ABCC7 p.Gly406Ala
| Predicted by SNAP2: | A: N (78%), C: N (61%), D: N (72%), E: N (72%), F: D (53%), H: N (53%), I: N (72%), K: N (78%), L: N (66%), M: N (57%), N: N (87%), P: N (82%), Q: N (87%), R: N (72%), S: N (87%), T: N (82%), V: N (78%), W: D (59%), Y: N (53%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Identification and partial characterization of a d... Curr Biol. 1995 Oct 1;5(10):1159-67. Sullivan SK, Agellon LB, Schick R
Identification and partial characterization of a domain in CFTR that may bind cyclic nucleotides directly.
Curr Biol. 1995 Oct 1;5(10):1159-67., [PMID:8548288]
Abstract [show]
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is activated by cAMP-dependent phosphorylation. CFTR channel activity is also stimulated by cGMP-dependent protein kinase and protein kinase C. RESULTS: Here, we show that CFTR channel activation by cGMP may also occur directly. In oocytes from one-third of Xenopus donors, the activation of CFTR by cGMP averaged 87% of the level achieved by cAMP. The currents activated by either cyclic nucleotide displayed similar current-voltage relationships, kinetics, pharmacology and halide selectivity. Sequential stimulation by cAMP and cGMP was not additive, suggesting that both cyclic nucleotides activate the same channel; cGMP was one order of magnitude more potent than cAMP, and its action was insensitive to protein kinase inhibitors. Analysis of the amino-acid sequence of CFTR revealed a domain in the amino-terminal portion of the third cytoplasmic loop that resembles a class of cyclic-nucleotide-binding domains related to that of the catabolite-gene activator protein, CAP. Two CFTR residues in this domain--Val397 and Lys420--were identified which, when changed to alanine, altered the response to cGMP independently of the response to cAMP. CONCLUSIONS: We conclude that direct cyclic nucleotide binding may play a role in channel gating of CFTR. The cGMP-binding domain may provide a useful target for pharmacologic intervention in cystic fibrosis.
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No. Sentence Comment
133 The G406A mutant responded normally to cGMP (Fig. 7a,c).
X
ABCC7 p.Gly406Ala 8548288:133:4
status: NEW148 (b) Effect of V397A substitution compared with the wild-type CFTR (n = 5).
X
ABCC7 p.Gly406Ala 8548288:148:14
status: NEW149 (c) Effect of G406A or K420A substitutions compared with wild-type CFTR (n= 4).
X
ABCC7 p.Gly406Ala 8548288:149:14
status: NEW152 The three other single-substitution mutants (V397A, G406A and K420A) produced functional channels that responded to cAMP in a manner identical to wild type, Direct activation may also be modulated by phosphorylation.
X
ABCC7 p.Gly406Ala 8548288:152:52
status: NEW175 The substitution of an alanine for the glycine at position 406, which replaced the minimal proton with a bulkier methyl group, had no effect on activation by cGMP As this glycine is invariant, the substitution was predicted to be disruptive.
X
ABCC7 p.Gly406Ala 8548288:175:23
status: NEW132 The G406A mutant responded normally to cGMP (Fig. 7a,c).
X
ABCC7 p.Gly406Ala 8548288:132:4
status: NEW151 The three other single-substitution mutants (V397A, G406A and K420A) produced functional channels that responded to cAMP in a manner identical to wild type, Direct activation may also be modulated by phosphorylation.
X
ABCC7 p.Gly406Ala 8548288:151:52
status: NEW174 The substitution of an alanine for the glycine at position 406, which replaced the minimal proton with a bulkier methyl group, had no effect on activation by cGMP As this glycine is invariant, the substitution was predicted to be disruptive.
X
ABCC7 p.Gly406Ala 8548288:174:23
status: NEW