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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


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Volume 400, Issue 10

Issues

CFTR structure, stability, function and regulation

Xin Meng
  • School of Biological Sciences, Faculty of Biology Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
  • Other articles by this author:
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/ Jack Clews
  • School of Biological Sciences, Faculty of Biology Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
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/ Anca D. Ciuta
  • School of Biological Sciences, Faculty of Biology Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
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/ Eleanor R. Martin
  • School of Biological Sciences, Faculty of Biology Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
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/ Robert C. FordORCID iD: https://orcid.org/0000-0002-0958-1505
Published Online: 2019-02-22 | DOI: https://doi.org/10.1515/hsz-2018-0470

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette family of proteins because it has evolved into a channel. Mutations in CFTR cause cystic fibrosis, the most common genetic disease in people of European origin. The F508del mutation is found in about 90% of patients and here we present data that suggest its main effect is on CFTR stability rather than on the three-dimensional (3D) folded state. A survey of recent cryo-electron microscopy studies was carried out and this highlighted differences in terms of CFTR conformation despite similarities in experimental conditions. We further studied CFTR structure under various phosphorylation states and with the CFTR-interacting protein NHERF1. The coexistence of outward-facing and inward-facing conformations under a range of experimental conditions was suggested from these data. These results are discussed in terms of structural models for channel gating, and favour the model where the mostly disordered regulatory-region of the protein acts as a channel plug.

This article offers supplementary material which is provided at the end of the article.

Keywords: ABC transporter; CFTR; electron microscopy; ion channel; membrane protein structure

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About the article

aCurrent address: Institute of Molecular Biology and Biophysics, ETH Zurich, HPK G11, Otto-Stern-Weg 5, CH-8093 Zurich, Switzerland.


Received: 2018-12-19

Accepted: 2019-01-30

Published Online: 2019-02-22

Published in Print: 2019-09-25


Funding Source: Cystic Fibrosis Foundation

Award identifier / Grant number: FORD13XX0

Funding Source: Cystic Fibrosis Trust

Award identifier / Grant number: F508del CFTR SRC

This work was partly funded by the Cystic Fibrosis Foundation (Funder Id: 10.13039/100000897, FORD13XX0) and the Cystic Fibrosis Trust (Funder Id: 10.13039/501100000292, F508del CFTR SRC). EM was funded by a joint studentship between the University of Manchester and ASTAR (Singapore). We thank Prof. Robert Robinson (ASTAR Singapore); Prof. Ineke Braakman, Dr Bertrand Kleizen and Laura Tade (Utrecht) for help and insights.


Conflict of interest statement: The authors declare no conflict of interest.


Citation Information: Biological Chemistry, Volume 400, Issue 10, Pages 1359–1370, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2018-0470.

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