ABCMdb

ABCC7 p.Gln1291Tyr

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
141 We found that Ap5A did not inhibit Clafa; current when Gln-1291 was replaced by amino acids with bulky side chains like phenylalanine (Q1291F), tryptophan (Q1291W), tyrosine (Q1291Y), or histidine (Q1291H). 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
207 Holding voltage was afa;80 mV for wild-type, Q1291W, and Q1291Y CFTR and afa;60 mV for Q1291H, Q1291F, and Q1291F/S1248F CFTR. Login to comment