi.org/10.1371/journal.pone.0015458