Understanding CFTR Functionality: A Comprehensive Review of Tests and Modulator Therapy in Cystic Fibrosis

Thakur, Shorya; Ankita,; Dash, Shubham; Verma, Rupali; Kaur, Charanjit; Kumar, Rajesh; Mazumder, Avijit; Singh, Gurvinder

doi:10.1007/s12013-023-01200-w

Cited by 5 publications

(1 citation statement)

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“…Malfunctioning or down regulation of CFTR channels trap chloride ions within cells, preventing the crucial hydration of cellular surfaces. This dehydration triggers the formation of thick and viscous mucus that can obstruct airways and cause various symptoms associated with cystic fibrosis (CF) (3, 4), such as chronic sinusitis, nasal polyps, bronchiectasis, primary sclerosing cholangitis, recurrent pancreatitis, and cervical mucus abnormality (5). CFTR belongs to ATP Binding Cassette (ABC) protein family, harboring two transmembrane domains (TMDs) that form the channel pore, each followed by a cytosolic NBD.…”

Section: Introductionmentioning

confidence: 99%

Probing Phosphorylation-Induced Vibrational Couplings in CFTR by 2D IR Spectra Simulations

Zhu,

Chen,

Zhao

et al. 2024

Preprint

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Phosphorylation of the regulator (R) domain underlies the basis for gating in the human cystic fibrosis transmembrane conductance regulator (CFTR), malfunction or down regulation of CFTR leads to defective apical chloride transport. The biophysical mechanism that underlies the regulatory effect of R domain is still unclear. Here, we utilize a combination of molecular dynamics simulations and theoretically calculated two-dimensional infrared (2D IR) spectra to probe both the structure and spectral signature of phosphorylated and unphosphorylated CFTR. We uncover an ATP-independent asymptotic movement of nucleotide binding domains (NBDs) driven by phosphorylated R domain. Utilizing non-rephasing cross ground-state bleach infrared (GB IR) spectra simulation, we overcome the interpretation hurdle caused by overlaps of multiple vibrational modes, and find distinct vibrational couplings induced by phosphorylation. By calculating exciton eigenfrequencies, we pinpoint specific vibrational couplings to individual amide I modes (carbonyl stretches), unveiling a critical role of serine residues in modulating the coupling state of neighboring amino acids. Our findings offer a bond-specific perspective on how intramolecular interactions within the R domain translate into its broader regulatory function.

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Section: Introductionmentioning

confidence: 99%