title: The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain.
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.
authors.affiliation: Department of Chemistry, Faculty of Science, Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Hoelen
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kleizen
authors.forename: Andre
authors.initials: A
authors.lastname: Schmidt
authors.forename: John
authors.initials: J
authors.lastname: Richardson
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Charitou
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thomas
authors.forename: Ineke
authors.initials: I
authors.lastname: Braakman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics*; D005816:Genetic Complementation Test; D015316:Genetic Therapy; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D014176:Protein Biosynthesis; D017510:Protein Folding; D017386:Sequence Homology, Amino Acid
chemical_list: C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator