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The folding of a protein to its final native state involves a series of complex steps of intra- and intermolecular interactions between the nascent polypeptide chain, its solvent environment, and the quality control machinery of the cell (1). These steps are often halting, as the unfolded protein visits a series of intermediates states en route to its final native structure. In the cell, undesirable reactions such as aggregation and proteolytic degradation compete for these folding intermediates, shuffling them off the productive folding pathway (see Fig. 1). Thus, in order to properly fold, many proteins require the oversight of molecular chaperones that bias intermediates towards productive folding rather than off-pathway self-associations (2). Changes in this delicate balance between on- and off-pathway reactions have ramifications both for human health and the study of proteins of structural interest or of commercial utility. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF), a severe autosomal recessive disorder, is marked by reduced regulated chloride conductance across the apical membrane of affected epithelia. This reduction is attributable to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which acts as an ATP-dependent cAMP-regulated chloride channel. As shown in Fig. 1, CFTR is a multidomain membrane protein composed of five functional domains: two nucleotide-bind-ing domains (NBD), two transmembrane domains (TMD), and a regulatory domain (R). The most prevalent cystic fibrosis-causing mutation is the deletion of the F508 residue in NBD1 of CFTR (2,2). This deletion affects the ability of the domain, and thus the CFTR protein, to fold into its native state (3), leading to its retention in the endoplasmic reticulum (ER) and subsequent degradation (4). [ABSTRACT FROM AUTHOR]