PT - JOURNAL ARTICLE AU - Stephanie Chin AU - Mohabir Ramjeesingh AU - Maurita Hung AU - June Ereño-Oreba AU - Chris Ing AU - Zhi W. Zeng AU - Hong Cui AU - Régis Pomès AU - Jean-Philippe Julien AU - Christine E. Bear TI - Lipid interactions enhance activation and potentiation of cystic fibrosis transmembrane conductance regulator (CFTR) AID - 10.1101/495010 DP - 2018 Jan 01 TA - bioRxiv PG - 495010 4099 - http://biorxiv.org/content/early/2018/12/16/495010.short 4100 - http://biorxiv.org/content/early/2018/12/16/495010.full 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.