ABCC7 p.Ser955Cys
| Predicted by SNAP2: | A: N (93%), C: N (78%), D: D (66%), E: D (66%), F: D (71%), G: N (66%), H: N (57%), I: D (71%), K: D (59%), L: D (66%), M: D (63%), N: N (78%), P: D (71%), Q: N (53%), R: N (57%), T: N (72%), V: D (63%), W: D (75%), Y: D (71%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, R: N, T: N, V: D, W: D, Y: D, |
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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
118 Supporting this argument, internal diamide also inhibited activity of a mutant S768C/K951C, S768C/H954C, or S768C/ S955C, and inhibition was reversed by 4-6 mM DTT (Fig. 2E).
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ABCC7 p.Ser955Cys 21059651:118:115
status: NEW119 In sharp contrast, both diamide and DTT had no effect on such CFTR constructs as K951C, H954C, and S955C.
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ABCC7 p.Ser955Cys 21059651:119:99
status: NEW122 Similarly, diamide also suppressed channel activity of mutants S737C/H954C, S737C/S955C, and S737C/Q958C, and suppression was reversed by DTT (Fig. 2E).
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ABCC7 p.Ser955Cys 21059651:122:82
status: NEW162 Because disulfide cross-linking of S768C to H950C inhibited more channel activity than that of S768C to S955C (Fig. 2E), it is more possible for His950 to form an inhibitory H-bond with Ser768 .
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ABCC7 p.Ser955Cys 21059651:162:104
status: NEW