Q4N2NEG2 ENHANCES CFTR ACTIVITY

摘要

Phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) by cyclic AMP− dependent protein kinase (PAK) is essential for opening the CFTR chloride channel. A short segment containing many negatively charged amino acids (817−838, NEG2) within the regulatory (R) domain of CFTR is a critical regulator of the chloride channel activity. An isolated NEG2 polypeptide may be expressed as a separate sequence that stimulates CFTR channel openings at lowe concentrations, but that inhibits CFTR channel openings at higher concentrations. Residues in the NEG2 sequence were substituted to produce a polypeptide that exerts only an activating effect on CFTR. One such polypeptide is the Q4N2NEG2 polypeptide. Exogenous Q4N2NEG2 exerts stimulatory effects on both wild−type and mutant G551D CFTR function, without exhibiting inhibitory activity at any concentration.