Folding correctors can retore CFTR post-translational folding landscape by allosteric domain-domain coupling

Numerous missense mutations cause misfolding and premature degradation of ATP-binding cassette (ABC)-transporters-transporters, accounting for several human conformational diseases with poorly under-stood molecular mechanisms. Recent breakthroughs in small molecule combination therapy led transformative improvement of patients’ outlook in cystic fibrosis (CF), caused by several mutations, including the most prevalent deletion of the F508 (delF508) in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, a member of the large ABC-transporter superfamily. By relying on hydrogen deuterium exchange mass spectrometry (HDX-MS), molecular dynamic simulations and biochemical techniques, we demonstrate that the recently approved pharmacophores (VX-445 [elexacaftor] and/or VX-809 [lumacaftor]) mechanism of action relies on a complex network of dynamic inter-domain allosteric interactions to restore the post-translational coupled domain folding and the final fold stability of mutant CFTRs.