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Activation mechanisms for the cystic fibrosis transmembrane conductance regulator protein involve direct binding of cAMP

Pereira, Malcolm Martin Claude, Parker, Jody, Stratford, Fiona L. L., McPherson, Margaret Ann and Dormer, Robert Leslie 2007. Activation mechanisms for the cystic fibrosis transmembrane conductance regulator protein involve direct binding of cAMP. Biochemical Journal 405 (1) , pp. 181-189. 10.1042/BJ20061879

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The CFTR [CF (cystic fibrosis) transmembrane conductance regulator] chloride channel is activated by cyclic nucleotide-dependent phosphorylation and ATP binding, but also by non-phosphorylation-dependent mechanisms. Other CFTR functions such as regulation of exocytotic protein secretion are also activated by cyclic nucleotide elevating agents. A soluble protein comprising the first NBD (nucleotide-binding domain) and R-domain of CFTR (NBD1–R) was synthesized to determine directly whether CFTR binds cAMP. An equilibrium radioligand-binding assay was developed, firstly to show that, as for full-length CFTR, the NBD1–R protein bound ATP. Half-maximal displacement of [3H]ATP by non-radioactive ATP at 3.5 µM and 3.1 mM was demonstrated. [3H]cAMP bound to the protein with different affinities from ATP (half-maximal displacement by cAMP at 2.6 and 167 µM). Introduction of a mutation (T421A) in a motif predicted to be important for cyclic nucleotide binding decreased the higher affinity binding of cAMP to 9.2 µM. The anti-CFTR antibody (MPNB) that inhibits CFTR-mediated protein secretion also inhibited cAMP binding. Thus binding of cAMP to CFTR is consistent with a role in activation of protein secretion, a process defective in CF gland cells. Furthermore, the binding site may be important in the mechanism by which drugs activate mutant CFTR and correct defective DF508-CFTR trafficking

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: cAMP ; Cyclic nucleotide ; Cystic fibrosis transmembrane conductance regulator ; Ligand binding ; Mutation ; Protein secretion
ISSN: 0264-6021
Last Modified: 18 Oct 2017 08:22

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