The structural basis of cystic fibrosis

Meng, Xianjun; Clews, Jack; Martin, Eleanor; Ciuta, Anca D; Ford, Robert C.

doi:10.1042/bst20180296

Cited by 15 publications

(12 citation statements)

References 42 publications

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“…It remains to be seen where these differences stem from, but overall these data support the idea that formation of the NBD sandwich dimer and the OF state is quite difficult in Pgp. Similar observations, as reflected in the recent glut of cryo-EM structures, are made for other eukaryotic ABC transporters (see, e.g., the 'grunt' model for CFTR/ABCC7 [103]).…”

Section: Structural\biophysical Studieschallenges and Limitationssupporting

confidence: 75%

What monomeric nucleotide binding domains can teach us about dimeric ABC proteins

Ford

Hellmich

2020

FEBS Letters

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The classic conceptualization of ATP binding cassette (ABC) transporter function is an ATP‐dependent conformational change coupled to transport of a substrate across a biological membrane via the transmembrane domains (TMDs). The binding of two ATP molecules within the transporter's two nucleotide binding domains (NBDs) induces their dimerization. Despite retaining the ability to bind nucleotides, isolated NBDs frequently fail to dimerize. ABC proteins without a TMD, for example ABCE and ABCF, have NBDs tethered via elaborate linkers, further supporting that NBD dimerization does not readily occur for isolated NBDs. Intriguingly, even in full‐length transporters, the NBD‐dimerized, outward‐facing state is not as frequently observed as might be expected. This leads to questions regarding what drives NBD interaction and the role of the TMDs or linkers. Understanding the NBD–nucleotide interaction and the subsequent NBD dimerization is thus pivotal for understanding ABC transporter activity in general. Here, we hope to provide new insights into ABC protein function by discussing the perplexing issue of (missing) NBD dimerization in isolation and in the context of full‐length ABC proteins.

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Section: Structural\biophysical Studieschallenges and Limitationssupporting

confidence: 75%

What monomeric nucleotide binding domains can teach us about dimeric ABC proteins

Ford

Hellmich

2020

FEBS Letters

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“…Indeed, it has been proposed that correctors exert their activity by interacting with different CFTR domains [ 8 ]. In this respect, CFTR has two nucleotide binding domains (NBD1 and NBD2), each one linked at the carboxy-terminus of a membrane-spanning domain (MSD1 and MSD2) [ 9 , 10 ]. A regulatory (R) domain connects the two MSD1-NBD1 and MSD2-NBD2 together [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…In this respect, CFTR has two nucleotide binding domains (NBD1 and NBD2), each one linked at the carboxy-terminus of a membrane-spanning domain (MSD1 and MSD2) [ 9 , 10 ]. A regulatory (R) domain connects the two MSD1-NBD1 and MSD2-NBD2 together [ 9 , 10 ]. Importantly, F508del does not only affect the stability of NBD1, where it is localized, but also affects other CFTR domains [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Capurro

Tomati

Sondo

et al. 2021

IJMS

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Deletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors. We investigated the efficacy and properties of VX-445, a newly developed corrector, which is one of the three active principles present in a drug (Trikafta®/Kaftrio®) recently approved for the treatment of CF patients with F508del mutation. We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function. In particular, in primary bronchial epithelial cells of CF patients, the maximal rescue obtained with corrector combinations including VX-445 was close to 60–70% of CFTR function in non-CF cells. Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.

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“…CFTR (ABCC7) is the member of the ATP binding cassette (ABC) superfamily. It consists of two transmembrane domains (TMD1 and TMD2), each consisting of 6 TM helices, two nucleotide binding domains (NBD1 and NBD2), and a disordered segment, called regulatory (R) domain [4,5]. The R domain phosphorylation is a prerequisite for channel gating.…”

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confidence: 99%

Discovering the chloride pathway in the CFTR channel

Farkas

Tordai

Padányi

et al. 2019

Cell. Mol. Life Sci.

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Cystic fibrosis (CF), a lethal monogenic disease, is caused by pathogenic variants of the CFTR chloride channel. The majority of CF mutations affect protein folding and stability leading overall to diminished apical anion conductance of epithelial cells. The recently published cryo-EM structures of full-length human and zebrafish CFTR provide a good model to gain insight into structure-function relationships of CFTR variants. Although, some of the structures were determined in the phosphorylated and ATP-bound active state, none of the static structures showed an open pathway for chloride permeation. Therefore, we performed molecular dynamics simulations to generate a conformational ensemble of the protein and used channel detecting algorithms to identify conformations with an opened channel. Our simulations indicate a main intracellular entry at TM4/6, a secondary pore at TM10/12, and a bottleneck region involving numerous amino acids from TM1, TM6, and TM12 in accordance with experiments. Since chloride ions entered the pathway in our equilibrium simulations, but did not traverse the bottleneck region, we performed metadynamics simulations, which revealed two possible exits. One of the chloride ions exits includes hydrophobic lipid tails that may explain the lipid-dependency of CFTR function. In summary, our in silico study provides a detailed description of a potential chloride channel pathway based on a recent cryo-EM structure and may help to understand the gating of the CFTR chloride channel, thus contributing to novel strategies to rescue dysfunctional mutants.

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The structural basis of cystic fibrosis

Cited by 15 publications

References 42 publications

What monomeric nucleotide binding domains can teach us about dimeric ABC proteins

What monomeric nucleotide binding domains can teach us about dimeric ABC proteins

Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment

Discovering the chloride pathway in the CFTR channel

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