ArticleProceedings of the National Academy of Sciences of the United States of America2012
Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Establishment and Phenotypic Analysis of the Novel Gaucher Disease Mouse Model With the Partially HumanizedFrontiers in genetics · 2022Article
- On the Corner of Models and Cure: Gene Editing in Cystic Fibrosis.Frontiers in pharmacology · 2021Review
- Activity of lumacaftor is not conserved in zebrafish Cftr bearing the major cystic fibrosis-causing mutation.FASEB bioAdvances · 2019Article
- VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level.Scientific reports · 2019Article
- Differential thermostability and response to cystic fibrosis transmembrane conductance regulator potentiators of human and mouse F508del-CFTR.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- Ligand binding to a remote site thermodynamically corrects the F508del mutation in the human cystic fibrosis transmembrane conductance regulator.The Journal of biological chemistry · 2018Article
- Functional characterization reveals that zebrafish CFTR prefers to occupy closed channel conformations.PloS one · 2018Article
- Altering intracellular pH reveals the kinetic basis of intraburst gating in the CFTR ClThe Journal of physiology · 2017Article
- Potentiators exert distinct effects on human, murine, and Xenopus CFTR.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Impact of the F508del mutation on ovine CFTR, a Cl- channel with enhanced conductance and ATP-dependent gating.The Journal of physiology · 2015Article
- Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia.The Journal of biological chemistry · 2015Article
- Interference with ubiquitination in CFTR modifies stability of core glycosylated and cell surface pools.Molecular and cellular biology · 2014Article
- Membrane protein stability can be compromised by detergent interactions with the extramembranous soluble domains.Protein science : a publication of the Protein Society · 2014Article
- Revertant mutants modify, but do not rescue, the gating defect of the cystic fibrosis mutant G551D-CFTR.The Journal of physiology · 2014Article
- The silent codon change I507-ATC->ATT contributes to the severity of the ΔF508 CFTR channel dysfunction.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2013Article
- CFTR mutations altering CFTR fragmentation.The Biochemical journal · 2013Article
- Allosteric coupling between the intracellular coupling helix 4 and regulatory sites of the first nucleotide-binding domain of CFTR.PloS one · 2013Article
- Article
- Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR.Journal of molecular biology · 2012Article
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Authors and funding
6 authors.
Funding
Abstract
The ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the most common cause of cystic fibrosis. The mutation disrupts biosynthetic processing, reduces channel opening rate, and decreases protein lifetime. In contrast to human CFTR (hCFTR)-ΔF508, mouse CFTR-ΔF508 is partially processed to the cell surface, although it exhibits a functional defect similar to hCFTR-ΔF508. To explore ΔF508 abnormalities, we generated human-mouse chimeric channels. Substituting mouse nucleotide-binding domain-1 (mNBD1) into hCFTR partially rescued the ΔF508-induced maturation defect, and substituting mouse membrane-spanning domain-2 or its intracellular loops (ICLs) into hCFTR prevented further ΔF508-induced gating defects. The protective effect of the mouse ICLs was reverted by inserting mouse NBDs. Our results indicate that the ΔF508 mutation affects maturation and gating via distinct regions of the protein; maturation of CFTR-ΔF508 depends on NBD1, and the ΔF508-induced gating defect depends on the interaction between the membrane-spanning domain-2 ICLs and the NBDs. These appear to be distinct processes, because none of the chimeras repaired both defects. This distinction was exemplified by the I539T mutation, which improved CFTR-ΔF508 processing but worsened the gating defect. Our results, together with previous studies, suggest that many different NBD1 modifications improve CFTR-ΔF508 maturation and that the effect of modifications can be additive. Thus, it might be possible to enhance processing by targeting several different regions of the domain or by targeting a network of CFTR-associated proteins. Because no one modification corrected both maturation and gating, perhaps more than a single agent will be required to correct all CFTR-ΔF508 defects.
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