Cystic fibrosis is a genetic disorder associated with recurrent lung infections, poor digestion, stunted growth, and a shortened life expectancy. It is caused by mutation of the gene that encodes the cystic fibrosis transmembrane conductance regulator protein (CFTR), which transports chloride ion across the apical membranes of epithelial cells, particularly in the respiratory and digestive tracts. A well-established but poorly understood clinical observation about cystic fibrosis is that female patients often suffer more severe disease than males. To better understand this phenomenon, Vanderbilt Basic Sciences investigator Chuck Sanders and his collaborators Carlos Vanoye (Northwestern University) and Wade Van Horn (Arizona State University) investigated the structure and function of KCNE3, a potassium channel modulating protein that is required for normal chloride ion transport. KCNE3 binds to the KCNQ1 potassium channel protein to form a dimeric channel that is permanently open. This enables a constant slow leak of potassium ions out of the cell that are then transported back into the with chloride ions. The investigators’ work revealed the three-dimensional structure of KCNE3, allowing them to predict precisely how it interacts with KCNQ1 to promote channel opening. The results also revealed how an estrogen-dependent phosphorylation of a key KCNE3 residue disrupts its interaction with KCNQ1. The latter finding helps to explain why cystic fibrosis is frequently more severe in female patients. Estrogen promotes a post-translational modification of KCNE3 that prevents its ability to maintain an open state of KCNQ1. This effect apparently does not cause problems in healthy individuals, but in cystic fibrosis patients who already suffer from impaired chloride transport, a reduction in the necessary potassium ion-based support mechanism can cause a significant exacerbation of the pathology. The findings provide important fundamental information concerning the function of key ion transport proteins and may lead to new approaches for the treatment of cystic fibrosis. The work is published in the journal Science Advances [B. M. Kroncke, et al. (2016), Sci. Adv., 2, e1501228].