ABCC7 p.Arg764Ala
| ClinVar: |
c.2290C>T
,
p.Arg764*
D
, Pathogenic
|
| CF databases: |
c.2290C>T
,
p.Arg764*
D
, CF-causing
|
| Predicted by SNAP2: | A: D (59%), C: D (66%), D: D (80%), E: D (66%), F: D (63%), G: D (63%), H: N (66%), I: N (53%), K: N (82%), L: D (53%), M: N (53%), N: D (66%), P: D (71%), Q: N (61%), S: D (59%), T: D (53%), V: N (53%), W: D (80%), Y: D (53%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: N, |
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[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.
Comments [show]
None has been submitted yet.
No. Sentence Comment
11 First, not only D835A, D836A and E838A but also K946A reduced the PKA dependent CFTR activation.
X
ABCC7 p.Arg764Ala 23060444:11:7
status: NEW13 Third, R764A and R766A mutants enhanced the PKA-dependent activation.
X
ABCC7 p.Arg764Ala 23060444:13:7
status: NEW116 The effects of R764A and R766A on the PKA-dependent channel activation - Because both S768 and D836 are close to H950 of CL3, it is fitting to ask if R764, R765 and R766 form a salt bridge with the N-terminal of NEG2 to cause the asymmetry of the electrostatic regulation.
X
ABCC7 p.Arg764Ala 23060444:116:15
status: NEW118 Fig. 4D demonstrates that both R764A and R766A exhibited a normal channel density.
X
ABCC7 p.Arg764Ala 23060444:118:31
status: NEW121 The K1/2 for PKA activation of R764A and R766A increased from 10 units/ml to 25 and 44 units/ml, respectively.
X
ABCC7 p.Arg764Ala 23060444:121:31
status: NEW140 Finally, it is very exciting that the putative electrostatic attraction between K946D/H950D and D835R/D836R/E838R dramatically suppressed the channel activity by stopping the channel processing or opening(10).
X
ABCC7 p.Arg764Ala 23060444:140:15
status: NEW145 Our finding shows that R764A and R766A suppressed not the channel processing and the current density but the channel activation by PKA (Fig. 4-6).
X
ABCC7 p.Arg764Ala 23060444:145:23
status: NEW142 Fig. 4D demonstrates that both R764A and R766A exhibited a normal channel density.
X
ABCC7 p.Arg764Ala 23060444:142:31
status: NEW151 The currents mediated by S768D/K946D/H950D/D836R and S768D/K946D/H950D/E838R were statistically smaller than the S768D/K946D/H950D current (n afd; 3,*, p b0d; 0.05, unpaired t test); error bars, S.E. TABLE 1 WholecellcurrentsIm (picoamperes)andcapacitancesCm (picofarads) of HEK-293T cells expressing CFTR constructs in response to forskolin Constructs Stimulated Im Control Cm Stimulated Cm n WT-CFTR 701.6 afe; 9.0 17.4 afe; 0.9 16.4 afe; 1.1 3 D835R/D836R/E838R 539.5 afe; 5.3 15.0 afe; 1.0 16.2 afe; 0.8 3 Asymmetric Electrostatic Regulation of CFTR 40488 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 287ߦNUMBER 48ߦNOVEMBER 23, 2012 at SEMMELWEIS UNIV OF MEDICINE on December , The K1/2 for PKA activation of R764A and R766A increased from 10 units/ml to 25 and 44 units/ml, respectively.
X
ABCC7 p.Arg764Ala 23060444:151:744
status: NEW173 The PKA-dependent activity of CFTR mutants R764A and R766A.
X
ABCC7 p.Arg764Ala 23060444:173:43
status: NEW179 B, PKA titration curves for CFTR mutants R764A and R766A (n afd; 3-5).
X
ABCC7 p.Arg764Ala 23060444:179:41
status: NEW184 Our finding shows that R764A and R766A suppressed not the channel processing and the current density but the channel activation by PKA (Figs. 4-6).
X
ABCC7 p.Arg764Ala 23060444:184:23
status: NEW