Cystic fibrosis transmembrane conductance regulator (CFTR) NBD1–ICL4 interface (CFTR NBD1–ICL4 interface)

The Cystic fibrosis transmembrane conductance regulator (CFTR) NBD1–ICL4 interface is a pivotal structural domain interaction between the first nucleotide-binding domain (NBD1) and the fourth intracellular loop (ICL4) of the CFTR protein (UniProt: P13569). This interface is vital for the conformational stability and correct folding of the CFTR channel, which facilitates chloride and bicarbonate transport across epithelial membranes (Fiedorczuk & Chen, Cell, 2019). The deletion of phenylalanine 508 (F508del), the most prevalent mutation in cystic fibrosis, destabilizes NBD1 and specifically disrupts its coupling with ICL4, leading to protein misfolding and premature degradation (Serohijos et al., PNAS, 2008). Small-molecule correctors like lumacaftor and tezacaftor function by binding to this interface, acting as pharmacological chaperones that bridge the gap between NBD1 and ICL4 (He et al., Nature, 2013). This stabilization allows the mutant protein to escape cellular quality control mechanisms and reach the plasma membrane (Loo & Clarke, J. Biol. Chem., 2017). Consequently, this interface represents a primary therapeutic site for restoring ion channel function in patients with the F508del mutation.

Other names

CFTR Intracellular Loop 4 interfaceNBD1-CL4 interfaceNBD1-ICL4 coupling siteCFTR ICL4

Pharmacological chaperone-mediated stabilization of the interdomain interface between the first nucleotide-binding domain (NBD1) and the fourth intracellular loop (ICL4) to promote proper protein folding and trafficking to the cell surface.