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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2021
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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. |
format | Online Article Text |
id | pubmed-8640958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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