The CFTR Ion Channel: Gating, Regulation, and Anion Permeation

Hwang, Tzyh Chang; Kirk, Kevin L.

doi:10.1101/cshperspect.a009498

Cited by 107 publications

(113 citation statements)

References 114 publications

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“…This model was based on the gating behavior of the CFTR channel. 10 Notably, our results do not preclude a NBDs-separated conformation. Indeed, such a conformation was recently reported for zebrafish and human CFTR.…”

Section: General Features Of the Refined Modelsmentioning

confidence: 71%

“…The CFTR gating cycle is controlled by R-region phosphorylation / de-phosphorylation and by ATP binding to and hydrolysis from the canonical and non-canonical sites at the NBD1:NBD2 interface (with residence time in the non-canonical site being considerably longer than in the canonical site). 10,58 The CFTR conformations presented in this work are compatible with a model whereby priming of CFTR by phosphorylation is linked to large conformational changes (i.e., from inward facing to outward facing), while rapid channel opening and closing is associated with small allosteric movements controlled by ATP binding and dissociation events 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 which do not require NBD1:NBD2 dimer dissociation. This model is compatible with the "limited NBD model" suggested for CFTR based on the gating behavior of the channel 10 as well as with the Mornon model suggesting chloride diffusion into the CFTR conducting pore via a lateral tunnel.…”

Section: Discussionmentioning

confidence: 99%

“…Backbone RMSD (Å) differences between reported CFTR models. Models [1, 2, 3 and 12], [4][5][6] and [13][14], [7][8][9], [10][11] and [15][16] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 …”

Section: Discussionmentioning

confidence: 99%

“…[5][6] Yet, in contrast with other members of this group, CFTR is the only ABC transporter known to function as an ion channel. [7][8][9][10] Despite this functional uniqueness, CFTR architecture is similar to that of other ABC transporters and its structure is comprised of two membrane spanning domains (MSDs) linked to two nucleotide binding domains (NBDs) through four intracellular linkers (ICLs). 5,[11][12] In addition, CFTR features a unique, largely disordered R-region which is located at the sequence level between NBD1 and MSD2 and which needs to be phosphorylated to enable channel gating.…”

Section: Introduction Cystic Fibrosis (Cf) Is a Lethal Inherited Dismentioning

confidence: 99%

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Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Simhaev

McCarty

Ford

et al. 2017

J. Chem. Inf. Model.

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Cystic Fibrosis (CF) is a lethal, genetic disease found in particular in humans of European origin which is caused by mutations in the CFTR chloride channel. The search for CF therapies acting by modulating the impaired function of mutant CFTR will be greatly advanced by high resolution structures of CFTR in different states. To date, two medium resolution EM structures of CFTR are available (one of a distant zebrafish (Danio rerio) CFTR ortholog and one of human CFTR). The two models are nearly identical to one another and both correspond to the inward-facing, NBDs separated, closed state of the channel. In addition, lower resolution structural data are available for human CFTR in an alternative conformation which likely features associated NBDs and thus geometrically resembles the conducting state of the channel.Multiple homology models of human CFTR in multiple states have been developed over the years, yet their correspondence to the existing structural information is unexplored. In this work we use molecular dynamics flexible fitting (MDFF) simulations to refine two previously described CFTR models based on the available cryo-EM map of the human protein. This map was recorded in the absence of ATP and consequently represents closed-state CFTR yet its features likely correspond to a NBDs associated conformation of the protein. Accordingly, the resulting models feature dimerized NBDs yet with no membrane traversing pore. Moreover, the open probability of the new models as deduced from the MDFF trajectories is significantly lower than that deduced from control MD trajectories initiated from the starting models. We propose that the new models correspond to a CFTR conformation which to date was largely unexplored yet one that is relevant to the gating cycle of the protein. In particular this conformation may participate in rapid channel opening and closing through small allosteric movements controlled by nucleotide binding and dissociation events. Analyzing the resulting trajectories (and not only the final models as is usually the case), we demonstrate that the refined models have good stereochemical properties and are also in favorable agreement with multiple experimental data.Moreover, despite different starting points, the final models share many common features.Finally, we propose that the combination of high resolution cryo-EM maps which are currently emerging from multiple labs and MDFF simulations will be of value for the development of yet more reliable CFTR models as well as for the identification of binding sites for CFTR modulators.

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Section: General Features Of the Refined Modelsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introduction Cystic Fibrosis (Cf) Is a Lethal Inherited Dismentioning

confidence: 99%

See 2 more Smart Citations

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Simhaev

McCarty

Ford

et al. 2017

J. Chem. Inf. Model.

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show abstract

“…Although multiple past studies focused on understanding the implications of ATP-controlled signaling with respect to endogenous transmembrane transporters such as ion channels [17,19,20,24,[28][29][30][31], there is a recent interest in understanding how ATP controls the lytic action of pore-forming toxins (PFTs) [22,26,27,[32][33][34]. PFTs introduce unregulated conducting pathways into the host cell plasmalemma [35][36][37][38][39], which is expected to yield direct cytolysis.…”

Section: Introductionmentioning

confidence: 99%

Purinergic control of lysenin’s transport and voltage-gating properties

Bryant

Shrestha

Carnig

et al. 2016

Purinergic Signalling

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Lysenin, a pore-forming protein extracted from the coelomic fluid of the earthworm Eisenia foetida, manifests cytolytic activity by inserting large conductance pores in host membranes containing sphingomyelin. In the present study, we found that adenosine phosphates control the biological activity of lysenin channels inserted into planar lipid membranes with respect to their macroscopic conductance and voltage-induced gating. Addition of ATP, ADP, or AMP decreased the macroscopic conductance of lysenin channels in a concentration-dependent manner, with ATP being the most potent inhibitor and AMP the least. ATP removal from the bulk solutions by buffer exchange quickly reinstated the macroscopic conductance and demonstrated reversibility. Singlechannel experiments pointed to an inhibition mechanism that most probably relies on electrostatic binding and partial occlusion of the channel-conducting pathway, rather than ligand gating induced by the highly charged phosphates. The Hill analysis of the changes in macroscopic conduction as a function of the inhibitor concentration suggested cooperative binding as descriptive of the inhibition process. Ionic screening significantly reduced the ATP inhibitory efficacy, in support of the electrostatic binding hypothesis. In addition to conductance modulation, purinergic control over the biological activity of lysenin channels has also been observed to manifest as changes of the voltage-induced gating profile. Our analysis strongly suggests that not only the inhibitor's charge but also its ability to adopt a folded conformation may explain the differences in the observed influence of ATP, ADP, and AMP on lysenin's biological activity.

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Bacterial multi‐solute transporters

et al. 2020

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Bacterial membrane proteins of the SbmA/BacA family are multi-solute transporters that mediate the uptake of structurally diverse hydrophilic molecules, including aminoglycoside antibiotics and antimicrobial peptides. Some family members are full-length ATP-binding cassette (ABC) transporters, whereas other members are truncated homologues that lack the nucleotidebinding domains and thus mediate ATP-independent transport. A recent cryo-EM structure of the ABC transporter Rv1819c from Mycobacterium tuberculosis has shed light on the structural basis for multi-solute transport and has provided insight into the mechanism of transport. Here, we discuss how the protein architecture makes SbmA/BacA family transporters prone to inadvertent import of antibiotics and speculate on the question which physiological processes may benefit from multi-solute transport.

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The CFTR Ion Channel: Gating, Regulation, and Anion Permeation

Cited by 107 publications

References 114 publications

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Molecular Dynamics Flexible Fitting Simulations Identify New Models of the Closed State of the Cystic Fibrosis Transmembrane Conductance Regulator Protein

Purinergic control of lysenin’s transport and voltage-gating properties

Bacterial multi‐solute transporters

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