Molecular Structure of the Human CFTR Ion Channel.
The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 Å structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function.
Laboratory of Membrane Biophysics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Tri-Institutional Training Program in Chemical Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Fangyu
F
Liu
Laboratory of Membrane Biophysics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA.
Zhe
Z
Zhang
Department of Medical Biochemistry and MTA-SE Ion Channel Research Group, Semmelweis University, Budapest 1094, Hungary.
László
L
Csanády
Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
David C
DC
Gadsby
Laboratory of Membrane Biophysics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA. Electronic address: juechen@rockefeller.edu.
Jue
J
Chen
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002417:Cattle; D020285:Cryoelectron Microscopy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D000072417:Protein Domains; D014982:Xenopus laevis; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry
D018528:ATP-Binding Cassette Transporters; C505032:CFTR protein, human; C000618329:CFTR protein, zebrafish; D029961:Zebrafish Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate
ABC transporter; anion channel; cryo-EM; human CFTR