Folding-function relationship of the most common cystic fibrosis-causing CFTR conductance mutants

Life Sci Alliance. 2019 Jan 18;2(1):e201800172. doi: 10.26508/lsa.201800172. Print 2019 Feb.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Aminophenols / pharmacology
  • Aminopyridines / pharmacology
  • Benzodioxoles / pharmacology
  • Biopsy
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / pathology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry*
  • Cystic Fibrosis Transmembrane Conductance Regulator / classification
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Genotype
  • HEK293 Cells
  • Humans
  • Mutation
  • Organoids / drug effects
  • Protein Folding / drug effects*
  • Protein Structure, Tertiary / drug effects
  • Quinolones / pharmacology
  • Rectum / pathology
  • Transfection


  • Aminophenols
  • Aminopyridines
  • Benzodioxoles
  • CFTR protein, human
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor
  • lumacaftor

Associated data

  • PDB/5UAK