RT Journal Article
SR Electronic
T1 Lipid interactions enhance activation and potentiation of cystic fibrosis transmembrane conductance regulator (CFTR)
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 495010
DO 10.1101/495010
A1 Stephanie Chin
A1 Mohabir Ramjeesingh
A1 Maurita Hung
A1 June Ereño-Oreba
A1 Chris Ing
A1 Zhi W. Zeng
A1 Hong Cui
A1 Régis Pomès
A1 Jean-Philippe Julien
A1 Christine E. Bear
YR 2018
UL http://biorxiv.org/content/early/2018/12/16/495010.abstract
AB 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.