The molecular evolution of function in the CFTR chloride channel

• Type of Material: Article
• Authors: Daniel T Infield, University of Iowa; Kerry M Strickland, Mercer University; Amit Gaggar, University of Alabama Birmingham; Nael McCarty, Emory University
• Language: English
• Date: 2021-10-14
• Publisher: ROCKEFELLER UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Infield et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1085/jgp.202012625
• Title of Journal or Parent Work: JOURNAL OF GENERAL PHYSIOLOGY
• Volume: 153
• Issue: 12
• Grant/Funding Information: This work was supported by the National Institutes of Health (HL102371 to A. Gaggar and HL149184 to D.T. Infield), the Cystic Fibrosis Foundation (MCCART17G0 and MCCART18G0 to N.A. McCarty), and the Marcus Professorship in Cystic Fibrosis (to N.A. McCarty).
• Keywords: TRANSMEMBRANE CONDUCTANCE REGULATOR; Life Sciences & Biomedicine; Science & Technology; ATP-BINDING; RESISTANCE PROTEIN MRP1; Physiology; CYSTIC-FIBROSIS; GENOME PROVIDES INSIGHTS; NUCLEOTIDE-BINDING DOMAIN; DEPENDENT HCO3-TRANSPORT; WALKER-B MOTIF; EXTRACELLULAR LOOP 1; CHARGED AMINO-ACIDS
• Research Categories: Chemistry, General

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.