Discovering the chloride pathway in the CFTR channel
| Autor: | Rita Padányi, János Gera, Tamás Hegedűs, Attila Tordai, Gábor Paragi, Hedvig Tordai, Bianka Farkas |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
In silico Mutant Cystic Fibrosis Transmembrane Conductance Regulator Gating Molecular Dynamics Simulation Molecular dynamics ABCC7 Chloride Cystic fibrosis 03 medical and health sciences Cellular and Molecular Neuroscience Adenosine Triphosphate Chlorides medicine Animals Molecular Biology Zebrafish Pharmacology 0303 health sciences Chemistry 030302 biochemistry & molecular biology Metadynamics Structure Cell Biology Zebrafish Proteins Chloride channel Biophysics Molecular Medicine Original Article Protein folding Ion Channel Gating Intracellular medicine.drug |
| Zdroj: | Cellular and Molecular Life Sciences |
| ISSN: | 1420-9071 1420-682X |
| DOI: | 10.1007/s00018-019-03211-4 |
| Popis: | 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. Electronic supplementary material The online version of this article (10.1007/s00018-019-03211-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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