Cell
Volume 169, Issue 1, 23 March 2017, Pages 85-95.e8
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Article
Molecular Structure of the Human CFTR Ion Channel

https://doi.org/10.1016/j.cell.2017.02.024Get rights and content
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Highlights

  • Molecular structure of human CFTR in the dephosphorylated, ATP-free form

  • Correlation between CFTR channel gating cycle and ATP hydrolysis rates

  • Identification of a structure feature distinguishing CFTR from other ABC transporters

Summary

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.

Keywords

human CFTR
cryo-EM
anion channel
ABC transporter

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