14-3-3 protein–CFTR regulatory domain protein-protein interface

The 14-3-3 protein–CFTR protein-protein interface refers to the direct interaction between members of the 14-3-3 family of regulatory adapter proteins and specific, phosphorylated motifs within the regulatory (R) domain of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is an ABC transporter family ion channel critical for chloride and bicarbonate transport across epithelial membranes, and is the causal protein underlying cystic fibrosis when mutated[2][4][10]. The multiphosphorylated CFTR R-domain contains a number of consensus 14-3-3 binding sites, with Ser768 acting as the principal anchor motif. Binding of 14-3-3 to CFTR enhances trafficking of CFTR to the plasma membrane, reduces its degradation, and increases functional expression, which is especially relevant for disease-causing variants like ΔF508. The 14-3-3–CFTR interaction is considered druggable; small molecules such as fusicoccin-A can stabilize this complex, suggesting a novel therapeutic strategy for cystic fibrosis. However, specific drugs targeting this interface are still experimental. This interface is best classified as a regulatory protein-protein interaction rather than a conventional single-molecule target[1][3][5][7].

Other names

14-3-3–CFTR interface14-3-3/CFTR interaction14-3-3 protein–cystic fibrosis transmembrane conductance regulator R-domain interaction

Stabilization of 14-3-3–CFTR interaction increases CFTR trafficking and surface expression, potentially restoring function to mistrafficked mutant CFTR (e.g., ΔF508 variant)[3][5][1].