Cystic fibrosis (CF) is a common recessive disorder with impaired vectorial transport across epithelial tissue. Over 750 mutations and 100 variations have been found in the affected gene and its product- the cystic fibrosis transmembrane conductance regulator (CFTR). The spectrum of the disease phenotype depends both on the nature of the mutation or combinations of mutations and on role of chloride transport and the regulatory properties of CFTR in individual epithelial tissues. A series of mutations that have been identified in patients that involve missense mutations in the first nucleotide binding fold (NBF1) or premature terminations in the carboxyl terminal region, will be used in model systems to understand the cellular machinery that participate in biogenesis and maintenance of CFTR at the cell surface. Preliminary data indicate that these mutations lead to diminished CFTR expression by two distinct mechanisms. Missense mutations in MBF1 accelerate the degradation of the immature CFTR at the endoplasmic reticulum. In contrast, premature termination at the C-terminal tail regions does not affect biosynthesis but leads to destabilization of mature CFTR.
The specific aims are to: 1) delineate the mechanism of mutations that show impaired biogenesis with features distinct from deltaF508CFTR, 2) elucidate the role of the carboxyl terminus in maintaining cell surface stability of CFTR, 3) identify the protein-protein interactions that participate in the recognition of the missense mutations or are critical in the maintenance of CFTR density at the cell surface. All aspects of biogenesis, routing and stability of CFTR must be understood and considered to design effective therapeutic strategies to control the symptoms of deficiencies in CF. This is notably challenging as it is readily evident that the biogenesis and routing of the multi-domain CFTR protein is a complex process involving a series of interactions and regulatory steps with rigorous quality control checks.
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