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Updated: Oct 17, 2025
Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
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.
Abstract:
The ATP-binding cassette (ABC) transporter superfamily includes many proteins of clinical relevance, with genes expressed in all domains of life. Although most members use the energy of ATP binding and hydrolysis to accomplish the active import or export of various substrates across membranes, the cystic fibrosis transmembrane conductance regulator (CFTR) is the only known animal ABC transporter that functions primarily as an ion channel. Defects in CFTR, which is closely related to ABCC subfamily members that bear function as bona fide transporters, underlie the lethal genetic disease cystic fibrosis. This article seeks to integrate structural, functional, and genomic data to begin to answer the critical question of how the function of CFTR evolved to exhibit regulated channel activity. We highlight several examples wherein preexisting features in ABCC transporters were functionally leveraged as is, or altered by molecular evolution, to ultimately support channel function. This includes features that may underlie (1) construction of an anionic channel pore from an anionic substrate transport pathway, (2) establishment and tuning of phosphoregulation, and (3) optimization of channel function by specialized ligand-channel interactions. We also discuss how divergence and conservation may help elucidate the pharmacology of important CFTR modulators.
Insights
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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