Cystic fibrosis (CF) is the most prevalent genetic condition in the Caucasian population that is caused by the impaired functional expression of a trans-membrane chloride ion channel, Cystic Fibrosis Trans-membrane conductance Regulator (CFTR). The defective channel retards salt and water transport at the apical membrane of epithelial cells. CFTR is a multi-domain integral membrane protein that belongs to the ABC transporter super-family. It contains two membrane spanning domains (MSD), two cytosolic nucleotide binding domains (NBD) and a regulatory domain (R) connecting the N- and C-terminal halves of the channel. Newly synthesized CFTR undergoes post-translation modification in the endoplasmic reticulum (ER) and is passed to the Golgi apparatus to complete its conformational maturation before being targeted to the cell surface. However, more than 50% of the newly synthesized wild-type CFTR is identified for degradation by the ER quality control mechanism due to misfolding. This makes CFTR very sensitive to the structural influence of genetic mutation on its folding mechanics during maturation and translocation from the cytoplasm to cell membrane. In fact, the most common CF-causing mutation results from the deletion of a single phenylalanine residue at position 508 (∆F508) in the cytosolic NBD1 domain. The ∆F508 mutation causes localized misfolding within NBD1, which in turn, destabilizes the interaction of NBD1 with the MSD1, MSD2 and NBD2. The folding defect in ∆F508-CFTR limits its translocation to the apical membrane and it is retained in the ER where it is targeted for degradation. This provides strong evidence that a local unfolding event within NBD1 disrupts a long-range cooperative folding mechanism, which is responsible for the conformational maturation of CFTR.

Research>Cancer Metabolism > Cystic Fibrosis > Bioluminescence