Repair of CFTR Folding Defects with Correctors that Function as Pharmacological Chaperones
The major cause of cystic fibrosis is the presence of processing mutations in CFTR (such as deletion of Phe-508 (F508del-CFTR)) that disrupt folding of the protein and trafficking to the cell surface. Processing mutations appear to inhibit folding of CFTR so that it accumulates in the endoplasmic reticulum as a partially folded protein. Expressing the proteins in the presence of small molecules called correctors can repair CFTR folding defects. Some correctors appear to function as pharmacological chaperones that specifically bind to the CFTR processing mutants and induce them to complete the folding process. In this chapter, we describe techniques to examine the effects of correctors on folding of CFTR processing mutants.
Key wordsF508del-CFTR corrector processing mutant protein folding glycosylation disulfide cross-linking protein maturation
This work was supported by funds from the Canadian Institutes for Health Research (Grant 62832) and the Cystic Fibrosis Foundation (Grant CLARKE08GO).