The Primary Folding Defect and Rescue of ΔF508 CFTR Emerge during Translation of the Mutant Domain

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 Delta F508 CFTR to the cell surface, but only I539T repaired Delta F508 NBD1. We demonstrated rescue of folding and stability of NBD1 from full-length Delta F508 CFTR expressed in cells to isolated purified domain. The co-translational rescue of Delta F508 NBD1 misfolding in CFTR by I539T advocates this domain as the most important drug target for cystic fibrosis.