Allosteric modulation balances thermodynamic stability and restores function of ΔF508 CFTR.
@article{Aleksandrov2012AllostericMB, title={Allosteric modulation balances thermodynamic stability and restores function of $\Delta$F508 CFTR.}, author={Andrei A. Aleksandrov and Pradeep Kota and Liying Cui and Timothy J. Jensen and Alexey E. Alekseev and Santiago Reyes and Lihua He and Martina Gentzsch and Luba A. Aleksandrov and Nikolay V. Dokholyan and John R. Riordan}, journal={Journal of molecular biology}, year={2012}, volume={419 1-2}, pages={ 41-60 } }
92 Citations
A topological switch in CFTR modulates channel activity and sensitivity to unfolding
- BiologyNature Chemical Biology
- 2021
This work shows that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold, which affects channel activity and, under certain conditions, leads to unfolding and protein degradation.
Thermal stability of purified and reconstituted CFTR in a locked open channel conformation.
- BiologyProtein expression and purification
- 2015
Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein
- BiologyFASEB journal : official publication of the Federation of American Societies for Experimental Biology
- 2013
It is shown that several compounds identified by high‐throughput screening to improve ΔF508 CFTR maturation, including the investigational drug VX‐809, caused a much greater increase in maturation at 27 than at 37°C (<2‐fold), and it is clearly demonstrate that ΔF504 CFTR can be completely assembled and evade cellular quality control systems, while remaining thermally unstable.
Domain-interface dynamics of CFTR revealed by stabilizing nanobodies
- BiologyNature Communications
- 2019
The data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures, likely to have major relevance for CF pathogenesis but also for the normal function ofCFTR and other ABC proteins.
A Topological Switch in the Cystic Fibrosis Transmembrane Conductance Regulator Modulates Channel Activity and Sensitivity to Disease-Causing Mutation
- Biology
- 2020
The data indicate that in wild-type CFTR switching to this topologically-swapped conformation of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation.
Domain-interface dynamics of CFTR revealed by stabilizing nanobodies
- BiologyNature Communications
- 2019
A conformation of CFTR is uncovered, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures, likely to have major relevance for CF pathogenesis but also for the normal function of CF TR and other ABC proteins.
Substitution of Yor1p NBD1 residues improves the thermal stability of Human Cystic Fibrosis Transmembrane Conductance Regulator
- BiologyProtein engineering, design & selection : PEDS
- 2017
This project investigates small changes in protein sequence that can alter the thermal stability of the large multi-domain CFTR protein and targets a conserved 70-residue α-subdomain located in the first nucleotide-binding domain that hosts the common misfolding mutation ∆F508.
Decoding F508del Misfolding in Cystic Fibrosis
- BiologyBiomolecules
- 2014
Current data support a central role for NBD1 in F508del misfolding and rescue and potential rational approaches have been proposed in an attempt to develop highly effective small molecule modulators that improve the cell surface functional expression of F508Del CFTR.
Mechanism-based corrector combination restores ΔF508-CFTR folding and function
- BiologyNature Chemical Biology
- 2013
The molecular targets of available correctors are elucidated: class I stabilizes the NBD1-MSD1 and N BD1- MSD2 interfaces, and class II targets NBD2, which stabilizes human ΔF508-NBD1.
CFTR trafficking mutations disrupt cotranslational protein folding by targeting biosynthetic intermediates
- BiologyNature Communications
- 2020
It is shown that inherited, disease-causing mutations located within the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator (CFTR) have distinct effects on nascent polypeptides, demonstrating that nascent folding intermediates can play an important role in disease pathogenesis and thus provide potential targets for pharmacological correction.
References
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The results suggest that the ΔF508 mutation causes the accumulation of a form of the protein that resembles an intermediate in the biogenesis of the wild type CFTR, rather than induces the production of non-native variant.
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Background: Thermal stability of the common cystic fibrosis mutant channel (ΔF508-CFTR) is unclear. Results: ΔF508-CFTR channels inactivate at 36.5 °C in excised patches. Constitutive cytosolic loop…
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It is demonstrated that ΔF508 is a kinetic folding mutation that affects a step early in the process, and that there is a significant energy barrier between the native state and the step affected by the mutation precluding the use of native state ligands to promote folding.
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Second‐site mutations that increase the solubility of isolated F508del‐NBD1 in vitro and suppress the trafficking defect of intact F508 del‐CFTR in vivo also stabilize the protein against this transition, supporting the hypothesize that it is responsible for the pathological trafficking of F508Del‐CF TR.
Limited proteolysis as a probe for arrested conformational maturation of delta F508 CFTR.
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The results suggest that the delta F508 mutation causes the accumulation of a form of the protein that resembles an intermediate in the biogenesis of the wild type CFTR, rather than induces the production of non-native variant.
The ΔF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR
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It is suggested that hydrophobic side chain interactions of Phe508 are required for vectorial folding of NBD2 and the domain-domain assembly of CFTR, representing a combined co- and post-translational folding mechanism that may be used by other multidomain membrane proteins.
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Processing and function of CFTR-ΔF508 are species-dependent
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There is a gradient in the severity of the CFTR-ΔF508 processing defect, with human more severe than pig or mouse, and these findings may explain some previously puzzling observations in CF mice.