title: Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences.
abstract: Misfolding of ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the ΔF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ΔF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.
authors.affiliation: Molecular Biophysics Program, and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Mendoza
authors.forename: André
authors.initials: A
authors.lastname: Schmidt
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nuvaga
authors.forename: Tyler
authors.initials: T
authors.lastname: Barrett
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bridges
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feranchak
authors.forename: Chad A
authors.initials: CA
authors.lastname: Brautigam
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thomas
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013489:Suppression, Genetic
chemical_list: D018528:ATP-Binding Cassette Transporters; C505032:CFTR protein, human; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator