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Decoding F508del Misfolding in Cystic Fibrosis

The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the disease. T...

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Autores principales: Wang, Xiaodong Robert, Li, Chenglong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101494/
https://www.ncbi.nlm.nih.gov/pubmed/24970227
http://dx.doi.org/10.3390/biom4020498
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author Wang, Xiaodong Robert
Li, Chenglong
author_facet Wang, Xiaodong Robert
Li, Chenglong
author_sort Wang, Xiaodong Robert
collection PubMed
description The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the disease. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1’s interactions with other domains. Such global misfolding produces a mutant chloride channel that is impaired in exocytic trafficking, peripheral stability, and channel gating. The nature and atomic details of F508del misfolding have been subject to extensive research during the past decade. Current data support a central role for NBD1 in F508del misfolding and rescue. Many cis-acting NBD1 second-site mutations rescue F508del misfolding in the context of full-length CFTR. While some of these mutations appear to specifically counteract the F508del-induced misfolding, others release certain inherent conformational constraints of the human wild-type CFTR. Several small-molecule correctors were recently found to act on key interdomain interfaces of F508del CFTR. Potential rational approaches have been proposed in an attempt to develop highly effective small molecule modulators that improve the cell surface functional expression of F508del CFTR.
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spelling pubmed-41014942014-07-28 Decoding F508del Misfolding in Cystic Fibrosis Wang, Xiaodong Robert Li, Chenglong Biomolecules Review The functional deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR), a plasma membrane chloride channel, leads to the development of cystic fibrosis. The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the disease. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1’s interactions with other domains. Such global misfolding produces a mutant chloride channel that is impaired in exocytic trafficking, peripheral stability, and channel gating. The nature and atomic details of F508del misfolding have been subject to extensive research during the past decade. Current data support a central role for NBD1 in F508del misfolding and rescue. Many cis-acting NBD1 second-site mutations rescue F508del misfolding in the context of full-length CFTR. While some of these mutations appear to specifically counteract the F508del-induced misfolding, others release certain inherent conformational constraints of the human wild-type CFTR. Several small-molecule correctors were recently found to act on key interdomain interfaces of F508del CFTR. Potential rational approaches have been proposed in an attempt to develop highly effective small molecule modulators that improve the cell surface functional expression of F508del CFTR. MDPI 2014-05-06 /pmc/articles/PMC4101494/ /pubmed/24970227 http://dx.doi.org/10.3390/biom4020498 Text en © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Review
Wang, Xiaodong Robert
Li, Chenglong
Decoding F508del Misfolding in Cystic Fibrosis
title Decoding F508del Misfolding in Cystic Fibrosis
title_full Decoding F508del Misfolding in Cystic Fibrosis
title_fullStr Decoding F508del Misfolding in Cystic Fibrosis
title_full_unstemmed Decoding F508del Misfolding in Cystic Fibrosis
title_short Decoding F508del Misfolding in Cystic Fibrosis
title_sort decoding f508del misfolding in cystic fibrosis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101494/
https://www.ncbi.nlm.nih.gov/pubmed/24970227
http://dx.doi.org/10.3390/biom4020498
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