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A more recent version of this article appeared on April 6, 2001
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M010403200v1
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Papers In Press, published online ahead of print December 21, 2000
J. Biol. Chem, 10.1074/jbc.M010403200
Submitted on November 16, 2000
Revised on December 15, 2000
Accepted on December 20, 2000

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

Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8

Corresponding Author: bear{at}sickkids.on.ca

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 (NBDs), 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 (DPC; an open pore inhibitor) also inhibit CFTR ATPase activity, revealing a novel mechanism for crosstalk 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 crosstalk between the pore and NBDs of CFTR may be important in the in vivo regulation of CFTR in health and disease.


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