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The molecular evolution of function in the CFTR chloride channel

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 c...

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Autores principales: Infield, Daniel T., Strickland, Kerry M., Gaggar, Amit, McCarty, Nael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640958/
https://www.ncbi.nlm.nih.gov/pubmed/34647973
http://dx.doi.org/10.1085/jgp.202012625
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author Infield, Daniel T.
Strickland, Kerry M.
Gaggar, Amit
McCarty, Nael A.
author_facet Infield, Daniel T.
Strickland, Kerry M.
Gaggar, Amit
McCarty, Nael A.
author_sort Infield, Daniel T.
collection PubMed
description 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.
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spelling pubmed-86409582022-06-06 The molecular evolution of function in the CFTR chloride channel Infield, Daniel T. Strickland, Kerry M. Gaggar, Amit McCarty, Nael A. J Gen Physiol Review 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. Rockefeller University Press 2021-10-14 /pmc/articles/PMC8640958/ /pubmed/34647973 http://dx.doi.org/10.1085/jgp.202012625 Text en © 2021 Infield et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Review
Infield, Daniel T.
Strickland, Kerry M.
Gaggar, Amit
McCarty, Nael A.
The molecular evolution of function in the CFTR chloride channel
title The molecular evolution of function in the CFTR chloride channel
title_full The molecular evolution of function in the CFTR chloride channel
title_fullStr The molecular evolution of function in the CFTR chloride channel
title_full_unstemmed The molecular evolution of function in the CFTR chloride channel
title_short The molecular evolution of function in the CFTR chloride channel
title_sort molecular evolution of function in the cftr chloride channel
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640958/
https://www.ncbi.nlm.nih.gov/pubmed/34647973
http://dx.doi.org/10.1085/jgp.202012625
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