Molecule of the Month: CFTR and Cystic Fibrosis

The cells that line our respiratory system need to manage the flow of ions and water across their membranes, to ensure that our protective coating of mucus is the right consistency. CFTR (cystic fibrosis transmembrane conductance regulator) is a key player in this regulation. It allows negatively-charged ions, such as chloride and bicarbonate, to pass through, and is opened and closed as needed to control the environment of the airway. When this function is blocked, it has dire consequences. Cystic fibrosis is a genetic disease caused by a faulty CFTR gene. The improper function of CFTR leads to thickened mucus, which causes life-threatening airway blockage and chronic lung infections.

CFTR is similar to many cell surface transporters, such as bacterial multidrug resistance transporters and our P-glycoprotein. These transporters have characteristic structures. A membrane-crossing region forms the pore, and two ATP-binding domains on the inside of the cell control its opening and closing. Unlike these other transporters, CFTR also includes a long, disordered loop that is phosphorylated by PKA (cAMP-dependent protein kinase), regulating its activity. CFTR is also unique among these proteins because it acts as an ion channel, allowing ions to pass freely through when it opens. All of the others are transporters that specifically traffic molecules one-at-a-time across the membrane.

Knowledge of CFTR structure and function has spurred the discovery of drugs to treat cystic fibrosis. PDB ID 8eiq includes three drugs that are often used together to treat individuals with the most common disease-causing variant of CFTR. They act in a different manner than most drugs: instead of blocking the action of CFTR, they instead enhance its function. The deletion of a single amino acid in CFTR, phenylalanine 508, destabilizes the protein. This causes many problems. First, when it is synthesized in lung cells, they sense that there is a problem, and destroy most of the protein. So these cells have less of the mutated CFTR on their surface. Second, the destabilized protein is not as effective as an ion pore. The drugs correct both of these problems. Ivacaftor binds to the pore-forming region and enhances the stability and effectiveness of the pore. Elexacaftor and tezacaftor, on the other hand, help with stability of the protein as it’s being constructed, ensuring that more the protein is present on the cell surface.

CFTR is not the only protein that manages the fluid balance of lung airways. Other proteins are also being studied in the hope of finding additional ways to treat cystic fibrosis. The epithelial sodium channel (PDB ID 6bqn) is one example. As indicated in its name, it manages the flow of sodium ions across cell membranes.