Stabilizing rescued surface-localized ?f508 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 (?F508), 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 ?F508. Here, we demonstrate the significance of protein-protein interactions in enhancing the stability of the ?F508 CFTR mutant channel protein at the plasma membrane. We determined that VX-809 prolongs the stability of ?F508 CFTR at the plasma membrane. Using competition-based assays, we demonstrated that ?F508 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 ?F508 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.

SUBMITTER: Arora K 

PROVIDER: S-EPMC4081048 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature