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Updated: Oct 17, 2025
09:59
Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
12.3K
The molecular evolution of function in the CFTR chloride channel
Daniel T Infield1, Kerry M Strickland2, Amit Gaggar3,4,5,6
1Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA.
The Journal of General Physiology
|October 14, 2021
Summary
The cystic fibrosis transmembrane conductance regulator (CFTR) evolved from substrate transporters to become an ion channel. This transition involved repurposing existing features for regulated channel activity, crucial for treating cystic fibrosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- The ATP-binding cassette (ABC) transporter superfamily is vital in all life domains.
- Most ABC transporters are active transporters; however, cystic fibrosis transmembrane conductance regulator (CFTR) is a unique animal ABC transporter functioning as an ion channel.
- CFTR defects cause cystic fibrosis, a severe genetic disorder.
Purpose of the Study:
- To investigate the evolutionary path of CFTR from a transporter to a regulated ion channel.
- To integrate structural, functional, and genomic data to understand CFTR's channel evolution.
- To identify key molecular adaptations enabling CFTR's ion channel function.
Main Methods:
- Comparative analysis of structural, functional, and genomic data.
- Examination of conserved and divergent features within the ABCC subfamily.
- Integration of evolutionary principles to explain functional transitions.
Main Results:
- Pre-existing features in ABCC transporters were adapted for CFTR's channel function.
- Evolutionary modifications facilitated the creation of an anionic pore, phosphoregulation, and ligand-channel interactions.
- Understanding these evolutionary steps provides insights into CFTR modulator pharmacology.
Conclusions:
- CFTR's ion channel function arose from the repurposing and modification of ancestral transporter features.
- Specific adaptations, including pore construction and regulatory mechanisms, were critical for CFTR's evolution.
- This evolutionary perspective aids in developing targeted CFTR modulator therapies.
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