ABCC7 p.Glu826Ala
| ClinVar: |
c.2476G>A
,
p.Glu826Lys
?
, not provided
|
| CF databases: |
c.2476G>A
,
p.Glu826Lys
(CFTR1)
?
, The above sequence alteration was found by DGGE analysis of a sarcoidosis patient. It was sequenced and confirmed with a Restriction site Generating PCR assay. It was absent by DGGE analysis in 208 control chromosomes, and by sequencing 60 chromosomes with unknown CFTR mutations.
|
| Predicted by SNAP2: | A: N (61%), C: D (53%), D: D (53%), F: N (53%), G: D (63%), H: N (66%), I: N (57%), K: N (66%), L: N (57%), M: N (61%), N: N (53%), P: D (63%), Q: N (66%), R: D (59%), S: N (53%), T: N (57%), V: N (53%), W: D (66%), Y: N (53%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, F: D, G: N, H: N, I: D, K: N, L: D, M: D, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: D, |
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[hide] State-dependent regulation of cystic fibrosis tran... J Biol Chem. 2010 Dec 24;285(52):40438-47. Epub 2010 Oct 15. Wang G
State-dependent regulation of cystic fibrosis transmembrane conductance regulator (CFTR) gating by a high affinity Fe3+ bridge between the regulatory domain and cytoplasmic loop 3.
J Biol Chem. 2010 Dec 24;285(52):40438-47. Epub 2010 Oct 15., 2010-12-24 [PMID:20952391]
Abstract [show]
The unique regulatory (R) domain differentiates the human CFTR channel from other ATP-binding cassette transporters and exerts multiple effects on channel function. However, the underlying mechanisms are unclear. Here, an intracellular high affinity (2.3 x 10(-19) M) Fe(3+) bridge is reported as a novel approach to regulating channel gating. It inhibited CFTR activity by primarily reducing an open probability and an opening rate, and inhibition was reversed by EDTA and phenanthroline. His-950, His-954, Cys-832, His-775, and Asp-836 were found essential for inhibition and phosphorylated Ser-768 may enhance Fe(3+) binding. More importantly, inhibition by Fe(3+) was state-dependent. Sensitivity to Fe(3+) was reduced when the channel was locked in an open state by AMP-PNP. Similarly, a K978C mutation from cytoplasmic loop 3 (CL3), which promotes ATP-independent channel opening, greatly weakened inhibition by Fe(3+) no matter whether NBD2 was present or not. Therefore, although ATP binding-induced dimerization of NBD1-NBD2 is required for channel gating, regulation of CFTR activity by Fe(3+) may involve an interaction between the R domain and CL3. These findings may support proximity of the R domain to the cytoplasmic loops. They also suggest that Fe(3+) homeostasis may play a critical role in regulating pathophysiological CFTR activity because dysregulation of this protein causes cystic fibrosis, secretary diarrhea, and infertility.
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No. Sentence Comment
132 Fig. 4, B and E, indicate that only D836A dramatically prevented inhibition by Fe3ϩ , whereas E822A, E826A, D828A, E831A, and D835A did not.
X
ABCC7 p.Glu826Ala 20952391:132:107
status: NEW