ZFIN ID: ZDB-PUB-170326-3
Molecular Structure of the Human CFTR Ion Channel
Liu, F., Zhang, Z., Csanády, L., Gadsby, D.C., Chen, J.
Date: 2017
Source: Cell 169: 85-95.e8 (Journal)
Registered Authors:
Keywords: ABC transporter, anion channel, cryo-EM, human CFTR
MeSH Terms:
  • ATP-Binding Cassette Transporters/chemistry
  • Adenosine Triphosphate/metabolism
  • Animals
  • Cattle
  • Cryoelectron Microscopy
  • Cystic Fibrosis Transmembrane Conductance Regulator/chemistry*
  • Humans
  • Hydrolysis
  • Models, Molecular
  • Protein Domains
  • Xenopus laevis
  • Zebrafish
  • Zebrafish Proteins/chemistry
PubMed: 28340353 Full text @ Cell
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.