Lipid interactions enhance activation and potentiation of cystic fibrosis transmembrane conductance regulator (CFTR)
| Autor: | Régis Pomès, Christopher Ing, Jean-Phillipe Julien, Zeng Zw, Stephanie Chin, Maurita Hung, Ramjeesingh M, Ereño-Oreba J, Cui H, Christine E. Bear |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
congenital hereditary and neonatal diseases and abnormalities biology Cholesterol 030302 biochemistry & molecular biology Long-term potentiation Biological membrane respiratory system Micelle Cystic fibrosis transmembrane conductance regulator digestive system diseases respiratory tract diseases Ivacaftor 03 medical and health sciences chemistry.chemical_compound chemistry medicine Biophysics biology.protein Phosphorylation lipids (amino acids peptides and proteins) Functional studies 030304 developmental biology medicine.drug |
| DOI: | 10.1101/495010 |
| Popis: | The recent cryo-electron microscopy structures of phosphorylated, ATP-bound CFTR in detergent micelles failed to reveal an open anion conduction pathway as expected on the basis of previous functional studies in biological membranes. We tested the hypothesis that interaction of CFTR with lipids is important for opening of its channel. Interestingly, molecular dynamics studies revealed that phospholipids associate with regions of CFTR proposed to contribute to its channel activity. More directly, we found that CFTR purified together with associated lipids using the amphipol: A8-35, exhibited higher rates of catalytic activity, channel activation and potentiation using ivacaftor, than did CFTR purified in detergent. Catalytic activity in CFTR detergent micelles was partially rescued by addition of phospholipids plus cholesterol, arguing that these lipids contribute directly to its modulation. In summary, these studies highlight the importance of lipids in regulated CFTR channel activation and potentiation. |
| Databáze: | OpenAIRE |
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