ABCC7 p.His1350Ala
| Predicted by SNAP2: | A: D (71%), C: D (71%), D: D (66%), E: N (53%), F: D (80%), G: D (53%), I: D (80%), K: D (53%), L: D (80%), M: D (66%), N: N (53%), P: D (85%), Q: N (87%), R: D (53%), S: N (57%), T: D (75%), V: D (75%), W: D (85%), Y: N (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, E: N, F: D, G: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, R: N, S: N, T: D, V: D, W: D, Y: N, |
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[hide] ClC and CFTR chloride channel gating. Annu Rev Physiol. 1998;60:689-717. Foskett JK
ClC and CFTR chloride channel gating.
Annu Rev Physiol. 1998;60:689-717., [PMID:9558482]
Abstract [show]
Chloride channels are widely expressed and play important roles in cell volume regulation, transepithelial transport, intracellular pH regulation, and membrane excitability. Most chloride channels have yet to be identified at a molecular level. The ClC gene family and the cystic fibrosis transmembrane conductance regulator (CFTR) are distinct chloride channels expressed in many cell types, and mutations in their genes are the cause of several diseases including myotonias, cystic fibrosis, and kidney stones. Because of their molecular definition and roles in disease, these channels have been studied intensively over the past several years. The focus of this review is on recent studies that have provided new insights into the mechanisms governing the opening and closing, i.e. gating, of the ClC and CFTR chloride channels.
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No. Sentence Comment
323 Mutation of this residue to glutamine (H1350Q; predicted to increase ATP hydrolysis rate) but not to alanine (H1350A; predicted to have no effect on hydrolysis) destabilized the open state (138), again supporting a role for hydrolysis at NBD2 in controlling the duration of the open state.
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ABCC7 p.His1350Ala 9558482:323:110
status: NEW[hide] Structural and functional similarities between the... Biophys J. 1995 Dec;69(6):2443-8. Carson MR, Welsh MJ
Structural and functional similarities between the nucleotide-binding domains of CFTR and GTP-binding proteins.
Biophys J. 1995 Dec;69(6):2443-8., [PMID:8599650]
Abstract [show]
The opening and closing of the CFTR Cl- channel are regulated by ATP hydrolysis at its two nucleotide binding domains (NBDs). However, the mechanism and functional significance of ATP hydrolysis are unknown. Sequence similarity between the NBDs of CFTR and GTP-binding proteins suggested the NBDs might have a structure and perhaps a function like that of GTP-binding proteins. Based on this similarity, we predicted that the terminal residue of the LSGGQ motif in the NBDs of CFTR corresponds to a highly conserved glutamine residue in GTP-binding proteins that directly catalyzes the GTPase reaction. Mutations of this residue in NBD1 or NBD2, which were predicted to increase or decrease the rate of hydrolysis, altered the duration of channel closed and open times in a specific manner without altering ion conduction properties or ADP-dependent inhibition. These results suggest that the NBDs of CFTR, and consequently other ABC transporters, may have a structure and a function analogous to those of GTP-binding proteins. We conclude that the rates of ATP hydrolysis at NBD1 and at NBD2 determine the duration of the two states of the channel, closed and open, much as the rate of GTP hydrolysis by GTP-binding proteins determines the duration of their active state.
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No. Sentence Comment
27 To test these hypotheses we used the excised inside-out patch-clamp technique to study CFTR variants containing the Q552A, Q552H, H1350Q, and H1350A mutations.
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ABCC7 p.His1350Ala 8599650:27:142
status: NEW77 Open circles, wild-type; open triangles, Q552A; open squares, Q552H; filled circles, H1350A; filled triangles, H1350Q.
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ABCC7 p.His1350Ala 8599650:77:85
status: NEW90 Fig. 2 A shows 0.250- B. 2000- mean closed-time between 1000- bursts (ms) 0- C. mean burst duration (ms) wild-type T T k" IffilI -.. wild- Q552A 0552H H1350Q H1350A type 3001 wilt'- type FIGURE 3 Effect of mutation of Q552 and H1350 on single channel activity.
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ABCC7 p.His1350Ala 8599650:90:158
status: NEW113 Fig. 4 shows that ADP inhibited ATP-supported current in the A. H1350A NBD2 mutants to an extent similar to that observed with wild-type CFTR.
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ABCC7 p.His1350Ala 8599650:113:64
status: NEW124 A, Time course of macroscopic current in excised membrane patches from cells expressing either H1350A (top panel) or H1350Q (bottom panel) channels.
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ABCC7 p.His1350Ala 8599650:124:95
status: NEW129 There was no difference between groups (p > 0.3 for all, n = 4, 3, and 3 for wild-type, H1350A, and H1350Q, respectively).
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ABCC7 p.His1350Ala 8599650:129:88
status: NEW131 'Wo I (pA) 150 0 1.5 3.0 4.5 6.0 7.5 time (min) 75- 50- % Inhibition by ADP 250- wild- H1350A H1350Q type Carson and Welsh Similarity between CFTR and GTP-Binding Proteins 2447 from the nucleotide-binding site.
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ABCC7 p.His1350Ala 8599650:131:87
status: NEW