ABCC7 p.Asp836Ala
| ClinVar: |
c.2506G>T
,
p.Asp836Tyr
?
, not provided
|
| CF databases: |
c.2506G>T
,
p.Asp836Tyr
(CFTR1)
?
, This mutation was found in a French adult patient. The defect on the other chromosome is not yet characterized.
|
| Predicted by SNAP2: | A: N (72%), C: N (57%), E: N (93%), F: D (63%), G: D (53%), H: N (57%), I: D (53%), K: N (66%), L: N (66%), M: N (53%), N: N (57%), P: D (66%), Q: N (82%), R: D (59%), S: N (61%), T: N (82%), V: N (53%), W: N (53%), Y: N (53%), |
| Predicted by PROVEAN: | A: N, C: D, E: 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: N, |
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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.Asp836Ala 20952391:132:36
status: NEW133 Similarly, activity of the D836A mutant was also potentiated by curcumin dramatically (Fig. 4B).
X
ABCC7 p.Asp836Ala 20952391:133:27
status: NEW145 In support of this proposal, H950A/H954A and D836A/C832A/ H774A completely prevented Fe3ϩ inhibition, which was reversed by EDTA (Fig. 4E).
X
ABCC7 p.Asp836Ala 20952391:145:45
status: NEW203 B-D, macroscopic currents across inside-out membrane patches excised from transfected HEK-293T cells expressing the D836A mutant (B), the mouse CFTR (mCFTR) (C), and the H950A mutant (D).
X
ABCC7 p.Asp836Ala 20952391:203:116
status: NEW[hide] Regulation of Activation and Processing of the Cys... J Biol Chem. 2012 Oct 11. Wang G, Duan DD
Regulation of Activation and Processing of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by a Complex Electrostatic Interaction between the Regulatory Domain and Cytoplasmic Loop 3.
J Biol Chem. 2012 Oct 11., [PMID:23060444]
Abstract [show]
NEG2, a short C-terminal segment (817-838) of the unique regulatory (R) domain of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, has been reported to regulate CFTR gating in response to cAMP-dependent R domain phosphorylation. The underlying mechanism, however, is unclear. Here, K946 of cytoplasmic loop 3 (CL3) is proposed as counter-ion of D835, D836 or E838 of NEG2 to prevent channel activation by PKA. R764 or R766 of the S768 phosphorylation site of the R domain is proposed to promote channel activation possibly by weakening the putative CL3-NEG2 electrostatic attraction. First, not only D835A, D836A and E838A but also K946A reduced the PKA dependent CFTR activation. Second, both K946D and D835R/D836R/E838R mutants were activated by ATP and curcumin to a different extent. Third, R764A and R766A mutants enhanced the PKA-dependent activation. On the other hand, it is very exciting that D835R/D836R/E838R and K946D/H950D and H950R exhibited normal channel processing and activity while D835R/D836R/E838R/K946D/H950D was misprocessed and silent in response to forskolin. Further, D836R and E838R played a critical role in the asymmetric electrostatic regulation of CFTR processing and S768 phosphorylation may not be involved. Thus, a complex interfacial interaction among CL3, NEG2 and the S768 phosphorylation site may be responsible for the asymmetric electrostatic regulation of CFTR activation and processing.
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No. Sentence Comment
11 First, not only D835A, D836A and E838A but also K946A reduced the PKA dependent CFTR activation.
X
ABCC7 p.Asp836Ala 23060444:11:23
status: NEW138 First, the PKA sensitivity of channel activation was significantly enhanced for K946A, D835A, D836A and E838A mutants (Fig.2).
X
ABCC7 p.Asp836Ala 23060444:138:94
status: NEW9 First, not only D835A, D836A, and E838A but also K946A reduced the PKA-dependent CFTR activation.
X
ABCC7 p.Asp836Ala 23060444:9:23
status: NEW62 In contrast, mutation of Lys-946 or Asp-836 to alanine clearly accelerated the channel activation and reduced the PKA dependence (Fig. 2, B and C).
X
ABCC7 p.Asp836Ala 23060444:62:36
status: NEW98 The PKA-dependent activity of CFTR mutants at the R-CL3 interface. A-C, macroscopic currents across inside-out membrane patches excised from transfected HEK-293T cells expressing WT CFTR (A) and mutants K946A (B) and D836A (C) by using a ramp protocol (afe;80 mV).
X
ABCC7 p.Asp836Ala 23060444:98:217
status: NEW167 First, the PKA sensitivity of channel activation was significantly enhanced for K946A, D835A, D836A, and E838A mutants (Fig. 2).
X
ABCC7 p.Asp836Ala 23060444:167:94
status: NEW