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Biol Chem. 2018 Dec 1. pii: /j/bchm.just-accepted/hsz-2018-0470/hsz-2018-0470.xml. doi: 10.1515/hsz-2018-0470. [Epub ahead of print]

CFTR structure, stability, function and regulation.

Author information

1
School of Biological Sciences, Faculty of Biology Medicine and Health, Michael Smith Building, The University of Manchester, Oxford Road, ManchesterM13 9PL,UK.

Abstract

CFTR (Cystic Fibrosis transmembrane conductance regulator) 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 origins. 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 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.

KEYWORDS:

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

PMID:
30738013
DOI:
10.1515/hsz-2018-0470

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