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Structure of transmembrane helix 8 and possible membrane defects in CFTR

Valentina Corradi, Ruo-Xu Gu, Paola Vergani, View ORCID ProfileD. Peter Tieleman
doi: https://doi.org/10.1101/218792
Valentina Corradi
*Center for Molecular Simulation and Dept. of Biological Sciences, University of Calgary, 2500 University Dr NW, Calgary, AB, Canada T2N 1N4
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Ruo-Xu Gu
*Center for Molecular Simulation and Dept. of Biological Sciences, University of Calgary, 2500 University Dr NW, Calgary, AB, Canada T2N 1N4
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Paola Vergani
†Dept. of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, UK, WC1E 6BT
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D. Peter Tieleman
*Center for Molecular Simulation and Dept. of Biological Sciences, University of Calgary, 2500 University Dr NW, Calgary, AB, Canada T2N 1N4
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  • ORCID record for D. Peter Tieleman
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ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that regulates the flow of anions across epithelia. Mutations in CFTR cause cystic fibrosis. CFTR belongs to the ATP-Binding Cassette (ABC) transporter superfamily, and gating is controlled by phosphorylation and ATP binding and hydrolysis. Recent ATP-free and ATP-bound structures of zebrafish CFTR revealed an unwound segment of transmembrane helix (TM) 8, which appears to be a unique feature of CFTR not present in other ABC transporter structures. Here, by means of 1 μs long molecular dynamics simulations, we investigate the interactions formed by this TM8 segment with nearby helices, in both ATP-free and ATP-bound states. We highlight the structural role of TM8 in maintaining the functional architecture of the pore and we describe a distinct membrane defect that is found near TM8 only in the ATP-free state. The results of the MD simulations are discussed in the context of the gating mechanism of CFTR.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 13, 2017.
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Structure of transmembrane helix 8 and possible membrane defects in CFTR
Valentina Corradi, Ruo-Xu Gu, Paola Vergani, D. Peter Tieleman
bioRxiv 218792; doi: https://doi.org/10.1101/218792
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Structure of transmembrane helix 8 and possible membrane defects in CFTR
Valentina Corradi, Ruo-Xu Gu, Paola Vergani, D. Peter Tieleman
bioRxiv 218792; doi: https://doi.org/10.1101/218792

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