Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator

The genetic disease cystic fibrosis is caused by defects in the chloride ch annel cystic fibrosis transmembrane conductance regulator (CFTR). CFTR belo ngs to the family of ABC transporters. In contrast to most other members of this family which transport substrates actively across a membrane, the mai n function of CFTR is to regulate passive flux of substrates across the pla sma membrane. Chloride channel activity of CFTR is dependent on protein pho sphorylation and presence of nucleoside triphosphates. From electrophysiolo gical studies of CFTR detailed models of its regulation by phosphorylation and nucleotide interaction have evolved. These investigations provide ample evidence that ATP hydrolysis is crucial for CFTR gating. It becomes appare nt that the two nucleotide binding domains on CFTR not only diverge strongl y in sequence, but also in function. Based on previous models and taking in to account new data from pre-steady-state experiments, a refined model for the action of nucleotides at two nucleotide binding domains was recently pr oposed. (C) 1999 Elsevier Science B.V. All rights reserved.