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

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.

Restoration of NBD1 thermal stability is necessary and sufficient to correct ∆F508 CFTR folding and assembly.

A Topological Switch Enables Misfolding of the Cystic Fibrosis Transmembrane Conductance Regulator

It is demonstrated that NBD1 of CFTR can adopt an alternative conformation that departs from the canonical NBD fold, which regulates channel function, but, in the presence of the F508del mutation, allows domain misfolding and subsequent protein degradation.

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, and is likely to have major relevance for CF pathogenesis but also for the normal function ofCFTR 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.
...

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