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Discovering the chloride pathway in the CFTR channel.

Authors
  • Farkas, Bianka1, 2
  • Tordai, Hedvig1
  • Padányi, Rita1, 3
  • Tordai, Attila4
  • Gera, János5
  • Paragi, Gábor6, 7
  • Hegedűs, Tamás8, 9
  • 1 Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary. , (Hungary)
  • 2 Faculty of Information Technology, Pázmány Péter Catholic University, Budapest, Hungary. , (Hungary)
  • 3 MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, Hungary. , (Hungary)
  • 4 Department of Pathophysiology, Semmelweis University, Budapest, Hungary. , (Hungary)
  • 5 Department of Medical Chemistry, University of Szeged, Szeged, Hungary. , (Hungary)
  • 6 MTA-SZTE Biomimetic System Research Group, Hungarian Academy of Sciences, Szeged, Hungary. , (Hungary)
  • 7 Institute of Physics, University of Pécs, Pecs, Hungary. , (Hungary)
  • 8 Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary. [email protected] , (Hungary)
  • 9 MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, Hungary. [email protected] , (Hungary)
Type
Published Article
Journal
Cellular and Molecular Life Sciences
Publisher
Springer-Verlag
Publication Date
Feb 01, 2020
Volume
77
Issue
4
Pages
765–778
Identifiers
DOI: 10.1007/s00018-019-03211-4
PMID: 31327045
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cystic fibrosis (CF), a lethal monogenic disease, is caused by pathogenic variants of the CFTR chloride channel. The majority of CF mutations affect protein folding and stability leading overall to diminished apical anion conductance of epithelial cells. The recently published cryo-EM structures of full-length human and zebrafish CFTR provide a good model to gain insight into structure-function relationships of CFTR variants. Although, some of the structures were determined in the phosphorylated and ATP-bound active state, none of the static structures showed an open pathway for chloride permeation. Therefore, we performed molecular dynamics simulations to generate a conformational ensemble of the protein and used channel detecting algorithms to identify conformations with an opened channel. Our simulations indicate a main intracellular entry at TM4/6, a secondary pore at TM10/12, and a bottleneck region involving numerous amino acids from TM1, TM6, and TM12 in accordance with experiments. Since chloride ions entered the pathway in our equilibrium simulations, but did not traverse the bottleneck region, we performed metadynamics simulations, which revealed two possible exits. One of the chloride ions exits includes hydrophobic lipid tails that may explain the lipid-dependency of CFTR function. In summary, our in silico study provides a detailed description of a potential chloride channel pathway based on a recent cryo-EM structure and may help to understand the gating of the CFTR chloride channel, thus contributing to novel strategies to rescue dysfunctional mutants.

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