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Stimulation of CFTR activity by its phosphorylated R domain

Author

Listed:
  • Michael C. Winter

    (Howard Hughes Medical Institute, University of Iowa College of Medicine)

  • Michael J. Welsh

    (Howard Hughes Medical Institute, University of Iowa College of Medicine)

Abstract

Phosphorylation controls the activity of ion channels in many tissues. In epithelia, the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is activated by phosphorylation of serine residues in its regulatory (R) domain and then gated by binding and hydrolysis of ATP by the nucleotide-binding domains1,2,3. Current models propose that the unphosphorylated R domain serves as an inhibitory particle that occludes the pore1,2,4,5,6, much like the inhibitory ‘ball’ in Shaker K+ channels7,8; presumably, phosphorylation relieves this inhibition. Here we test this by adding an R-domain peptide to a CFTR variant in which much of the R domain had been deleted (CFTR-ΔR/S660A): in contrast to predictions, we found that adding an unphosphorylated R domain to CFTR-ΔR/S660A did not inhibit activity, whereas a phosphorylated R-domain peptide stimulated activity. To investigate how phosphorylation controls activity, we studied channel gating and found that phosphorylation of the R domain increases the rate of channel opening by enhancing the sensitivity to ATP. Our results indicate that CFTR is regulated by a new mechanism in which phosphorylation of one domain stimulates the interaction of ATP with another domain, thereby increasing activity.

Suggested Citation

  • Michael C. Winter & Michael J. Welsh, 1997. "Stimulation of CFTR activity by its phosphorylated R domain," Nature, Nature, vol. 389(6648), pages 294-296, September.
  • Handle: RePEc:nat:nature:v:389:y:1997:i:6648:d:10.1038_38514
    DOI: 10.1038/38514
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    Cited by:

    1. Nitesh Kumar Khandelwal & Cinthia R. Millan & Samantha I. Zangari & Samantha Avila & Dewight Williams & Tarjani M. Thaker & Thomas M. Tomasiak, 2022. "The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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