Manipulating the Folding Pathway of ΔF508 CFTR Using Chemical Chaperones

Defects in protein folding constitute the basis of many genetic diseases: cystic fibrosis, alpha-1 antitrypsin deficiency, familial hypercholesterolemia, and congenital nephrogenic diabetes insipidus, to name but a few (see Table 1 for a complete list). In each of these, point mutations or deletions result in a protein product that fails to achieve its properly folded state. For example, in the case of the cystic fibrosis transmembrane conductance regular protein (CFTR), the most common mutation in patients is the loss of a single phenylalanine residue (at position 508) within a polypeptide of 1480 amino acids (1 ). This seemingly minor alteration results in the newly synthesized CFTR protein being unable to fold properly and traffic to its proper destination at the plasma membrane (2 ). Instead, the vast majority of the mutant protein is retained at an early point in its maturation pathway and over time is targeted to a degradative pathway (3 -5 ). As a consequence, cells expressing the mutant protein are unable to transport chloride ions across the plasma membrane in response to rises in intracellular cAMP levels.