ABCMdb

ABCC7 p.Gln1291Gly

ClinVar:	c.3872A>G , p.Gln1291Arg ? , not provided c.3871C>T , p.Gln1291* ? , not provided c.3873G>C , p.Gln1291His D , Pathogenic
CF databases:	c.3872A>G , p.Gln1291Arg (CFTR1) D , Q1291R, an A->G substitution at nucleotide position 4004 in exon 20 has a haplotype of 2-2-1 (KM19-D9-J44) with seven GATT repeats. The mutation creates a new BsaJI site.
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: N (82%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), R: N (78%), 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, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Mutating the Conserved Q-loop Glutamine 1291 Selec... J Biol Chem. 2015 May 29;290(22):14140-53. doi: 10.1074/jbc.M114.611616. Epub 2015 Apr 17. Dong Q, Ernst SE, Ostedgaard LS, Shah VS, Ver Heul AR, Welsh MJ, Randak CO
Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia.
J Biol Chem. 2015 May 29;290(22):14140-53. doi: 10.1074/jbc.M114.611616. Epub 2015 Apr 17., [PMID:25887396]

Abstract [show]
The ATP-binding cassette (ABC) transporter cystic fibrosis transmembrane conductance regulator (CFTR) and two other non-membrane-bound ABC proteins, Rad50 and a structural maintenance of chromosome (SMC) protein, exhibit adenylate kinase activity in the presence of physiologic concentrations of ATP and AMP or ADP (ATP + AMP left arrow over right arrow 2 ADP). The crystal structure of the nucleotide-binding domain of an SMC protein in complex with the adenylate kinase bisubstrate inhibitor P(1),P(5)-di(adenosine-5') pentaphosphate (Ap5A) suggests that AMP binds to the conserved Q-loop glutamine during the adenylate kinase reaction. Therefore, we hypothesized that mutating the corresponding residue in CFTR, Gln-1291, selectively disrupts adenylate kinase-dependent channel gating at physiologic nucleotide concentrations. We found that substituting Gln-1291 with bulky side-chain amino acids abolished the effects of Ap5A, AMP, and adenosine 5'-monophosphoramidate on CFTR channel function. 8-Azidoadenosine 5'-monophosphate photolabeling of the AMP-binding site and adenylate kinase activity were disrupted in Q1291F CFTR. The Gln-1291 mutations did not alter the potency of ATP at stimulating current or ATP-dependent gating when ATP was the only nucleotide present. However, when physiologic concentrations of ADP and AMP were added, adenylate kinase-deficient Q1291F channels opened significantly less than wild type. Consistent with this result, we found that Q1291F CFTR displayed significantly reduced Cl(-) channel function in well differentiated primary human airway epithelia. These results indicate that a highly conserved residue of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Furthermore, the results suggest that adenylate kinase activity is important for normal CFTR channel function in airway epithelia.

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No. Sentence Comment
142 Gln mutations that resulted in shortening (Q1291A) or deletion (Q1291G) of the side chain reduced Ap5A inhibition (Fig. 3, A FIGURE 1. Login to comment
154 To further evaluate the effect of these mutations, we tested inhibition of Q1291G CFTR current with a range of ApA concentrations. Login to comment
181 No significant differences were detected between bars 1, 3, 4, 5, 6, 7, and 8 (one-way ANOVA followed by Holm-Sidak`s method of all pairwise multiple comparisons; wild-type CFTR, n afd; 13; F508del CFTR, n afd; 10; Q1291A CFTR, n afd; 4; Q1291G CFTR, n afd; 4; Q1291F CFTR, n afd; 6; Q1291H CFTR, n afd; 6; Q1291W CFTR, n afd; 6; Q1291Y CFTR, n afd; 6). Login to comment
189 *, p b0d; 0.01 when compared with bar 1, 3, 4, 5, 6, or 7 (one-way ANOVA followed by Holm-Sidak`s method of multiple comparisons versus control group; wild-type CFTR, n afd; 6; F508del CFTR, n afd; 4; Q1291G CFTR, n afd; 4; Q1291F CFTR, n afd; 6; Q1291HCFTR,nafd;4;Q1291WCFTR,nafd;4;Q1291YCFTR,nafd;4).Nosignificantdifferencesweredetectedbetweenbars1,3,4,5,6,and7(one-wayANOVA).Error bars, S.E. Selective Disruption of Adenylate Kinase-coupled CFTR Gating 14144 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 290ߦNUMBER 22ߦMAY 29, 2015 To further probe ATPase-dependent gating of Q1291F CFTR, we studied the effect of adenosine 5b18;-(beta,ॹ-imido)triphosphate (AMPPNP). Login to comment
196 *, p b0d; 0.05 compared with wild type; double daggers, p b0d; 0.001 compared with Q1291G (one-way ANOVA followed by Holm-Sidak`s method of multiple comparisons versus control group). Login to comment
241 If the Gln-1291 side chain interacted with AMP as predicted based on the SMC-NBD structure (Fig. 1) (19), then removal of this side chain (Q1291G mutation) should affect the interaction of AMP with CFTR. Login to comment
284 D, removal of the Gln-1291 side chain (Q1291G mutation) reduces the potency of AMP to increase CFTR Clafa; current. Login to comment
316 Columns show the means afe; S.E. (error bars) of 15 (wild type), 11 (Q1291F mutant), and 5 (Q1291G mutant) individual experiments obtained from two (wild type) and three (Q1291F and Q1291G mutants) membrane patches. Login to comment