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Combining theoretical and experimental data to decipher CFTR 3D structures and functions

Cellular and Molecular Life Sciences volume 75, pages 3829–3855 (2018)Cite this article

Abstract

Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.

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Acknowledgements

This work was funded by the French Association Vaincre La Mucoviscidose (Paris). It was granted access to the HPC resources of IDRIS/CINES under the allocations 2014-077206, 2015-077206, 2016-077206, and 0020707206 made by GENCI.

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Author notes

  1. Brice Hoffmann

    Present address: Iktos, Paris, France

  2. Jean-Paul Mornon and Isabelle Callebaut are co-senior authors.

  3. Brice Hoffmann and Ahmad Elbahnsi contribute equally to the work.

Authors and Affiliations

  1. Sorbonne Université, Muséum National d’Histoire Naturelle, UMR CNRS 7590, IRD, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, 75005, Paris, France

    Brice Hoffmann, Ahmad Elbahnsi, Fabio Pietrucci, Jean-Paul Mornon & Isabelle Callebaut

  2. INSERM U1078, SFR ScInBioS, Université de Bretagne Occidentale, Brest, France

    Pierre Lehn

  3. CNRS UMR5063, Université Grenoble-Alpes, Grenoble, France

    Jean-Luc Décout

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Hoffmann, B., Elbahnsi, A., Lehn, P. et al. Combining theoretical and experimental data to decipher CFTR 3D structures and functions. Cell. Mol. Life Sci. 75, 3829–3855 (2018). https://doi.org/10.1007/s00018-018-2835-7

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