Cholesterol Interaction Directly Enhances Intrinsic Activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Cells
Stephanie ChinChristine E Bear

Abstract

The recent cryo-electron microscopy structures of zebrafish and the human cystic fibrosis transmembrane conductance regulator (CFTR) provided unprecedented insights into putative mechanisms underlying gating of its anion channel activity. Interestingly, despite predictions based on channel activity measurements in biological membranes, the structure of the detergent purified, phosphorylated, and ATP-bound human CFTR protein did not reveal a stably open conduction pathway. This study tested the hypothesis that the functional properties of the detergent solubilized CFTR protein used for structural determinations are different from those exhibited by CFTR purified under conditions that retain associated lipids native to the membrane. It was found that CFTR purified together with phospholipids and cholesterol using amphipol: A8-35, exhibited higher rates of catalytic activity, phosphorylation dependent channel activation and potentiation by the therapeutic compound, ivacaftor, than did CFTR purified in detergent. The catalytic activity of phosphorylated CFTR detergent micelles was rescued by the addition of phospholipids plus cholesterol, but not by phospholipids alone, arguing for a specific role for cholesterol in modulating this...Continue Reading

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Citations

Aug 6, 2020·International Journal of Molecular Sciences·Nara LiessiClarissa Braccia
Nov 1, 2020·Science Advances·Fengjiang LiuZihe Rao
Jan 22, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Bruno StiegerKaspar P Locher
Aug 4, 2020·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Onofrio LaselvaChristine E Bear
Apr 4, 2021·International Journal of Molecular Sciences·Birgitta Strandvik
May 1, 2021·Journal of Personalized Medicine·Onofrio LaselvaChristine E Bear
Jun 4, 2020·Molecular Therapy. Methods & Clinical Development·Steven ErwoodEvgueni A Ivakine

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