ABCC7 p.Leu548Cys
| CF databases: |
c.1643T>A
,
p.Leu548Gln
(CFTR1)
?
,
|
| Predicted by SNAP2: | A: D (85%), C: D (75%), D: D (95%), E: D (95%), F: D (63%), G: D (95%), H: D (91%), I: D (71%), K: D (95%), M: D (75%), N: D (95%), P: D (95%), Q: D (91%), R: D (95%), S: D (91%), T: D (91%), V: D (75%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Mutations at the signature sequence of CFTR create... J Gen Physiol. 2009 Jan;133(1):69-77. Wang X, Bompadre SG, Li M, Hwang TC
Mutations at the signature sequence of CFTR create a Cd(2+)-gated chloride channel.
J Gen Physiol. 2009 Jan;133(1):69-77., [PMID:19114635]
Abstract [show]
The canonical sequence LSGGQ, also known as the signature sequence, defines the adenosine triphosphate (ATP)-binding cassette transporter superfamily. Crystallographic studies reveal that the signature sequence, together with the Walker A and Walker B motifs, forms the ATP-binding pocket upon dimerization of the two nucleotide-binding domains (NBDs) in a head-to-tail configuration. The importance of the signature sequence is attested by the fact that a glycine to aspartate mutation (i.e., G551D) in cystic fibrosis transmembrane conductance regulator (CFTR) results in a severe phenotype of cystic fibrosis. We previously showed that the G551D mutation completely eliminates ATP-dependent gating of the CFTR chloride channel. Here, we report that micromolar [Cd(2+)] can dramatically increase the activity of G551D-CFTR in the absence of ATP. This effect of Cd(2+) is not seen in wild-type channels or in G551A. Pretreatment of G551D-CFTR with the cysteine modification reagent 2-aminoethyl methane thiosulfonate hydrobromide protects the channel from Cd(2+) activation, suggesting an involvement of endogenous cysteine residue(s) in mediating this effect of Cd(2+). The mutants G551C, L548C, and S549C, all in the signature sequence of CFTR's NBD1, show robust response to Cd(2+). On the other hand, negligible effects of Cd(2+) were seen with T547C, Q552C, and R553C, indicating that a specific region of the signature sequence is involved in transmitting the signal of Cd(2+) binding to the gate. Collectively, these results suggest that the effect of Cd(2+) is mediated by a metal bridge formation between yet to be identified cysteine residue(s) and the engineered aspartate or cysteine in the signature sequence. We propose that the signature sequence serves as a switch that transduces the signal of ligand binding to the channel gate.
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No. Sentence Comment
22 The mutants G551C, L548C, and S549C, all in the signature sequence of CFTR`s NBD1, show robust response to Cd2+ .
X
ABCC7 p.Leu548Cys 19114635:22:19
status: NEW107 However, for L548C, S549C, and G551C, the specificity of the ligand is altered so that Cd2+ becomes more effective at gating Cd2+ Is More Potent on G551C than on G551D We considered two possible mechanisms for the effect of Cd2+ on G551D-CFTR.
X
ABCC7 p.Leu548Cys 19114635:107:13
status: NEW148 D I S C U S S I O N Here, we show that micromolar concentrations of Cd2+ can dramatically increase the activity of G551D-CFTR, a disease-associated mutant, as well as G551C-CFTR, L548C, and S549C-CFTR, in the absence of ATP.
X
ABCC7 p.Leu548Cys 19114635:148:179
status: NEW