Localizing a gate in CFTR

Xiaolong Gao, Tzyh Chang Hwang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Experimental and computational studies have painted a picture of the chloride permeation pathway in cystic fibrosis transmembrane conductance regulator (CFTR) as a short narrow tunnel flanked by wider inner and outer vestibules. Although these studies also identified a number of transmembrane segments (TMs) as porelining, the exact location of CFTR's gate(s) remains unknown. Here, using a channel-permeant probe, [Au(CN)2]-, we provide evidence that CFTR bears a gate that coincides with the predicted narrow section of the pore defined as residues 338-341 in TM6. Specifically, cysteines introduced cytoplasmic to the narrow region (i.e., positions 344 in TM6 and 1148 in TM12) can be modified by intracellular [Au(CN)2]-, in both open and closed states, corroborating the conclusion that the internal vestibule does not harbor a gate. However, cysteines engineered to positions external to the presumed narrow region (e.g., 334, 335, and 337 in TM6) are all nonreactive toward cytoplasmic [Au(CN)2]-, in the absence of ATP, whereas they can be better accessed by extracellular [Au(CN)2]-, when the open probability ismarkedly reduced by introducing a second mutation, G1349D. As [Au(CN)2]-, and chloride ions share the same permeation pathway, these results imply a gate is situated between amino acid residues 337 and 344 along TM6, encompassing the very segment that may also serve as the selectivity filter for CFTR. The unique position of a gate in the middle of the ion translocation pathway diverges from those seen in ATP-binding cassette (ABC) transporters and thus distinguishes CFTR from other members of the ABC transporter family.

Original languageEnglish
Pages (from-to)2461-2466
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
StatePublished - 18 Mar 2015


  • Abc transporters
  • Anion channels
  • Cystic fibrosis
  • Gating


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