A topological switch in CFTR modulates channel activity and sensitivity to unfolding

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due mutations the cftr gene leads fibrosis. Here, we show that first nucleotide-binding domain (NBD1) can spontaneously adopt an alternate conformation departs from canonical NBD fold previously observed. Crystallography reveals this involves a topological reorganization NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows equilibrium between conformations regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as disease-causing mutation F508del, conformational flexibility enables unfolding ?-subdomain. Our data indicate that, wild-type CFTR, transition NBD1 regulates function, but, presence F508del mutation, it allows misfolding and subsequent protein degradation. work provides framework design conformation-specific therapeutics prevent noxious transitions. its domain, which affects activity and, certain