CYSTIC-FIBROSIS - CHANNEL, CATALYTIC, AND FOLDING PROPERTIES OF THE CFTR PROTEIN

The identification and characterization of the CFTR gene and protein h ave provided not only a major impetus to the dissection of the molecul ar pathophysiology of cystic fibrosis (CF) but also a new perspective on the structure and function of the large superfamily of membrane tra nsport proteins to which it belong. While the mechanism of the active vectorial translocation of many hydrophobic substrates by several of t hese transporters remains nearly as perplexing as it has for several d ecades, considerable insight has been gained into the control of the b i-directional permeation of chloride ions through a single CFTR channe l by the phosphorylation of the R-domain and ATP interactions at the t wo nucleotide binding domains. However, details of these catalytic and allosteric mechanisms remain to be elucidated and await the replaceme nt of two-dimensional conceptualizations with three dimensional struct ure information. Secondary and tertiary structure determination is req uired both for the understanding of the mechanism of action of the mol ecule and to enable a more complete appreciation of the misfolding and misprocessing of mutant CFTR molecules. This is the primary cause of the disease in the majority of the patients and hence understanding th e details of the cotranslational interactions with multiple molecular chaperones, the ubiquitin-proteasome pathway and other components of t he quality control machinery at the endoplasmic reticulum could provid e a basis for the development of new therapeutic interventions.