CFTR: folding, misfolding and correcting the ΔF508 conformational defect

GL Lukacs, AS Verkman - Trends in molecular medicine, 2012 - cell.com
Trends in molecular medicine, 2012cell.com
Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is
caused by loss-of-function mutations of the CF transmembrane conductance regulator
(CFTR), a cyclic AMP-regulated plasma membrane chloride channel. The most common
mutation, deletion of phenylalanine 508 (ΔF508), impairs CFTR folding and, consequently,
its biosynthetic and endocytic processing as well as chloride channel function.
Pharmacological treatments may target the ΔF508 CFTR structural defect directly by binding …
Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is caused by loss-of-function mutations of the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated plasma membrane chloride channel. The most common mutation, deletion of phenylalanine 508 (ΔF508), impairs CFTR folding and, consequently, its biosynthetic and endocytic processing as well as chloride channel function. Pharmacological treatments may target the ΔF508 CFTR structural defect directly by binding to the mutant protein and/or indirectly by altering cellular protein homeostasis (proteostasis) to promote ΔF508 CFTR plasma membrane targeting and stability. This review discusses recent basic research aimed at elucidating the structural and trafficking defects of ΔF508 CFTR, a prerequisite for the rational design of CF therapy to correct the loss-of-function phenotype.
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