Cystic fibrosis transmembrane conductance regulator (CFTR) ΔF508 NBD1-ICL4 interface (ΔF508-CFTR NBD1-ICL4 interface)

The ΔF508-CFTR NBD1-ICL4 interface is a critical structural junction within the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, which functions as a cAMP-regulated chloride channel (UniProt P13569). In the wild-type protein, the phenylalanine at position 508 (F508) in the first nucleotide-binding domain (NBD1) mediates a vital interaction with the fourth intracellular loop (ICL4), which is essential for the correct folding and assembly of the channel (PubMed: 23792957). The deletion of this residue (ΔF508) disrupts this interface, leading to misfolding, premature degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway, and a lack of functional chloride channels at the cell surface (NIH, 2023). This defect is the primary cause of cystic fibrosis in the majority of patients worldwide (StatPearls, 2023). Therapeutic agents known as "correctors," such as lumacaftor and tezacaftor, target this structural instability by acting as pharmacological chaperones (PubMed: 21164002). These drugs aim to stabilize the NBD1-ICL4 interface or compensate for its loss, allowing the mutant protein to escape degradation and reach the plasma membrane where it can function as an ion channel (PubMed: 30413611).

Other names

F508del-CFTR NBD1-ICL4 interfaceCFTR intracellular loop 4-nucleotide binding domain 1 interfaceΔF508-CFTR ICL4/NBD1 interfaceCFTR MSD2-NBD1 interface

Pharmacological chaperone that stabilizes the interaction between the first nucleotide-binding domain (NBD1) and the fourth intracellular loop (ICL4) to correct the folding and trafficking of the ΔF508-CFTR protein.