ABCMdb

ABCC7 p.Arg555Gln

ClinVar:	c.1663A>G , p.Arg555Gly ? , not provided
CF databases:	c.1663A>G , p.Arg555Gly (CFTR1) ? , This mutation was detected by multiplex heteroduplex analysis on the MDE gel matrix. It was found in one Native Canadian CF patient (second mutation: Y1307X).
Predicted by SNAP2:	A: D (85%), C: D (85%), D: D (95%), E: D (91%), F: D (91%), G: D (91%), H: D (85%), I: D (91%), K: D (75%), L: D (71%), M: D (85%), N: D (85%), P: D (95%), Q: D (85%), S: D (85%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%),
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, Q: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] CFTR channel opening by ATP-driven tight dimerizat... Nature. 2005 Feb 24;433(7028):876-80. Vergani P, Lockless SW, Nairn AC, Gadsby DC
CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains.
Nature. 2005 Feb 24;433(7028):876-80., 2005-02-24 [PMID:15729345]

Abstract [show]
ABC (ATP-binding cassette) proteins constitute a large family of membrane proteins that actively transport a broad range of substrates. Cystic fibrosis transmembrane conductance regulator (CFTR), the protein dysfunctional in cystic fibrosis, is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing of the pore have been linked to ATP binding and hydrolysis at CFTR's two nucleotide-binding domains, NBD1 and NBD2 (see, for example, refs 1, 2). Isolated NBDs of prokaryotic ABC proteins dimerize upon binding ATP, and hydrolysis of the ATP causes dimer dissociation. Here, using single-channel recording methods on intact CFTR molecules, we directly follow opening and closing of the channel gates, and relate these occurrences to ATP-mediated events in the NBDs. We find that energetic coupling between two CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The two monitored side chains are independent of each other in closed channels but become coupled as the channels open. The results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide-binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily.

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Sentences [show]
No. Sentence Comment
85 c, Mutations at Arg 555 in NBD1 'tail` affect mean open burst (R555Q) and closed interburst (R555K) dwell times. Login to comment
86 R555Q opened with rates comparable to WT (R555Q, tib ¼ 2.84 ^ 0.53 s (15)) despite expected loss of the interfacial hydrogen bond, suggesting possible compensation by other factors, for example the removal of repulsive electrostatic forces. Login to comment
95 We first mutated Arg 555, and found that the charge-removing mutation R555Q slowed channel closing (mean open burst duration was 3.20 ^ 0.35 s (n ¼ 18) for R555Q, compared with 0.43 ^ 0.02 s (n ¼ 32) for WT; Fig. 2c), consistent with Arg 555 being part of the composite NBD2 catalytic site, where the ATP hydrolysis that times closing of WT channels occurs. Login to comment