ABCMdb

ABCC7 p.Ser737Cys

ClinVar:	c.2210C>T , p.Ser737Phe ? , not provided
CF databases:	c.2210C>T , p.Ser737Phe (CFTR1) ? , This nucleotide change was identified in two Italian patients.
Predicted by SNAP2:	A: N (61%), C: D (59%), D: D (75%), E: D (66%), F: N (61%), G: N (66%), H: D (63%), I: N (57%), K: N (57%), L: N (53%), M: N (53%), N: N (72%), P: D (71%), Q: N (66%), R: D (66%), T: N (78%), V: N (61%), W: D (75%), 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: D, M: D, N: N, P: N, Q: N, R: N, T: N, V: D, W: D, Y: D,

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Publications
[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
94 S768C or S737C were fixed as an anchor point to search other inhibitory targets from CL3 (Fig. 2A). Login to comment
122 Similarly, diamide also suppressed channel activity of mutants S737C/H954C, S737C/S955C, and S737C/Q958C, and suppression was reversed by DTT (Fig. 2E). Login to comment
125 Fig. 3 demonstrates that a CFTR construct with a single cysteine S768C, S737C, H950C, or H954C exhibited a clear single band no matter whether diamide or DTT was added. Login to comment
126 In sharp contrast, CFTR constructs with a cysteine pair (Cys-free background), S737C/H950C, S737C/H954C, S768C/H950C, and S768C/H954C, exhibited an additional cross-linked (X-linked) band because it was induced by diamide but was weakened by DTT. Login to comment
128 Therefore, a disulfide bond can be formed between H950C (or H954C) and S768C or between H954C (or H950C) and S737C. Login to comment
143 In contrast, curcumin had no such effect on S737A and H954A mutants, suggesting that they may be weak inhibitory residues, although disulfide cross-linking of S737C to H954C strongly inhibited channel activity (Figs. 2E and 4E). Login to comment