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초록·키워드
Activation of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl<sup>‒</sup> channel requires PKA phosphorylation at the regulatory (R) domain to relieve inhibition of ATP-dependent channel activity. This study aimed to identify the primary inhibitory site that prevents channel activation. CFTR mutants with deletion of residues 760 to 783 (ΔR<sub>760-783</sub>) elicited constitutive macroscopic and single-channel Cl<sup>‒</sup> currents in the presence of ATP before PKA phosphorylation, suggesting that protein segment R<sub>760-783</sub> in the R domain blocks CFTR activation. With the background of ΔR<sub>760-835</sub>, further deletion of R<sub>708-759</sub> led to fully active channels in the presence of ATP, but the absence of PKA, suggesting that R<sub>708-759</sub> prevents the activation of ΔR<sub>760-835</sub>-CFTR. R<sub>760-783</sub> peptides were unstructured in buffered solutions in CD spectroscopy and the N771P mutation that interrupts the α-helix formation induced no apparent constitutive current before PKA phosphorylation. These data suggest that interpeptide interactions by α-helices likely contribute trivially to the blocking effect of R<sub>760-783</sub>. CFTR mutants with small deletions or alanine replacements containing any one of residues R<sup>766</sup> and S<sup>768</sup> in a PKA consensus sequence and M<sup>773</sup> and T<sup>774</sup> generated PKA-independent CFTR Cl<sup>‒</sup> currents. Similarly, introducing the mutations Q767C or T774C into a control CFTR construct produced constitutive CFTR Cl<sup>‒</sup> currents by positively charged 2-(trimethylammonium)ethylmethanethiosulfonate modification of target cysteines. Moreover, PKA-independent single-channel activity was evidently observed in R766K-, S768K-, and T774K-CFTR mutants. Therefore, the four residues, R<sup>766</sup>, S<sup>768</sup>, M<sup>773</sup>, and T<sup>774</sup>, may form an inhibitory module that precludes CFTR activation through side-chain interactions. This inhibitory mechanism might be emulated by other PKA-dependent proteins.
#Regulator
#Cystic fibrosis transmembrane conductance regulator
#Inhibitory postsynaptic potential
#Cystic fibrosis
#Cell biology
#Chemistry
#Domain (mathematical analysis)
#Transmembrane protein
#Transmembrane domain
#Conductance
#Biophysics
#Cluster (spacecraft)
#Biochemistry
#Biology
#Neuroscience
#Membrane
#Physics
#Computer science
#Receptor
#Mathematics
#Genetics
#Gene
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