Structural and Proteostatic Mechanisms of Cystic Fibrosis Corrector Response

Abstract

Cystic fibrosis (CF) is a lethal genetic disease caused by mutations in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), an epithelial anion channel protein. CFTR variants disrupt CFTR protein folding, leading to premature degradation. Lack of CFTR causes defective anion transport in the lungs and other organs, leading to poor mucus recycling which becomes infected. The emergence of small molecule correctors has transformed CF therapy by stabilizing CFTR structural defects and promoting proper folding. However, the efficacy of correctors varies widely amongst different CFTR variants, necessitating a deeper understanding of variant-specific responses or theratypes. Recent research has shed light on the intricate interplay between CFTR structural defects, proteostasis factors in protein quality control, and correctors mechanisms. These insights have paved the way for personalized medicine approaches in CF treatment, yet a rational application of correctors to specific variants is lacking. Here, we used interactomics and computational modeling to delineate the molecular mechanisms underlying variant-specific responses to correctors. Proteostasis profiling elucidated the impact of correctors on mutant CFTR interactions with degradation machinery, while computational modeling showed stabilization of corrector binding pockets. We revealed selectively responsiveness variants to specific correctors are proximate to the corrector binding site, while others remain non-responsive. Future research directions include the classification of non-responsive variants and the prediction of corrector responses based on sequence, with the goal of expanding therapeutic options for all individuals with CF.