Conformational changes opening and closing the CFTR chloride channel

Cystic fibrosis is a common, fatal hereditary disease that occurs in children who inherit a mutant gene from each of their parents. Only one gene is involved, and this gene controls the production of a protein called CFTR that is found in the membrane surrounding cells in the lungs, pancreas, sweat glands, reproductive system, and other organs. The role of CFTR is to allow salt and water to move across the cell membrane, which is important in controlling fluid secretion by each of these organs. When secretion doesn't occur in cystic fibrosis, thick, sticky mucus builds up that stops these organs from functioning properly. Research in my lab uses precise electrical recording techniques to study the movement of chloride ions, one component of salt, as they move through CFTR and across the cell membrane. We hope to understand how CFTR moves chloride and how this process is disrupted by mutations in cystic fibrosis. To understand how the CFTR protein molecule works, we change its structure by introducing designed changes into the gene. Normal and mutated forms of CFTR are then introduced into cells growing in culture in the lab, allowing any changes in the way the CFTR protein works to be investigated in fine detail using electrical recordings. We are particularly interested in the ways in which the 3-dimensional shape of an individual CFTR protein molecule changes as it goes about its normal function of moving chloride across the membrane. These structural rearrangements are a necessary part of CFTR function, and drugs that influence these rearrangements are able to increase CFTR activity in cystic fibrosis patients and thereby improve disease symptoms. We believe that understanding the ways in which the CFTR protein rearranges itself during chloride transport is key to developing new drugs to improve CFTR function and so bring relief to people suffering with cystic fibrosis.