Discovering the chloride pathway in the CFTR channel

Bianka Farkas, H. Tordai, Rita Padányi, A. Tordai, János Gera, Gábor Paragi, T. Hegedűs

Research output: Article

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.

Original languageEnglish
JournalCellular and Molecular Life Sciences
DOIs
Publication statusPublished - jan. 1 2019

Fingerprint

Chloride Channels
Chlorides
Cystic Fibrosis
Ions
Lipids
Protein Stability
Protein Folding
Zebrafish
Molecular Dynamics Simulation
Computer Simulation
Anions
Tail
Adenosine Triphosphate
Epithelial Cells
Amino Acids
Mutation
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Discovering the chloride pathway in the CFTR channel. / Farkas, Bianka; Tordai, H.; Padányi, Rita; Tordai, A.; Gera, János; Paragi, Gábor; Hegedűs, T.

In: Cellular and Molecular Life Sciences, 01.01.2019.

Research output: Article

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AU - Padányi, Rita

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AU - Paragi, Gábor

AU - Hegedűs, T.

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