Requirements for efficient correction of ?F508 CFTR revealed by analyses of evolved sequences.

ABSTRACT: Misfolding of ?F508 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 ?F508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ?F508 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.

SUBMITTER: Mendoza JL 

PROVIDER: S-EPMC3266553 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature