TY - JOUR T1 - Folding–function relationship of the most common cystic fibrosis–causing CFTR conductance mutants JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201800172 VL - 2 IS - 1 SP - e201800172 AU - Marcel van Willigen AU - Annelotte M Vonk AU - Hui Ying Yeoh AU - Evelien Kruisselbrink AU - Bertrand Kleizen AU - Cornelis K van der Ent AU - Maarten R Egmond AU - Hugo R de Jonge AU - Ineke Braakman AU - Jeffrey M Beekman AU - Peter van der Sluijs Y1 - 2019/02/01 UR - https://www.life-science-alliance.org/content/2/1/e201800172.abstract N2 - Cystic fibrosis is caused by mutations in the CFTR gene, which are subdivided into six classes. Mutants of classes III and IV reach the cell surface but have limited function. Most class-III and class-IV mutants respond well to the recently approved potentiator VX-770, which opens the channel. We here revisited function and folding of some class-IV mutants and discovered that R347P is the only one that leads to major defects in folding. By this criterion and by its functional response to corrector drug VX-809, R347P qualifies also as a class-II mutation. Other class-IV mutants folded like wild-type CFTR and responded similarly to VX-809, demonstrating how function and folding are connected. Studies on both types of defects complement each other in understanding how compounds improve mutant CFTR function. This provides an attractive unbiased approach for characterizing mode of action of novel therapeutic compounds and helps address which drugs are efficacious for each cystic fibrosis disease variant. ER -