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J. Biol. Chem., Vol. 276, Issue 15, 11575-11581, April 13, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/15/11575    most recent M010403200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kogan, I. Articles by Bear, C. E. Search for Related Content PubMed PubMed Citation Articles by Kogan, I. Articles by Bear, C. E. Social Bookmarking                      What's this?

Perturbation of the Pore of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Inhibits Its ATPase Activity^*

Ilana Kogan^§, Mohabir Ramjeesingh, Ling-Jun Huan, Yanchun Wang, and Christine E. Bear^¶

From the Research Institute, Hospital for Sick Children and the  Physiology Department, University of Toronto, Toronto M5G 1XB, Canada

Mutations in the cystic fibrosis gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) lead to altered chloride (Cl) flux in affected epithelial tissues. CFTR is a Cl channel that is regulated by phosphorylation, nucleotide binding, and hydrolysis. However, the molecular basis for the functional regulation of wild type and mutant CFTR remains poorly understood. CFTR possesses two nucleotide binding domains, a phosphorylation-dependent regulatory domain, and two transmembrane domains that comprise the pore through which Cl permeates. Mutations of residues lining the channel pore (e.g. R347D) are typically thought to cause disease by altering the interaction of Cl with the pore. However, in the present study we show that the R347D mutation and diphenylamine-2-carboxylate (an open pore inhibitor) also inhibit CFTR ATPase activity, revealing a novel mechanism for cross-talk from the pore to the catalytic domains. In both cases, the reduction in ATPase correlates with a decrease in nucleotide turnover rather than affinity. Finally, we demonstrate that glutathione (GSH) inhibits CFTR ATPase and that this inhibition is altered in the CFTR-R347D variant. These findings suggest that cross-talk between the pore and nucleotide binding domains of CFTR may be important in the in vivo regulation of CFTR in health and disease.

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