Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell

Miklos Bagdany, Guido Veit, Ryosuke Fukuda, Radu G. Avramescu, Tsukasa Okiyoneda, Imad Baaklini, Jay Singh, Guy Sovak, Haijin Xu, Pirjo M. Apaja, Sara Sattin, Lenore K. Beitel, Ariel Roldan, Giorgio Colombo, William Balch, Jason C. Young, Gergely L. Lukacs

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Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (ΔF508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 °C and concomitant functional inactivation of ΔF508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at single-molecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart. Thus, molecular chaperones can contribute to functional maintenance of ΔF508-CFTR by reshaping the conformational energetics of its final fold, a mechanism with implication in the regulation of metastable ABC transporters and other plasma membrane proteins activity in health and diseases.

Original languageEnglish
Article number398
Number of pages15
JournalNature Communications
Publication statusPublished - 30 Aug 2017
Externally publishedYes

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  • molecular chaperone
  • CFTR
  • plasma membrane
  • chaperone activity
  • ∆F508-CFTR
  • Conformational analysis


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