RT Journal Article
SR Electronic
T1 Cryo-EM visualization of an active high open probability CFTR ion channel
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 274316
DO 10.1101/274316
A1 Jonathan F. Fay
A1 Luba A. Aleksandrov
A1 Timothy J. Jensen
A1 Liying L. Cui
A1 Joseph N. Kousouros
A1 Lihua He
A1 Andrei A. Aleksandrov
A1 Drew S. Gingerich
A1 John R. Riordan
A1 James Z. Chen
YR 2018
UL http://biorxiv.org/content/early/2018/03/02/274316.abstract
AB The Cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, crucial to epithelial salt and water homeostasis, and defective due to mutations in its gene in patients with cystic fibrosis is a unique member of the large family of ATP-binding cassette transport proteins. Regulation of CFTR channel activity is stringently controlled by phosphorylation and nucleotide binding. Structural changes that underlie transitions between active and inactive functional states are not yet fully understood. Indeed the first 3D structures of dephosphorylated, ATP-free and phosphorylated ATP-bound states were only recently reported. Here we have determined the structure of inactive and active states of a thermally stabilized CFTR with very high channel open probability, confirmed after reconstitution into proteoliposomes. The unique repositioning of the TMHs and R domain density that we observe provide insights into the structural transition between active and inactive functional states of CFTR.HighlightsStructures of thermostabilized avian CFTR in dephosphorylated or phosphorylated forms at 4.3 Å and 6.6 Å resolution, respectively.Conformational differences of transmembrane helices 7 & 8 compared to zebra fish and human CFTR structures reveal an extracellular vestibule that may provide anion access to the pore.R-domain density appears to “plug” the intercellular vestibule in the dephosphorylated avian CFTR cryo-EM map.