ABCC7 p.Val769Cys
| Predicted by SNAP2: | A: N (61%), C: N (66%), D: D (80%), E: D (75%), F: N (66%), G: D (75%), H: D (75%), I: N (82%), K: D (75%), L: N (82%), M: N (72%), N: D (71%), P: D (80%), Q: D (63%), R: D (80%), S: N (61%), T: N (66%), W: D (75%), Y: D (63%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: D, H: D, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, W: D, Y: N, |
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[hide] The inhibition mechanism of non-phosphorylated Ser... J Biol Chem. 2011 Jan 21;286(3):2171-82. Epub 2010 Nov 8. Wang G
The inhibition mechanism of non-phosphorylated Ser768 in the regulatory domain of cystic fibrosis transmembrane conductance regulator.
J Biol Chem. 2011 Jan 21;286(3):2171-82. Epub 2010 Nov 8., 2011-01-21 [PMID:21059651]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette transporters but serves as a chloride channel dysfunctional in cystic fibrosis. The activity of CFTR is tightly controlled not only by ATP-driven dimerization of its nucleotide-binding domains but also by phosphorylation of a unique regulatory (R) domain by protein kinase A (PKA). The R domain has multiple excitatory phosphorylation sites, but Ser(737) and Ser(768) are inhibitory. The underlying mechanism is unclear. Here, sulfhydryl-specific cross-linking strategy was employed to demonstrate that Ser(768) or Ser(737) could interact with outwardly facing hydrophilic residues of cytoplasmic loop 3 regulating channel gating. Furthermore, mutation of these residues to alanines promoted channel opening by curcumin in an ATP-dependent manner even in the absence of PKA. However, mutation of Ser(768) and His(950) with different hydrogen bond donors or acceptors clearly changed ATP- and PKA-dependent channel activity no matter whether curcumin was present or not. More importantly, significant activation of a double mutant H950R/S768R needed only ATP. Finally, in vitro and in vivo single channel recordings suggest that Ser(768) may form a putative hydrogen bond with His(950) of cytoplasmic loop 3 to prevent channel opening by ATP in the non-phosphorylated state and by subsequent cAMP-dependent phosphorylation. These observations support an electron cryomicroscopy-based structural model on which the R domain is closed to cytoplasmic loops regulating channel gating.
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No. Sentence Comment
120 Furthermore, channel activity of V769C/H950C was also inhibited by diamide (Fig. 2E), suggesting that phosphorylation of Ser768 may not affect the CL3-R interface.
X
ABCC7 p.Val769Cys 21059651:120:33
status: NEW