CFTR activity involves binding of the RD to the front half of CFTR

Cystic fibrosis (CF), a life-threatening genetic disease affecting one in every 3,600 children born in Canada, is caused by defects in the CFTR protein. One part of this protein, called regulatory region (R-region), is responsible for its function. The R-region contains amino acids that work like "on/off switches" called phosphorylation sites. These sites are critical for the good functioning of the CFTR protein. Understanding the mechanism by which the CFTR protein function in the cell is necessary to develop strategies to correct deficient CFTR proteins that cause CF disease. In this study we use engineered CFTR proteins broken up in three parts (front half-FH; back half-BH and R-region) to investigate the R-region interactions with the rest of the protein. we use techniques based on fluorescence to detect each time the R-region interacts with other parts of the CFTR protein. We found that the R-region strongly interacts with the front half of CFTR, at a specific location called the lasso motif, after being primed by phosphorylation We also found that one particular phosphorylation site (S686) is the most critical site of interaction with the R-region. This explains how the CFTR protein functions. Our data provide important fundamental knowledge that could be used to develop new drugs to treat CF patients by targeting the molecular root of the disease, the CFTR channel.