ABCMdb

ABCC7 p.Gly1349Ile

ClinVar:	c.4046G>A , p.Gly1349Asp D , Pathogenic c.4045G>A , p.Gly1349Ser ? , not provided
CF databases:	c.4046G>A , p.Gly1349Asp D , CF-causing ; CFTR1: We tested 20 non-[delta]F508 CF chromosomes and did not find a second example of this mutation. The mutation destroys an NcoI site. c.4045G>A , p.Gly1349Ser (CFTR1) D , The mutation was found using SSCP analysis and direct sequencing. It was detected in one of the CFTR alleles of a Japanese CBAVD patient. The patient has another mutation Q1352H in the other allele.
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (66%), E: D (95%), F: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Optimization of the degenerated interfacial ATP bi... J Biol Chem. 2010 Nov 26;285(48):37663-71. Epub 2010 Sep 22. Tsai MF, Jih KY, Shimizu H, Li M, Hwang TC
Optimization of the degenerated interfacial ATP binding site improves the function of disease-related mutant cystic fibrosis transmembrane conductance regulator (CFTR) channels.
J Biol Chem. 2010 Nov 26;285(48):37663-71. Epub 2010 Sep 22., 2010-11-26 [PMID:20861014]

Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, an ATP binding cassette (ABC) protein whose defects cause the deadly genetic disease cystic fibrosis (CF), encompasses two nucleotide binding domains (NBD1 and NBD2). Recent studies indicate that in the presence of ATP, the two NBDs coalesce into a dimer, trapping an ATP molecule in each of the two interfacial composite ATP binding sites (site 1 and site 2). Experimental evidence also suggests that CFTR gating is mainly controlled by ATP binding and hydrolysis in site 2, whereas site 1, which harbors several non-canonical substitutions in ATP-interacting motifs, is considered degenerated. The CF-associated mutation G551D, by introducing a bulky and negatively charged side chain into site 2, completely abolishes ATP-induced openings of CFTR. Here, we report a strategy to optimize site 1 for ATP binding by converting two amino acid residues to ABC consensus (i.e. H1348G) or more commonly seen residues in other ABC proteins (i.e. W401Y,W401F). Introducing either one or both of these mutations into G551D-CFTR confers ATP responsiveness for this disease-associated mutant channel. We further showed that the same maneuver also improved the function of WT-CFTR and the most common CF-associated DeltaF508 channels, both of which rely on site 2 for gating control. Thus, our results demonstrated that the degenerated site 1 can be rebuilt to complement or support site 2 for CFTR function. Possible approaches for developing CFTR potentiators targeting site 1 will be discussed.

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No. Sentence Comment
120 Interestingly, we found that non-conservative mutations L1346Q and S1347G (Fig. 3A) and G1349I greatly reduced the nucleotide-dependent activation of W401F/G551D channels. Login to comment
189 These mutations include W401G,W401I (Fig. 1, B-D), which eliminate a ring-ring stacking interaction, S1347G (supplemental Fig. S6), which may break a hydrogen bond between ATP and the NBD2 signature motif, and G1349I (supplemental Fig. S6), whose side chain likely protrudes into site 1 and causes a steric clash with ATP (22-24). Login to comment