ABCC7 p.Glu822Ala
| ClinVar: |
c.2464G>A
,
p.Glu822Lys
?
, not provided
c.2464G>T , p.Glu822* D , Pathogenic |
| CF databases: |
c.2464G>T
,
p.Glu822*
D
, CF-causing
c.2464G>A , p.Glu822Lys (CFTR1) ? , A nucleotide change, G->A was observed in exon 13 at position 2596 leading to E822K. The patient is 13 years old, and pancreatic insufficient. The other mutation is still unknown. This mutation was found once among 28 Belgian CF chromosomes. |
| Predicted by SNAP2: | A: D (53%), C: D (66%), D: D (66%), F: D (75%), G: D (71%), H: D (71%), I: D (63%), K: N (61%), L: D (66%), M: D (71%), N: D (71%), P: D (80%), Q: D (59%), R: D (75%), S: D (66%), T: D (63%), V: D (59%), W: D (80%), Y: D (75%), |
| 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: D, 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.Glu822Ala 20952391:132:100
status: NEW