title: Stabilizing rescued surface-localized δf508 CFTR by potentiation of its interaction with Na(+)/H(+) exchanger regulatory factor 1.
abstract: Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in CFTR, a plasma-membrane-localized anion channel. The most common mutation in CFTR, deletion of phenylalanine at residue 508 (ΔF508), causes misfolding of CFTR resulting in little or no protein at the plasma membrane. The CFTR corrector VX-809 shows promise for treating CF patients homozygous for ΔF508. Here, we demonstrate the significance of protein-protein interactions in enhancing the stability of the ΔF508 CFTR mutant channel protein at the plasma membrane. We determined that VX-809 prolongs the stability of ΔF508 CFTR at the plasma membrane. Using competition-based assays, we demonstrated that ΔF508 CFTR interacts poorly with Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) compared to wild-type CFTR, and VX-809 significantly increased this binding affinity. We conclude that stabilized CFTR-NHERF1 interaction is a determinant of the functional efficiency of rescued ΔF508 CFTR. Our results demonstrate the importance of macromolecular-complex formation in stabilizing rescued mutant CFTR at the plasma membrane and suggest this to be foundational for the development of a new generation of effective CFTR-corrector-based therapeutics.
authors.affiliation: Division of Pulmonary Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center , MLC2021 3333 Burnet Avenue, Cincinnati, Ohio 45229, United States.
authors.forename: Kavisha
authors.initials: K
authors.lastname: Arora
authors.forename: Changsuk
authors.initials: C
authors.lastname: Moon
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhang
authors.forename: Sunitha
authors.initials: S
authors.lastname: Yarlagadda
authors.forename: Himabindu
authors.initials: H
authors.lastname: Penmatsa
authors.forename: Aixia
authors.initials: A
authors.lastname: Ren
authors.forename: Chandrima
authors.initials: C
authors.lastname: Sinha
authors.forename: Anjaparavanda P
authors.initials: AP
authors.lastname: Naren
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D011487:Protein Conformation; D055550:Protein Stability; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor