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
        }
}
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A topological switch in CFTR modulates channel activity and sensitivity to unfolding

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Thermal stability of purified and reconstituted CFTR in a locked open channel conformation.

Correctors of ΔF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein

  • Lihua HeP. Kota J. Riordan
  • Biology
    FASEB 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

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

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

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

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

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

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

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.
...

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