Discovering the chloride pathway in the CFTR channel.

Adenosine Triphosphate / metabolism Animals Chlorides / metabolism Cystic Fibrosis Transmembrane Conductance Regulator / chemistry Ion Channel Gating Molecular Dynamics Simulation Protein Conformation Zebrafish / metabolism Zebrafish Proteins / chemistry
ABCC7 Chloride channel Cystic fibrosis Molecular dynamics Structure

Journal

Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402

Informations de publication

Date de publication:
Feb 2020
Historique:
received: 22 02 2019
accepted: 26 06 2019
revised: 22 06 2019
pubmed: 22 7 2019
medline: 7 3 2020
entrez: 22 7 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1007/s00018-019-03211-4 PMID: 31327045 PMC: PMC7039865
pubmed: 31327045
doi: 10.1007/s00018-019-03211-4
pii: 10.1007/s00018-019-03211-4
pmc: PMC7039865
doi:

Substances chimiques

CFTR protein, zebrafish 0
Chlorides 0
Zebrafish Proteins 0
Cystic Fibrosis Transmembrane Conductance Regulator 126880-72-6
Adenosine Triphosphate 8L70Q75FXE

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

765-778

Subventions

Organisme : Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal (HU)
ID : K111678
Organisme : Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal (HU)
ID : K127961
Organisme : Cystic Fibrosis Foundation (US)
ID : HEGEDU18I0
Organisme : Semmelweis Egyetem
ID : Sci_Innov18

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Auteurs

Bianka Farkas (B)

Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
Faculty of Information Technology, Pázmány Péter Catholic University, Budapest, Hungary.

Hedvig Tordai (H)

Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.

Rita Padányi (R)

Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, Hungary.

Attila Tordai (A)

Department of Pathophysiology, Semmelweis University, Budapest, Hungary.

János Gera (J)

Department of Medical Chemistry, University of Szeged, Szeged, Hungary.

Gábor Paragi (G)

MTA-SZTE Biomimetic System Research Group, Hungarian Academy of Sciences, Szeged, Hungary.
Institute of Physics, University of Pécs, Pecs, Hungary.

Tamás Hegedűs (T)

Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary. hegedus@hegelab.org.
MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, Hungary. hegedus@hegelab.org.

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Classifications MeSH

Recherchemedicale.com › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › Adénosine triphosphate › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Eucaryotes › Animaux › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Produits chimiques inorganiques › Électrolytes › Ions › Anions › Chlorures › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Pompes ioniques › Transporteurs d'anions › Transporteurs d'anions organiques › Transporteurs d'anions organiques ATP-dépendants › Protéines associées à la multirésistance aux médicaments › Protéine CFTR › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Phénomènes physiologiques › Phénomènes électrophysiologiques › Ouverture et fermeture des portes des canaux ioniques › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Poissons › Cypriniformes › Cyprinidae › Danio zébré › Discovering the chloride pathway in the CFTR channel.
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines de poisson › Protéines de poisson-zèbre › Discovering the chloride pathway in the CFTR channel.