ABCC7 p.His1350Gln
| 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] Insight in eukaryotic ABC transporter function by ... FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19. Frelet A, Klein M
Insight in eukaryotic ABC transporter function by mutation analysis.
FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19., 2006-02-13 [PMID:16442101]
Abstract [show]
With regard to structure-function relations of ATP-binding cassette (ABC) transporters several intriguing questions are in the spotlight of active research: Why do functional ABC transporters possess two ATP binding and hydrolysis domains together with two ABC signatures and to what extent are the individual nucleotide-binding domains independent or interacting? Where is the substrate-binding site and how is ATP hydrolysis functionally coupled to the transport process itself? Although much progress has been made in the elucidation of the three-dimensional structures of ABC transporters in the last years by several crystallographic studies including novel models for the nucleotide hydrolysis and translocation catalysis, site-directed mutagenesis as well as the identification of natural mutations is still a major tool to evaluate effects of individual amino acids on the overall function of ABC transporters. Apart from alterations in characteristic sequence such as Walker A, Walker B and the ABC signature other parts of ABC proteins were subject to detailed mutagenesis studies including the substrate-binding site or the regulatory domain of CFTR. In this review, we will give a detailed overview of the mutation analysis reported for selected ABC transporters of the ABCB and ABCC subfamilies, namely HsCFTR/ABCC7, HsSUR/ABCC8,9, HsMRP1/ABCC1, HsMRP2/ABCC2, ScYCF1 and P-glycoprotein (Pgp)/MDR1/ABCB1 and their effects on the function of each protein.
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No. Sentence Comment
212 Q552H (NBD1) slowed CFTR channel opening without affecting closing, whereas the converse mutation, H1350Q (NBD2) accelerated channel closing without influencing the channel opening rate [68].
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ABCC7 p.His1350Gln 16442101:212:99
status: NEW[hide] Structure and function of the CFTR chloride channe... Physiol Rev. 1999 Jan;79(1 Suppl):S23-45. Sheppard DN, Welsh MJ
Structure and function of the CFTR chloride channel.
Physiol Rev. 1999 Jan;79(1 Suppl):S23-45., [PMID:9922375]
Abstract [show]
Structure and Function of the CFTR Chloride Channel. Physiol. Rev. 79, Suppl.: S23-S45, 1999. - The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl- channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function. The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.
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No. Sentence Comment
382 In addition, the observation that the H1350Q mutation, which would be predicted to increase the ratechannel.
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ABCC7 p.His1350Gln 9922375:382:38
status: NEW[hide] Control of CFTR channel gating by phosphorylation ... Physiol Rev. 1999 Jan;79(1 Suppl):S77-S107. Gadsby DC, Nairn AC
Control of CFTR channel gating by phosphorylation and nucleotide hydrolysis.
Physiol Rev. 1999 Jan;79(1 Suppl):S77-S107., [PMID:9922377]
Abstract [show]
Control of CTFR Channel Gating by Phosphorylation and Nucleotide Hydrolysis. Physiol. Rev. 79, Suppl.: S77-S107, 1999. - The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is the protein product of the gene defective in cystic fibrosis, the most common lethal genetic disease among Caucasians. Unlike any other known ion channel, CFTR belongs to the ATP-binding cassette superfamily of transporters and, like all other family members, CFTR includes two cytoplasmic nucleotide-binding domains (NBDs), both of which bind and hydrolyze ATP. It appears that in a single open-close gating cycle, an individual CFTR channel hydrolyzes one ATP molecule at the NH2-terminal NBD to open the channel, and then binds and hydrolyzes a second ATP molecule at the COOH-terminal NBD to close the channel. This complex coordinated behavior of the two NBDs is orchestrated by multiple protein kinase A-dependent phosphorylation events, at least some of which occur within the third large cytoplasmic domain, called the regulatory domain. Two or more kinds of protein phosphatases selectively dephosphorylate distinct sites. Under appropriately controlled conditions of progressive phosphorylation or dephosphorylation, three functionally different phosphoforms of a single CFTR channel can be distinguished on the basis of channel opening and closing kinetics. Recording single CFTR channel currents affords an unprecedented opportunity to reproducibly examine, and manipulate, individual ATP hydrolysis cycles in a single molecule, in its natural environment, in real time.
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No. Sentence Comment
466 opening without affecting closing, whereas making the converse mutation, H1350Q, in NBD2 accelerated channel closing without influencing the channel opening rate (27).2.
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ABCC7 p.His1350Gln 9922377:466:73
status: NEW[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.His1350Gln 9558482:323:39
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.His1350Gln 8599650:27:130
status: NEW77 Open circles, wild-type; open triangles, Q552A; open squares, Q552H; filled circles, H1350A; filled triangles, H1350Q.
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ABCC7 p.His1350Gln 8599650:77:111
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.His1350Gln 8599650:90:151
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.His1350Gln 8599650:124:117
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.His1350Gln 8599650:129:100
status: NEW130 301 ATP 1 ADP (pA) 1 D0 N 0 1.5 3.0 4.5 6.0 7.5 time (min) H1350Q 1 ATP 4; A 1 ADP 30- A.
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ABCC7 p.His1350Gln 8599650:130:59
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.His1350Gln 8599650:131:94
status: NEW146 First, NBD2 mutations at K1250 that are predicted to inhibit hydrolysis prolong the duration of bursts (in contrast to the H1350Q mutation, which shortens bursts) (Carson et al., 1995).
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ABCC7 p.His1350Gln 8599650:146:123
status: NEW