The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Rosenberg, Mark F.; O'Ryan, Liam; Hughes, Guy; Zhao, Zhenqun; Aleksandrov, Luba A.; Riordan, John R.; Ford, Robert C.

doi:10.1074/jbc.m111.292268

Cited by 61 publications

(14 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Qian et al (10) interpreted their results as providing evidence for a gate that lies deeper in the pore from the cytoplasmic side, although there are striking differences between their findings and those of Bai et al (9) that are not easily resolved in terms of differences in experimental conditions. Rosenberg et al (66) interpreted the results of electron diffraction by two-dimensional crystals of CFTR as suggesting a gate roughly at the level of R352, but they also indicate that this could be an artifact produced by detergent bound within the crystals. It seems unlikely, therefore, that the CFTR gate lies at the most cytoplasmic extent of the transmembrane segments.…”

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator: A Molecular Model Defines the Architecture of the Anion Conduction Path and Locates a “Bottleneck” in the Pore

et al. 2012

View full text Add to dashboard Cite

We developed molecular models for the CFTR chloride channel based on the prokaryotic ABC transporter, Sav1866. Here we analyze predicted pore geometry and side-chain orientations for TMs 3, 6, 9 and 12; with particular attention to the location of the rate-limiting barrier for anion conduction. Side-chain orientations assayed by cysteine scanning were found to be from 77% to 90% in accord with model predictions. The predicted geometry of the anion conduction path was defined by a space-filling model of the pore and confirmed by visualizing the distribution of water molecules from a molecular dynamics (MD) simulation. Pore shape is that of an asymmetric hour glass, comprising a shallow outward-facing vestibule that tapers rapidly toward a narrow “bottleneck” linking the outer vestibule to a large inner cavity extending toward the cytoplasmic extent of the lipid bilayer. The junction between the outer vestibule and the bottleneck features an outward–facing rim marked by T338 in TM6 and I1131 in TM12, consistent with the observation that cysteines at both of these locations reacted with both channel-permeant and channel-impermeant, thiol-directed reagents. Conversely, cysteines substituted for S341 in TM6 or T1134 in TM12, predicted by the model to lie below the rim of the bottleneck, were found to react exclusively with channel-permeant reagents applied from the extracellular side. The predicted dimensions of the bottleneck are consistent with the demonstrated permeation of Cl− pseudohalide anions, water and urea.

show abstract

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator: A Molecular Model Defines the Architecture of the Anion Conduction Path and Locates a “Bottleneck” in the Pore

et al. 2012

View full text Add to dashboard Cite

show abstract

“…In the case of CFTR, two MSDs (MSD1 and MSD2) form an anion conducting pore [2]. Four intracellular loops (ICL1 – 4) connect MSDs and NBDs presumably in domain swapping formation [16–18] and transmit the mechanical force generated in NBDs to MSDs.…”

Section: Structure and Gating Mechanism Of Cftrmentioning

confidence: 99%

Curcumin and Genistein: the Combined Effects on Disease-associated CFTR Mutants and their Clinical Implications

Saito¹,

Yu²,

Hwang

2013

CPD

View full text Add to dashboard Cite

Genistein and curcumin are major components of Asian foods, soybean and curry turmeric respectively. These compounds have been intensively investigated for their chemical and biological features conferring their anti-cancer activity. Genistein and curcumin have also been investigated for their potentiation effects on disease-associated CFTR mutants such as ΔF508 and G551D. Recently, we investigated the combined effect of genistein and curcumin on G551D-CFTR, which exhibits gating defects without abnormalities in protein synthesis or trafficking using the patch-clamp technique. We found that genistein and curcumin showed additive effects on their potentiation of G551D-CFTR in high concentration range and also, more importantly, showed a significant synergistic effect in their minimum concentration ranges. These results are consistent with the idea that multiple mechanisms are involved in the action of these CFTR potentiators. In this review, we revisit the pharmacology of genistein and curcumin on CFTR and also propose new pharmaceutical implications of combined use of these compounds in the development of drugs for CF pharmacotherapy.

show abstract

“…The structural basis for this remarkable departure in function in CFTR has not yet been fully elucidated. While high-resolution X-ray crystal structures of the nucleotide binding domains exist [11]–[13], structural information on the MSDs and the unique-to-CFTR R domain has been scarce, with only low-resolution NMR and cryo-EM electron density maps currently available [14], [15]. However, since ATP binding and tight NBD dimerization are necessary for channel opening [16], it has been hypothesized that CFTR evolved from a degraded ABC exporter whose ATP-bound outward-facing state (equivalent to the state in which the substrate binding pocket faces the extracellular space) corresponds to the open CFTR channel [17].…”

Section: Introductionmentioning

confidence: 99%

Modeling the Conformational Changes Underlying Channel Opening in CFTR

et al. 2013

View full text Add to dashboard Cite

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Changes in side-chain interactions are observed in all major domains of the protein, and experimental confirmation was obtained for a novel intra-protein salt bridge that breaks near the end of the transition. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel.

show abstract

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Cited by 61 publications

References 61 publications

Cystic Fibrosis Transmembrane Conductance Regulator: A Molecular Model Defines the Architecture of the Anion Conduction Path and Locates a “Bottleneck” in the Pore

Cystic Fibrosis Transmembrane Conductance Regulator: A Molecular Model Defines the Architecture of the Anion Conduction Path and Locates a “Bottleneck” in the Pore

Curcumin and Genistein: the Combined Effects on Disease-associated CFTR Mutants and their Clinical Implications

Modeling the Conformational Changes Underlying Channel Opening in CFTR

Contact Info

Product

Resources

About