ArticleProceedings of the National Academy of Sciences of the United States of America2007
Chimeric constructs endow the human CFTR Cl- channel with the gating behavior of murine CFTR.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Protein kinase A phosphorylation potentiates cystic fibrosis transmembrane conductance regulator gating by relieving autoinhibition on the stimulatory C terminus of the regulatory domain.The Journal of biological chemistry · 2020Article
- Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2020Review
- 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
- Structural mechanisms of CFTR function and dysfunction.The Journal of general physiology · 2018Review
- Functional characterization reveals that zebrafish CFTR prefers to occupy closed channel conformations.PloS one · 2018Article
- Alteration of protein function by a silent polymorphism linked to tRNA abundance.PLoS biology · 2017Article
- Altering intracellular pH reveals the kinetic basis of intraburst gating in the CFTR ClThe Journal of physiology · 2017Article
- Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants.Cellular and molecular life sciences : CMLS · 2017Review
- Potentiators exert distinct effects on human, murine, and Xenopus CFTR.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- The extracellular calcium-sensing receptor regulates human fetal lung development via CFTR.Scientific reports · 2016Article
- Murine and human CFTR exhibit different sensitivities to CFTR potentiators.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Impact of the F508del mutation on ovine CFTR, a Cl- channel with enhanced conductance and ATP-dependent gating.The Journal of physiology · 2015Article
- Marked repression of CFTR mRNA in the transgenic Cftr(tm1kth) mouse model.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2014Article
- Human-mouse cystic fibrosis transmembrane conductance regulator (CFTR) chimeras identify regions that partially rescue CFTR-ΔF508 processing and alter its gating defect.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Regulatory domain phosphorylation to distinguish the mechanistic basis underlying acute CFTR modulators.American journal of physiology. Lung cellular and molecular physiology · 2011Article
- Mutant cycles at CFTR's non-canonical ATP-binding site support little interface separation during gating.The Journal of general physiology · 2011Article
- Targeting F508del-CFTR to develop rational new therapies for cystic fibrosis.Acta pharmacologica Sinica · 2011Review
- Application of high-resolution single-channel recording to functional studies of cystic fibrosis mutants.Methods in molecular biology (Clifton, N.J.) · 2011Article
- Changes in accessibility of cytoplasmic substances to the pore associated with activation of the cystic fibrosis transmembrane conductance regulator chloride channel.The Journal of biological chemistry · 2010Article
- Folding and rescue of a cystic fibrosis transmembrane conductance regulator trafficking mutant identified using human-murine chimeric proteins.The Journal of biological chemistry · 2010Article
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Authors and funding
11 authors.
Funding
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl(-) channel gated by ATP-driven nucleotide-binding domain (NBD) dimerization. Here we exploit species differences between human and murine CFTR to investigate CFTR channel gating. Using homologous recombination, we constructed human-murine CFTR (hmCFTR) chimeras with sequences from NBD1, NBD2, or the regulatory domain (RD) of human CFTR replaced by the equivalent regions of murine CFTR. The gating behavior of hmRD and human CFTR were indistinguishable, whereas hmNBD1 and hmNBD2 had subtle effects on channel gating, prolonging both burst duration and interburst interval. By contrast, hmNBD1+2, containing both NBDs of murine CFTR, reproduced the gating behavior of the subconductance state of murine CFTR, which has dramatically prolonged channel openings. The CFTR potentiator pyrophosphate (PP(i)) enhanced human, hmRD, and hmNBD1 CFTR Cl(-) currents, but not those of hmNBD2, hmNBD1+2, and murine CFTR. By analyzing the rate-equilibrium free-energy relationships of chimeric channels, we obtained snapshots of the conformation of the NBDs during ATP-driven dimerization. Our data demonstrate that the conformation of NBD1 changes before that of NBD2 during channel opening. This finding suggests that NBD dimerization does not proceed by a symmetric tweezer-like motion, but instead in an asymmetric fashion led by NBD1. We conclude that the NBDs of murine CFTR determine the unique gating behavior of its subconductance state, whereas NBD2 controls channel potentiation by PP(i).
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.