ABCC7 p.Glu838Ala
| Predicted by SNAP2: | A: N (78%), C: N (72%), D: N (87%), F: D (63%), G: N (72%), H: N (82%), I: N (72%), K: N (78%), L: N (78%), M: N (78%), N: N (82%), P: N (61%), Q: N (93%), R: N (72%), S: N (87%), T: N (82%), V: N (78%), W: D (71%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, 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.
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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.Glu838Ala 23060444:11:33
status: NEW60 Similar observations with D835A and E838A were summarized in Fig. 2D. The K1/2 for PKA activation reduced from 10 units/ml to 5 units/ml once K946 from the CL3, and D835, D836 and E838 from NEG2 were mutated to alanines (Fig.2D).
X
ABCC7 p.Glu838Ala 23060444:60:36
status: NEW138 First, the PKA sensitivity of channel activation was significantly enhanced for K946A, D835A, D836A and E838A mutants (Fig.2).
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ABCC7 p.Glu838Ala 23060444:138:104
status: NEW9 First, not only D835A, D836A, and E838A but also K946A reduced the PKA-dependent CFTR activation.
X
ABCC7 p.Glu838Ala 23060444:9:34
status: NEW63 Similar observations with D835A and E838A are summarized in Fig. 2D.
X
ABCC7 p.Glu838Ala 23060444:63:36
status: NEW167 First, the PKA sensitivity of channel activation was significantly enhanced for K946A, D835A, D836A, and E838A mutants (Fig. 2).
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ABCC7 p.Glu838Ala 23060444:167:105
status: NEW