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 and Gergely L. Lukacs ()
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Miklos Bagdany: McGill University
Guido Veit: McGill University
Ryosuke Fukuda: McGill University
Radu G. Avramescu: McGill University
Tsukasa Okiyoneda: McGill University
Imad Baaklini: McGill University
Jay Singh: The Scripps Research Institute
Guy Sovak: McGill University
Haijin Xu: McGill University
Pirjo M. Apaja: McGill University
Sara Sattin: Università degli Studi di Milano
Lenore K. Beitel: McGill University
Ariel Roldan: McGill University
Giorgio Colombo: Istituto di Chimica del Riconoscimento Molecolare
William Balch: The Scripps Research Institute
Jason C. Young: McGill University
Gergely L. Lukacs: McGill University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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 (∆F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 °C and concomitant functional inactivation of ∆F508-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 ∆F508-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.

Date: 2017
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DOI: 10.1038/s41467-017-00444-4

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