RT Journal Article
SR Electronic
T1 Folding–function relationship of the most common cystic fibrosis–causing CFTR conductance mutants
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800172
DO 10.26508/lsa.201800172
VO 2
IS 1
A1 Marcel van Willigen
A1 Annelotte M Vonk
A1 Hui Ying Yeoh
A1 Evelien Kruisselbrink
A1 Bertrand Kleizen
A1 Cornelis K van der Ent
A1 Maarten R Egmond
A1 Hugo R de Jonge
A1 Ineke Braakman
A1 Jeffrey M Beekman
A1 Peter van der Sluijs
YR 2019
UL https://www.life-science-alliance.org/content/2/1/e201800172.abstract
AB 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.