ABCC7 p.Lys420Ala
| Predicted by SNAP2: | A: N (57%), C: N (53%), D: N (57%), E: N (53%), F: D (53%), G: N (66%), H: N (66%), I: N (57%), L: N (57%), M: D (59%), N: N (87%), P: D (53%), Q: N (61%), R: N (78%), S: N (66%), T: N (66%), V: N (57%), W: D (71%), Y: D (53%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: 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
135 The V397A mutant displayed a cGMP response that was enhanced by 66 + 19 % (n = 5; p < 0.05) relative to the wild-type channel (Fig. 7a,b).
X
ABCC7 p.Lys420Ala 8548288:135:4
status: NEW136 The K420A substitution, which produced the largest effect, reduced the cGMP response by 75 ± 6 % (n = 4; p < 0.005; Fig. 7a,c) compared with the wild-type channel.
X
ABCC7 p.Lys420Ala 8548288:136:4
status: NEW148 (b) Effect of V397A substitution compared with the wild-type CFTR (n = 5).
X
ABCC7 p.Lys420Ala 8548288:148:23
status: NEW149 (c) Effect of G406A or K420A substitutions compared with wild-type CFTR (n= 4).
X
ABCC7 p.Lys420Ala 8548288:149:23
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.Lys420Ala 8548288:152:62
status: NEW178 The substitution of an alanine for the lysine at position 420 was predicted to disrupt an ionic interaction with exocyclic phosphate oxygen, resulting in reduced activation by cGMP.
X
ABCC7 p.Lys420Ala 8548288:178:23
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.Lys420Ala 8548288:151:62
status: NEW177 The substitution of an alanine for the lysine at position 420 was predicted to disrupt an ionic interaction with exocyclic phosphate oxygen, resulting in reduced activation by cGMP.
X
ABCC7 p.Lys420Ala 8548288:177:23
status: NEW