What is the consequence of F508 mutation in CFTR?
DeltaF508, deletion of phenylalanine at position 508 in nucleotide-binding domain 1 of CFTR, is most prevalent cystic fibrosis mutation worldwide present in approximately 70 percent patients. F508 lies at interface between NBD1 and intracellular loops from transmembrane domains, crucial for domain assembly during co-translational folding. Loss destabilizes NBD1 thermally, impairs interdomain contacts, causing kinetic folding trap recognized by chaperones Hsp70 and Hsp90, ubiquitination by RNF4 and retention in endoplasmic reticulum for ER-associated degradation via proteasome. Even when manipu
Ref: Lukacs & Verkman, Trends Mol Med 2012, F508del processing; Riordan, Annu Rev Biochem 2008, CFTR folding.