Gating of CFTR by the STAS domain of SLC26 transporters

Shigeru B.H. Ko, Weizhong Zeng, Michael R. Dorwart, Xiang Luo, Kil Hwan Kim, Linda Millen, Hidemi Goto, Satoru Naruse, Abigail Soyombo, Philip J. Thomas, Shmuel Muallem

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Abstract

Chloride absorption and bicarbonate secretion are vital functions of epithelia1-6, as highlighted by cystic fibrosis and diseases associated with mutations in members of the SLC26 chloride-bicarbonate exchangers. Many SLC26 transporters (SLC26T) are expressed in the luminal membrane together with CFTR7, which activates electrogenic chloride-bicarbonate exchange by SLC26T8. However, the ability of SLC26T to regulate CFTR and the molecular mechanism of their interaction are not known. We report here a reciprocal regulatory interaction between the SLC26T DRA, SLC26A6 and CFTR. DRA markedly activates CFTR by increasing its overall open probablity (NPo) sixfold. Activation of CFTR by DRA was facilitated by their PDZ ligands and binding of the SLC26T STAS domain to the CFTR R domain. Binding of the STAS and R domains is regulated by PKA-mediated phosphorylation of the R domain. Notably, CFTR and SLC26T co-localize in the luminal membrane and recombinant STAS domain activates CFTR in native duct cells. These findings provide a new understanding of epithelial chloride and bicarbonate transport and may have important implications for both cystic fibrosis and diseases associated with SLC26T.

Original languageEnglish
Pages (from-to)343-350
Number of pages8
JournalNature Cell Biology
Volume6
Issue number4
DOIs
Publication statusPublished - 2004 Apr 1
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Ko, S. B. H., Zeng, W., Dorwart, M. R., Luo, X., Kim, K. H., Millen, L., Goto, H., Naruse, S., Soyombo, A., Thomas, P. J., & Muallem, S. (2004). Gating of CFTR by the STAS domain of SLC26 transporters. Nature Cell Biology, 6(4), 343-350. https://doi.org/10.1038/ncb1115