The regulatory (R) domain of CFTR is phosphorylated by:
Regulatory R domain of CFTR spanning approximately residues 590 to 850 is an intrinsically disordered segment bridging NBD1 and TMD2 containing numerous consensus PKA and PKC phosphorylation sites. Phosphorylation is central to activation. Elevated intracellular cAMP activates protein kinase A which phosphorylates serines including Ser660, Ser737, Ser795, Ser813 and Ser768, neutralizing inhibitory interactions between R domain and NBDs and between NBD1-NBD2 interface. This conformational unblocking permits ATP binding to NBDs, dimer formation, and pore opening. Protein kinase C, Ca2+/calmodulin kinase and Src kinases provide modulatory phosphorylation but PKA is obligatory; non-phosphorylated CFTR remains closed even with ATP present. Dephosphorylation by PP2A and PP2C closes channel. Disease variants lacking PKA sites or with R domain deletions show reduced open probability. Potentiator ivacaftor enhances gating after phosphorylation, illustrating therapeutic relevance of understanding kinase regulation of this atypical ABC channel in epithelial fluid secretion and electrolyte homeostasis. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.
Ref: Hwang & Sheppard, Trends Pharmacol Sci 2009, CFTR R domain regulation; Riordan, Annu Rev Biochem 2008.