ABCC7 p.Tyr1219Ile
Predicted by SNAP2: | A: D (85%), C: D (85%), D: D (95%), E: D (91%), F: D (80%), G: D (91%), H: D (85%), I: D (85%), K: D (91%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (91%), R: D (91%), S: D (91%), T: D (91%), V: D (85%), W: D (80%), |
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, R: D, S: D, T: D, V: D, W: D, |
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[hide] The two ATP binding sites of cystic fibrosis trans... J Gen Physiol. 2006 Oct;128(4):413-22. Epub 2006 Sep 11. Zhou Z, Wang X, Liu HY, Zou X, Li M, Hwang TC
The two ATP binding sites of cystic fibrosis transmembrane conductance regulator (CFTR) play distinct roles in gating kinetics and energetics.
J Gen Physiol. 2006 Oct;128(4):413-22. Epub 2006 Sep 11., [PMID:16966475]
Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ABC (ATP binding cassette) transporter family, is a chloride channel whose activity is controlled by protein kinase-dependent phosphorylation. Opening and closing (gating) of the phosphorylated CFTR is coupled to ATP binding and hydrolysis at CFTR's two nucleotide binding domains (NBD1 and NBD2). Recent studies present evidence that the open channel conformation reflects a head-to-tail dimerization of CFTR's two NBDs as seen in the NBDs of other ABC transporters (Vergani et al., 2005). Whether these two ATP binding sites play an equivalent role in the dynamics of NBD dimerization, and thus in gating CFTR channels, remains unsettled. Based on the crystal structures of NBDs, sequence alignment, and homology modeling, we have identified two critical aromatic amino acids (W401 in NBD1 and Y1219 in NBD2) that coordinate the adenine ring of the bound ATP. Conversion of the W401 residue to glycine (W401G) has little effect on the sensitivity of the opening rate to [ATP], but the same mutation at the Y1219 residue dramatically lowers the apparent affinity for ATP by >50-fold, suggesting distinct roles of these two ATP binding sites in channel opening. The W401G mutation, however, shortens the open time constant. Energetic analysis of our data suggests that the free energy of ATP binding at NBD1, but not at NBD2, contributes significantly to the energetics of the open state. This kinetic and energetic asymmetry of CFTR's two NBDs suggests an asymmetric motion of the NBDs during channel gating. Opening of the channel is initiated by ATP binding at the NBD2 site, whereas separation of the NBD dimer at the NBD1 site constitutes the rate-limiting step in channel closing.
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No. Sentence Comment
106 The ATP dose-response relationships of Y1219F and Y1219I mutants lie between those of WT and Y1219G.
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ABCC7 p.Tyr1219Ile 16966475:106:50
status: NEW113 Since the opening rate of Y1219G is not saturated at 20 mM ATP, we also studied single-channel kinetics of Y1219I, which shows a smaller shift in the ATP dose-response relationship (Fig. 2 A).
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ABCC7 p.Tyr1219Ile 16966475:113:107
status: NEW115 The opening rate of Y1219I at 10 or 20 mM ATP is very similar to that of WT at 2.75 mM ATP (Fig. 2, B and C), indicating that mutations at the Y1219 residue likely affect the ATP binding step with minimal effect on the post-binding events.
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ABCC7 p.Tyr1219Ile 16966475:115:20
status: NEW116 Fig. 2 C shows the relationship between the opening rate and [ATP] for WT, W401G, Y1219I, and Y1219G.
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ABCC7 p.Tyr1219Ile 16966475:116:82
status: NEW122 (A) Normalized ATP dose-response relationships of WT (black line, Michaelis-Menten fit from Fig. 1 D), Y1219W (brown), Y1219F (pink), Y1219I (blue), and Y1219G (green line, Michaelis-Menten fit from Fig. 1 D).
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ABCC7 p.Tyr1219Ile 16966475:122:134
status: NEW124 K1/2 values are 0.13 ± 0.02 mM (Y1219W), 0.46 ± 0.06 mM (Y1219F), and 0.94 ± 0.20 mM (Y1219I), respectively.
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ABCC7 p.Tyr1219Ile 16966475:124:101
status: NEW125 (B) Representative single-channel current traces of WT, W401G, Y1219G, and Y1219I in response to [ATP] as marked.
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ABCC7 p.Tyr1219Ile 16966475:125:75
status: NEW126 (C) Relationships between channel opening rates and [ATP] for WT (black), W401G (red), Y1219I (blue), and Y1219G (green).
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ABCC7 p.Tyr1219Ile 16966475:126:87
status: NEW127 Solid lines are Michaelis-Menten fits to the data of WT (black) and Y1219I (blue).
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ABCC7 p.Tyr1219Ile 16966475:127:68
status: NEW128 The maximal opening rate and K1/2 values are 2.42 ± 0.11 s-1 and 0.11 ± 0.02 mM for WT, and 2.60 ± 0.11 s-1 and 1.73 ± 0.26 mM for Y1219I, respectively.
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ABCC7 p.Tyr1219Ile 16966475:128:151
status: NEW129 (D) Relationships between channel opening rates and [ATP] for ∆R-CFTR (black), ∆R-Y1219I (blue), and ∆R-Y1219G (green).
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ABCC7 p.Tyr1219Ile 16966475:129:96
status: NEW130 K1/2 from Michaelis-Menten fits (solid lines) are 0.16 ± 0.04 mM and 1.27 ± 0.16 mM for ∆R-CFTR and ∆R-Y1219I, respectively.
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ABCC7 p.Tyr1219Ile 16966475:130:127
status: NEW134 Fig. 2 D shows a similar rightward shift of the ATP dose-response relationships for Y1219I and Y1219G mutants under the ∆R-CFTR background.
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ABCC7 p.Tyr1219Ile 16966475:134:84
status: NEW205 The Y1219I mutation lowers the sensitivity of the opening rate to [ATP] without altering the maximal opening rate (Fig. 2), indicating that this mutation indeed decreases the binding affinity for ATP at the NBD2 site.
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ABCC7 p.Tyr1219Ile 16966475:205:4
status: NEW[hide] Cystic fibrosis transmembrane conductance regulato... Sheng Li Xue Bao. 2007 Aug 25;59(4):431-42. Bompadre SG, Hwang TC
Cystic fibrosis transmembrane conductance regulator: a chloride channel gated by ATP binding and hydrolysis.
Sheng Li Xue Bao. 2007 Aug 25;59(4):431-42., 2007-08-25 [PMID:17700963]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that belongs to the ATP-binding cassette (ABC) transporter superfamily. Defective function of CFTR is responsible for cystic fibrosis (CF), the most common lethal autosomal recessive disorder in Caucasian populations. The disease is manifested in defective chloride transport across the epithelial cells in various tissues. To date, more than 1400 different mutations have been identified as CF-associated. CFTR is regulated by phosphorylation in its regulatory (R) domain, and gated by ATP binding and hydrolysis at its two nucleotide-binding domains (NBD1 and NBD2). Recent studies reveal that the NBDs of CFTR may dimerize as observed in other ABC proteins. Upon dimerization of CFTR's two NBDs, in a head-to-tail configuration, the two ATP-binding pockets (ABP1 and ABP2) are formed by the canonical Walker A and B motifs from one NBD and the signature sequence from the partner NBD. Mutations of the amino acids that interact with ATP reveal that the two ABPs play distinct roles in controlling ATP-dependent gating of CFTR. It was proposed that binding of ATP to the ABP2, which is formed by the Walker A and B in NBD2 and the signature sequence in NBD1, is critical for catalyzing channel opening. While binding of ATP to the ABP1 alone may not increase the opening rate, it does contribute to the stabilization of the open channel conformation. Several disease-associated mutations of the CFTR channel are characterized by gating defects. Understanding how CFTR's two NBDs work together to gate the channel could provide considerable mechanistic information for future pharmacological studies, which could pave the way for tailored drug design for therapeutical interventions in CF.
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No. Sentence Comment
180 The mutation Y1219G shows an ATP dose-response relationship shifted more than 50-fold towards higher [ATP], however more conservative mutations (Y1219I, Y1219F) show smaller shifts, indicating the importance of the nature of the side chain in the interaction with the ATP molecule.
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ABCC7 p.Tyr1219Ile 17700963:180:145
status: NEW[hide] CLC-0 and CFTR: chloride channels evolved from tra... Physiol Rev. 2008 Apr;88(2):351-87. Chen TY, Hwang TC
CLC-0 and CFTR: chloride channels evolved from transporters.
Physiol Rev. 2008 Apr;88(2):351-87., [PMID:18391167]
Abstract [show]
CLC-0 and cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels play important roles in Cl(-) transport across cell membranes. These two proteins belong to, respectively, the CLC and ABC transport protein families whose members encompass both ion channels and transporters. Defective function of members in these two protein families causes various hereditary human diseases. Ion channels and transporters were traditionally viewed as distinct entities in membrane transport physiology, but recent discoveries have blurred the line between these two classes of membrane transport proteins. CLC-0 and CFTR can be considered operationally as ligand-gated channels, though binding of the activating ligands appears to be coupled to an irreversible gating cycle driven by an input of free energy. High-resolution crystallographic structures of bacterial CLC proteins and ABC transporters have led us to a better understanding of the gating properties for CLC and CFTR Cl(-) channels. Furthermore, the joined force between structural and functional studies of these two protein families has offered a unique opportunity to peek into the evolutionary link between ion channels and transporters. A promising byproduct of this exercise is a deeper mechanistic insight into how different transport proteins work at a fundamental level.
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No. Sentence Comment
787 The ATP dose-response relationships of Y1219F and Y1219I mutants lie between those of wild type and Y1219G, suggesting a correlation between changes of the ATP sensitivity and the chemical natures of the side chain at this position.
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ABCC7 p.Tyr1219Ile 18391167:787:50
status: NEW788 Single-channel kinetic analysis indicates that the shifts of the ATP dose-response relationships in Y1219G and Y1219I mutants are mainly due to changes of the opening rate (360).
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ABCC7 p.Tyr1219Ile 18391167:788:111
status: NEW[hide] Review. ATP hydrolysis-driven gating in cystic fib... Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):247-55. Muallem D, Vergani P
Review. ATP hydrolysis-driven gating in cystic fibrosis transmembrane conductance regulator.
Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):247-55., 2009-01-27 [PMID:18957373]
Abstract [show]
Proteins belonging to the ATP-binding cassette superfamily couple ATP binding and hydrolysis at conserved nucleotide-binding domains (NBDs) to diverse cellular functions. Most superfamily members are transporters, while cystic fibrosis transmembrane conductance regulator (CFTR), alone, is an ion channel. Despite this functional difference, recent results have suggested that CFTR shares a common molecular mechanism with other members. ATP binds to partial binding sites on the surface of the two NBDs, which then associate to form a NBD dimer, with complete composite catalytic sites now buried at the interface. ATP hydrolysis and gamma-phosphate dissociation, with the loss of molecular contacts linking the two sides of the composite site, trigger dimer dissociation. The conformational signals generated by NBD dimer formation and dissociation are transmitted to the transmembrane domains where, in transporters, they drive the cycle of conformational changes that translocate the substrate across the membrane; in CFTR, they result in opening and closing (gating) of the ion-permeation pathway.
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No. Sentence Comment
65 The dose-response curve of channel opening rate as a function of [ATP] was seen to shift dramatically to the right when the consensus site 2 was mutated ( Y1219G or Y1219I) but not when the degenerate site 1 was altered (W401G).
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ABCC7 p.Tyr1219Ile 18957373:65:165
status: NEW63 The dose-response curve of channel opening rate as a function of [ATP] was seen to shift dramatically to the right when the consensus site 2 was mutated ( Y1219G or Y1219I) but not when the degenerate site 1 was altered (W401G).
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ABCC7 p.Tyr1219Ile 18957373:63:165
status: NEW[hide] A stable ATP binding to the nucleotide binding dom... J Physiol Sci. 2010 Sep;60(5):353-62. doi: 10.1007/s12576-010-0102-2. Epub 2010 Jul 14. Shimizu H, Yu YC, Kono K, Kubota T, Yasui M, Li M, Hwang TC, Sohma Y
A stable ATP binding to the nucleotide binding domain is important for reliable gating cycle in an ABC transporter CFTR.
J Physiol Sci. 2010 Sep;60(5):353-62. doi: 10.1007/s12576-010-0102-2. Epub 2010 Jul 14., [PMID:20628841]
Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, a member of ABC transporter superfamily, gates following ATP-dependent conformational changes of the nucleotide binding domains (NBD). Reflecting the hundreds of milliseconds duration of the channel open state corresponding to the dimerization of two NBDs, macroscopic WT-CFTR currents usually showed a fast, single exponential relaxation upon removal of cytoplasmic ATP. Mutations of tyrosine1219, a residue critical for ATP binding in second NBD (NBD2), induced a significant slow phase in the current relaxation, suggesting that weakening ATP binding affinity at NBD2 increases the probability of the stable open state. The slow phase was effectively diminished by a higher affinity ATP analogue. These data suggest that a stable binding of ATP to NBD2 is required for normal CFTR gating cycle, andthat the instability of ATP binding frequently halts the gating cycle in the open state presumably through a failure of ATP hydrolysis at NBD2.
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No. Sentence Comment
19 The degree of dose-response shift, a descending order of Y1218G, Y1219I, Y1219F and Y1219W, seemed to depend on the similarity of chemical properties, e.g., hydrophobicity and p bond by aromatic ring, of the side chains introduced by the mutations to tyrosine.
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ABCC7 p.Tyr1219Ile 20628841:19:65
status: NEW59 Figure 2b compares macroscopic current relaxations for Y1219G, Y1219I, Y1219F and Y1219W mutants.
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ABCC7 p.Tyr1219Ile 20628841:59:63
status: NEW60 Although a slow phase of current decay can be seen with Y1219G and Y1219I, this second phase is hardly discernable for the Y1219W mutant.
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ABCC7 p.Tyr1219Ile 20628841:60:67
status: NEW65 b A representative current trace of WT-CFTR channel showing immediate closing upon a rapid removal of ATP somewhere between Y1219W and Y1219I.
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ABCC7 p.Tyr1219Ile 20628841:65:136
status: NEW67 The time constants of the initial fast phase for all the Y1219 mutants are within hundreds of milliseconds (sfast: 504 &#b1; 76 ms, n = 5 for Y1219G; 450 &#b1; 44 ms, n = 7 for Y1219I; 571 &#b1; 142 ms, n = 4 for Y1219F; 513 &#b1; 66 ms, n = 5 for Y1219W) and there is not significant difference in the fast time constant among these Y1219 mutants (Fig. 2b).
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ABCC7 p.Tyr1219Ile 20628841:67:177
status: NEW68 On the other hand, the time constants of the slow component for Y1219F and Y1219W are shorter than those of Y1219G and Y1219I (Fig. 3a).
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ABCC7 p.Tyr1219Ile 20628841:68:119
status: NEW69 More importantly, the fraction of the slow component (Fig. 3b) shows a gradual decrease as the mutation becomes less 'preserved` (Y1219G [ Y1219I [ Y1219F [ Y1219W).
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ABCC7 p.Tyr1219Ile 20628841:69:139
status: NEW80 b Macroscopic current relaxations upon ATP wash-out for Y1219G, Y1219I, Y1219F and Y1219W.
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ABCC7 p.Tyr1219Ile 20628841:80:64
status: NEW82 The time constant and the fraction of the slow component are summarized in Fig. 3. c Single channel recording of Y1219G-CFTR showing a long opening even after ATP removal 35 30 25 20 15 10 5 0 Y1219G Y1219I Y1219F Y1219W 0.5 0.4 0.3 0.2 0.1 0.0 Y1219G Y1219I Y1219F Y1219W A slow / (A slow + A fast ) c4; slow (s) A B Fig. 3 Kinetic parameters of macroscopic current relaxations for Y1219G, Y1219I, Y1219F and Y1219W.
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ABCC7 p.Tyr1219Ile 20628841:82:200
status: NEWX
ABCC7 p.Tyr1219Ile 20628841:82:252
status: NEWX
ABCC7 p.Tyr1219Ile 20628841:82:394
status: NEW83 a Time constants of the slow component of the current relaxation for the Y1219 mutants. Y1219G: n = 5; Y1219I: n = 7; Y1219F: n = 4; and Y1219W: n = 5. b Fraction of the slow component (Aslow/Aslow ?
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ABCC7 p.Tyr1219Ile 20628841:83:103
status: NEW84 Afast) for the Y1219 mutants. Y1219G: n = 5; Y1219I: n = 7; Y1219F: n = 4; and Y1219W: n = 5 ATP because of their similar rate-limiting hydrolyzing rates [11].
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ABCC7 p.Tyr1219Ile 20628841:84:45
status: NEW85 Figure 4 shows the effects of application and removal of 5 mM ATP and 100 lM P-ATP on the macroscopic current of the Y1219I mutant.
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ABCC7 p.Tyr1219Ile 20628841:85:117
status: NEW92 Since the slow phase of current decay in Y1219I-CFTR channels was diminished when opened by P-ATP (Fig. 4a), we next examined the accessibility of P-ATP to the binding site during the long-lasting open state by testing if P-ATP can rapidly close Y1219I channels in the long-lasting open state.
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ABCC7 p.Tyr1219Ile 20628841:92:41
status: NEWX
ABCC7 p.Tyr1219Ile 20628841:92:246
status: NEW93 We first opened Y1219I-CFTR channels with ATP.
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ABCC7 p.Tyr1219Ile 20628841:93:16
status: NEW109 We show a correlation between the occurrence of these events and the degree of P-ATP 100 bc;M ATP 5 mM P-ATP 100 bc;M P-ATP 100 bc;M A B 50 s 20 pA 10 s 5 pA ATP 5 mM Fig. 4 Effects of P-ATP on Y1219I mutant.
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ABCC7 p.Tyr1219Ile 20628841:109:203
status: NEW110 a A representative macroscopic current trace of Y1219I-CFTR responding to rapid application and removal of 5 mM ATP or 100 lM P-ATP.
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ABCC7 p.Tyr1219Ile 20628841:110:48
status: NEW112 b Effects of a brief rapid application of P-ATP on Y1219I macroscopic current during the slow phase of the current relaxation after ATP wash-out.
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ABCC7 p.Tyr1219Ile 20628841:112:51
status: NEW132 Although the results with Y1219G and Y1219I mutations are quantified accurately, this may not be the case with the data for Y1219F and Y1219W.
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ABCC7 p.Tyr1219Ile 20628841:132:37
status: NEW135 This effect is expected to be small when the probability of the stable open state is high such as in Y1219G or Y1219I.
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ABCC7 p.Tyr1219Ile 20628841:135:111
status: NEW139 Since P-ATP has a [50-fold higher affinity to NBD2 compared with ATP [11], P-ATP may also assume a high affinity for the Y1219 mutants. Indeed, while we need millimolar ATP to elicit significant currents from Y1219I-CFTR, 100 lM P-ATP can generate a current similar to the initial current induced by 5 mM ATP (Fig. 4a), indicating that P-ATP is more potent in opening Y1219I channels.
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ABCC7 p.Tyr1219Ile 20628841:139:209
status: NEWX
ABCC7 p.Tyr1219Ile 20628841:139:368
status: NEW140 Thus, the high-affinity ATP analog, P-ATP, can effectively abolish the stable open state of Y1219I-CFTR, corroborating the idea that weakening ATP binding at NBD2 promotes the stable open state.
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ABCC7 p.Tyr1219Ile 20628841:140:92
status: NEW146 Although P-ATP is able to shorten the lifetime of ATP-opened Y1219I mutants (Fig. 4a), we could not conclude whether the bound ATP has dissociated so that the binding pocket is now unoccupied or the dislocated ATP is still in the binding pocket.
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ABCC7 p.Tyr1219Ile 20628841:146:61
status: NEW151 In fact, even when ATP affinity is drastically reduced by mutations such as Y1219G and Y1219I, the probability of the stable open state remains quite low compared to the short-lived open state.
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ABCC7 p.Tyr1219Ile 20628841:151:87
status: NEW162 If different mutations at Y1219 can affect the entry rate and the exit rate differently as shown in Table 2, this hypothesis may explain most of the results Table 1 Parameter sets (s-1 ) for the ''kiss and run`` hypothesis kCO1 kO1C kO1O2 kO2C Y1219G 3 or 0a 3 2 9 10-2 3.8 9 10-2 Y1219I : : 1.3 9 10-2 : Y1219F : : 1.1 9 10-2 : Y1219W : : 4 9 10-3 : a kCO1 was set to 3 s-1 for simulating the ''with ATP`` condition and 0 s-1 for simulating the ''after the ATP washout`` condition.
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ABCC7 p.Tyr1219Ile 20628841:162:281
status: NEW166 b Representative reproduced macroscopic current relaxations mimicking those in Y1219G (red), Y1219I (green), Y1219F (cyan) and Y1219W (blue).
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ABCC7 p.Tyr1219Ile 20628841:166:93
status: NEW172 In addition, the slow time constant for Y1219G is not different from that for Y1219I despite the fraction of the slow phase is different between these two mutants.
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ABCC7 p.Tyr1219Ile 20628841:172:78
status: NEW[hide] A single amino acid substitution in CFTR converts ... J Gen Physiol. 2014 Oct;144(4):311-20. doi: 10.1085/jgp.201411247. Epub 2014 Sep 15. Lin WY, Jih KY, Hwang TC
A single amino acid substitution in CFTR converts ATP to an inhibitory ligand.
J Gen Physiol. 2014 Oct;144(4):311-20. doi: 10.1085/jgp.201411247. Epub 2014 Sep 15., [PMID:25225552]
Abstract [show]
Cystic fibrosis (CF), one of the most common lethal genetic diseases, is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel that, when phosphorylated, is gated by ATP. The third most common pathogenic mutation, a glycine-to-aspartate mutation at position 551 or G551D, shows a significantly decreased open probability (Po) caused by failure of the mutant channel to respond to ATP. Recently, a CFTR-targeted drug, VX-770 (Ivacaftor), which potentiates G551D-CFTR function in vitro by boosting its Po, has been approved by the FDA to treat CF patients carrying this mutation. Here, we show that, in the presence of VX-770, G551D-CFTR becomes responsive to ATP, albeit with an unusual time course. In marked contrast to wild-type channels, which are stimulated by ATP, sudden removal of ATP in excised inside-out patches elicits an initial increase in macroscopic G551D-CFTR current followed by a slow decrease. Furthermore, decreasing [ATP] from 2 mM to 20 microM resulted in a paradoxical increase in G551D-CFTR current. These results suggest that the two ATP-binding sites in the G551D mutant mediate opposite effects on channel gating. We introduced mutations that specifically alter ATP-binding affinity in either nucleotide-binding domain (NBD1 or NBD2) into the G551D background and determined that this disease-associated mutation converts site 2, formed by the head subdomain of NBD2 and the tail subdomain of NBD1, into an inhibitory site, whereas site 1 remains stimulatory. G551E, but not G551K or G551S, exhibits a similar phenotype, indicating that electrostatic repulsion between the negatively charged side chain of aspartate and the gamma-phosphate of ATP accounts for the observed mutational effects. Understanding the molecular mechanism of this gating defect lays a foundation for rational drug design for the treatment of CF.
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No. Sentence Comment
133 Y1219F, Y1219I, and Y1219G, mutations known to cause a graded change of the apparent affinity for Figure 3.ߓ Paradoxical [ATP] dependence of G551D-CFTR currents supports the hypothesis of two ATP-binding sites exerting opposite actions.
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ABCC7 p.Tyr1219Ile 25225552:133:8
status: NEW168 (A-C) Real-time current traces in response to ATP removal for G551D/Y1219F (A), G551D/Y1219I (B), and G551D/Y1219G (C).
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ABCC7 p.Tyr1219Ile 25225552:168:86
status: NEW