ABCMdb

ABCC7 p.Arg334His

ClinVar:	c.1000C>T , p.Arg334Trp D , Pathogenic c.1001G>T , p.Arg334Leu ? , not provided c.1001G>A , p.Arg334Gln ? , not provided
CF databases:	c.1000C>T , p.Arg334Trp D , CF-causing ; CFTR1: This mutation has been found in two Spanish CF chromosomes. One of the patients has the [delta]F508 mutation in the other chromosome and the other patient does not. We have not found this mutation on 30 normal chromosomes with the same haplotype, and in 88 CF chromosomes without the [delta]F508, and in 24 with the [delta]F508. The mutation destroys a MapI site and is easily identified by agarose gel electrophoresis after PCR with intron primers. c.1001G>A , p.Arg334Gln (CFTR1) ? , The above mutation was found by DGGE and direct sequencing in Caucasian patients. c.1001G>T , p.Arg334Leu (CFTR1) D , Missense mutation E334L was detected in a German CBAVD patient who is compound heterozygous for the R334L and I336K mutations.
Predicted by SNAP2:	A: D (91%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (91%), I: D (95%), K: D (85%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (91%), S: D (91%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: D,

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[hide] CFTR: covalent and noncovalent modification sugges... J Gen Physiol. 2001 Oct;118(4):407-31. Smith SS, Liu X, Zhang ZR, Sun F, Kriewall TE, McCarty NA, Dawson DC
CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction.
J Gen Physiol. 2001 Oct;118(4):407-31., [PMID:11585852]

Abstract [show]
The goal of the experiments described here was to explore the possible role of fixed charges in determining the conduction properties of CFTR. We focused on transmembrane segment 6 (TM6) which contains four basic residues (R334, K335, R347, and R352) that would be predicted, on the basis of their positions in the primary structure, to span TM6 from near the extracellular (R334, K335) to near the intracellular (R347, R352) end. Cysteines substituted at positions 334 and 335 were readily accessible to thiol reagents, whereas those at positions 347 and 352 were either not accessible or lacked significant functional consequences when modified. The charge at positions 334 and 335 was an important determinant of CFTR channel function. Charge changes at position 334--brought about by covalent modification of engineered cysteine residues, pH titration of cysteine and histidine residues, and amino acid substitution--produced similar effects on macroscopic conductance and the shape of the I-V plot. The effect of charge changes at position 334 on conduction properties could be described by electrodiffusion or rate-theory models in which the charge on this residue lies in an external vestibule of the pore where it functions to increase the concentration of Cl adjacent to the rate-limiting portion of the conduction path. Covalent modification of R334C CFTR increased single-channel conductance determined in detached patches, but did not alter open probability. The results are consistent with the hypothesis that in wild-type CFTR, R334 occupies a position where its charge can influence the distribution of anions near the mouth of the pore.

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318 pH Titration of R334H CFTR Altered Conductance and the Shape of the I-V Relation It was of interest to compare the response to changes in bath pH of R334C CFTR with that of R334H CFTR. Login to comment
320 An I-V plot from a representative experiment in which the pH of the solution bathing an oocyte expressing R334H CFTR was acidified from 7.4 to 6.02 and then 4.80 is shown in Fig. 15 A. Login to comment
324 Stepwise acidification of the bath led to stepwise increases in the conductance of oocytes expressing R334C or R334H CFTR and corresponding, stepwise increases in the rectification ratio, whereas similar pH changes resulted in only modest changes in the conductance of oocytes expressing wt CFTR. Login to comment
327 The observed changes seen with wt CFTR were opposite of those seen with oocytes expressing R334C or R334H CFTR, suggesting that the pH induced changes due to protonation of R334C or R334H were, if anything, slightly underestimated. Login to comment
328 The distinct pKa`s of the R334C and R334H variants favor the notion that these pH-dependent effects are due to titration of the side chain at position 334, as opposed to a mutation-induced exposure of a titratable site at another locus (Coulter et al., 1995). Login to comment
341 However, for two mutants, R334H and K335A, the RR value clearly deviated significantly from that predicted by the general trend. Login to comment
344 The Effects of Charge Deposition at Position 334 Were Consistent with the Predictions of Charged-vestibule Models for the Anion Conduction Path The results of covalent modification and pH titration of R334C and R334H CFTR, as well as the functional impact of amino acid substitutions at this site, pointed to an important role for the charge at position 334 in determining the conduction properties of CFTR. Login to comment
350 pH titration of oocytes expressing R334H CFTR altered both the conductance and the shape of the I-V relation. Login to comment
351 (A) I-V plots from an oocyte expressing R334H CFTR. Login to comment
397 Titration of R334C and R334H CFTR by varying bath pH was also well described by a continuum model in which the changes in conductance and I-V shape were largely attributed to changes in ⌿o (unpublished data). Login to comment
417 Fig. 18 A summarizes the data from experiments in which charge changes were effected in R334C and R334H CFTR by means of chemical modification or pH titration. Login to comment
420 Data points include charge changes brought about by thiol modification of R334C CFTR with positively charged reagents (open triangles), and negatively charged reagents (closed triangles), pH titration of R334C CFTR (closed circles), and pH titration of R334H CFTR (open circles). Login to comment
423 Thiol modification of R334C CFTR with positively charged reagents (open triangles) was treated as adding a single positive charge; thiol modification of R334C with negatively charged reagents (closed triangles) was treated as adding a single negative charge; pH titration of R334H CFTR (open circles) was treated as adding a time-average positive charge determined by the bath pH, assuming a pKa of 5.68; and pH titration of R334C CFTR (closed circles) was treated as adding a time-average negative charge determined by the bath pH assuming a pKa of 8.17. Login to comment

[hide] Molecular determinants and role of an anion bindin... J Physiol. 2003 Jun 1;549(Pt 2):387-97. Epub 2003 Apr 4. Gong X, Linsdell P
Molecular determinants and role of an anion binding site in the external mouth of the CFTR chloride channel pore.
J Physiol. 2003 Jun 1;549(Pt 2):387-97. Epub 2003 Apr 4., 2003-06-01 [PMID:12679372]

Abstract [show]
Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is blocked by highly lyotropic permeant anions which bind tightly within the pore. Here we show that several different substitutions of a positively charged amino acid residue, arginine R334, in the putative outer mouth of the CFTR pore, greatly reduce the block caused by lyotropic Au(CN)2- ions applied to the intracellular side of the channel. Fixed positive charge at this site appears to play a role in Au(CN)2- binding, as judged by multiple substitutions of differently charged amino acid side chains and also by the pH dependence of block conferred by the R334H mutant. However, non-charge-dependent effects also appear to contribute to Au(CN)2- binding. Mutation of R334 also disrupts the apparent electrostatic interaction between intracellular Au(CN)2- ions and extracellular permeant anions, an interaction which normally acts to relieve channel block. All six mutations studied at R334 significantly weakened this interaction, suggesting that arginine possesses a unique ability to coordinate ion-ion interactions at this site in the pore. Our results suggest that lyotropic anions bind tightly to a site in the outer mouth of the CFTR pore that involves interaction with a fixed positive charge. Binding to this site is also involved in coordination of multiple permeant anions within the pore, suggesting that anion binding in the outer mouth of the pore is an important aspect in the normal anion permeation mechanism.

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11 Fixed positive charge at this site appears to play a role in Au(CN)2 _ binding, as judged by multiple substitutions of differently charged amino acid side chains and also by the pH dependence of block conferred by the R334H mutant. Login to comment
53 Block of wild-type, R334C-, R334E-, R334H-, R334K-, R334L- and R334Q-CFTR by 100 mM and 1 mM intracellular Au(CN)2 _ are compared in Fig. 4B. Login to comment
79 Adirectinvestigationoftheroleofpositivecharge A previous mutagenic investigation of arginine 334 emphasized the role played by the fixed positive charge at this position, and elegantly demonstrated this effect by titrating the side chain charge in R334H by changing the external pH (Smith et al. 2001). Login to comment
80 Although we have studied mutants with neutral, positively charged and negatively charged side chains, the pH dependence of R334H provides a unique opportunity to examine the effect of side chain charge independently of side chain shape. Login to comment
81 We therefore examined the effect of changing extracellular pH on Au(CN)2 _ block of wild-type and R334H-CFTR. Login to comment
82 As shown in Fig. 7, Au(CN)2 _ blocked R334H more strongly at pH 5.5 than at pH 9.0, whereas block of wild-type was X. Gong and P. Linsdell392 J Physiol549.2 Figure 5. Login to comment
88 However, the effect of changing the extracellular anion on the apparent affinity of Au(CN)2 _ block was not strongly pH dependent in R334H (Fig. 8), and at all pHs studied the effect of changing from extracellular gluconate to Cl_ , or from Cl_ to SCN_ , was small (as judged by the Kd(0) ratio) compared to the effect seen in wild-type at pH 7.4. Login to comment
89 These experiments on R334H at different pHs strongly suggest that Au(CN)2 _ blocking affinity and the interaction between intracellular Au(CN)2 _ ions and extracellular anions show different dependencies on side chain charge at position 334. Login to comment
94 Consistent with this notion, and again as noted by Smith et al. (2001), rectification was pH dependent in R334H but not in wild-type (Fig. 9A). Login to comment
101 Extracellular pH modifies Au(CN)2 _ block of R334H- but not wild-type CFTR A, example I-V relationships for wild-type and R334H at extracellular pHs of 5.5 and 9.0, before (control) and after (+Au(CN)2) addition of 100 mM Au(CN)2 _ to the intracellular solution. Login to comment
103 Mean of data from 3-5 patches, fitted as in Fig. 1B. C, effect of extracellular pH on Kd(0) in wild-type (0) and R334H (1). Login to comment
112 Extracellular pH does not affect extracellular anion dependence of Au(CN)2 _ block in R334H-CFTR The effect of changing the extracellular anion (from Cl_ to gluconate or from Cl_ to SCN_ ), quantified by the Kd(0) ratio as in Fig. 3D, appears independent of pH in R334 and is significantly reduced relative to wild-type at pH 7.4. Login to comment
116 Furthermore, this rectification acquires pH dependence in R334H not seen in wild-type. Login to comment
143 In R334H, positive charge does appear to enhance Au(CN)2 _ binding, since low pH, which is expected to favour protonation of this side chain (see also Smith et al. 2001), increases the apparent affinity of block (Fig. 7). Login to comment
147 These different effects of side chain charge are clearly demonstrated in R334H, which shows pH-dependent rectification (Fig. 9A) and Au(CN)2 _ affinity (Fig. 7) but pH-independent interactions between intracellular Au(CN)2 _ and extracellular anions (Fig. 8). Login to comment
148 The fact that tight Au(CN)2 _ binding and strong Au(CN)2 _ -anion interactions are separable by mutagenesis is also evident in R334H and R334L (Fig. 5). Login to comment

[hide] CFTR: what's it like inside the pore? J Exp Zool A Comp Exp Biol. 2003 Nov 1;300(1):69-75. Liu X, Smith SS, Dawson DC
CFTR: what's it like inside the pore?
J Exp Zool A Comp Exp Biol. 2003 Nov 1;300(1):69-75., 2003-11-01 [PMID:14598388]

Abstract [show]
The Cystic Fibrosis Conductance Regulator (CFTR) functions as a cAMP-activated, anion-selective channel, but the structural basis for anion permeation is not well understood. Here we summarize recent studies aimed at understanding how anions move through the CFTR channel, and the nature of the environment anions experience inside the pore. From these studies it is apparent that anion permeability selectivity and anion binding selectivity of the pore are consistent with a model based on a "dielectric tunnel." The selectivity pattern for halides and pseudohalides can be predicted if it is assumed that permeant anions partition between bulk water and a polarizable space that is characterized by an effective dielectric constant of about 19. Covalent labeling of engineered cysteines and pH titration of engineered cysteines and histidines lead to the conclusion that the CFTR anion conduction path includes a positively charged outer vestibule. A residue in transmembrane segment 6 (TM6) (R334) appears to reside in the outer vestibule of the CFTR pore where it creates a positive electrostatic potential that enhances anion conduction.

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No. Sentence Comment
96 Summarized in Figure 4 are charge-induced changes in R334C or R334H CFTR conductance that result from alteration of external pH or exposure of oocytes expressing R334C CFTR to charged methanethiosulfonate (MTS) reagents. Login to comment
98 Acidification of the bath solution of oocytes expressing R334C or R334H CFTR, or modification of R334C CFTR by a positively charged MTS Fig. 4. Login to comment
104 (C) pH titration of R334H. Login to comment
108 On the other hand, alkalinization of the bath solution of oocytes expressing R334C or R334H CFTR or modification of R334C CFTR by a negatively charged MTS reagent, MTSES (sodium [2-sulfonatoethyl]methanethiosulfonate), decreased the whole cell conductance and enhanced the inward rectification of the shape of the I-V plots. Login to comment

[hide] Direct and indirect effects of mutations at the ou... J Membr Biol. 2007 Apr;216(2-3):129-42. Epub 2007 Aug 3. Zhou JJ, Fatehi M, Linsdell P
Direct and indirect effects of mutations at the outer mouth of the cystic fibrosis transmembrane conductance regulator chloride channel pore.
J Membr Biol. 2007 Apr;216(2-3):129-42. Epub 2007 Aug 3., [PMID:17673962]

Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel pore is thought to contain multiple binding sites for permeant and impermeant anions. Here, we investigate the effects of mutation of different positively charged residues in the pore on current inhibition by impermeant Pt(NO(2)) (4) (2-) and suramin anions. We show that mutations that remove positive charges (K95, R303) influence interactions with intracellular, but not extracellular, Pt(NO(2))(4)(2-) ions, consistent with these residues being situated within the pore inner vestibule. In contrast, mutation of R334, supposedly located in the outer vestibule of the pore, affects block by both extracellular and intracellular Pt(NO(2))(4)(2-). Inhibition by extracellular Pt(NO(2))(4)(2-) requires a positive charge at position 334, consistent with a direct electrostatic interaction resulting in either open channel block or surface charge screening. In contrast, inhibition by intracellular Pt(NO(2))(4)(2-) is weakened in all R334-mutant forms of the channel studied, inconsistent with a direct interaction. Furthermore, mutation of R334 had similar effects on block by intracellular suramin, a large organic molecule that is apparently unable to enter deeply into the channel pore. Mutation of R334 altered interactions between intracellular Pt(NO(2))(4)(2-) and extracellular Cl(-) but not those between intracellular Pt(NO(2))(4)(2-) and extracellular Pt(NO(2))(4)(2-). We propose that while the positive charge of R334 interacts directly with extracellular anions, mutation of this residue also alters interactions with intracellular anions by an indirect mechanism, due to mutation-induced conformational changes in the protein that are propagated some distance from the site of the mutation in the outer mouth of the pore.

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No. Sentence Comment
85 Figure 3 shows the blocking effects of internally applied Pt(NO2)4 2À in six different channel mutants (R334C, R334E, R334H, R334K, R334L, R334Q) under conditions of both low (Fig. 3a) and high (Fig. 3b) extracellular ClÀ concentration. Login to comment
91 With elevated extracellular ClÀ , the Kd(0) was significantly increased only in R334C and R334E; not significantly altered in R334K, R334L and R334Q; and significantly decreased in R334H (Fig. 5b). Login to comment
93 These R334 mutations also exhibited a weakened sensitivity of blocker voltage dependence (quantified as -zd, Fig. 5) to external ClÀ concentration (Fig. 5c), although because of the small magnitude of this effect only R334C, R334H and R334Q reached a level of statistical significance (Fig. 5c). Login to comment
106 Comparison of the mean Kd estimated for suramin (at 0 mV) shows that R334C, R334E, R334K, R334L and R334Q were all associated with weakened suramin block, with only R334H failing to significantly affect suramin block (Fig. 7). Login to comment
129 Mean of data from three to eight patches. Fitted lines are to equation 1 as described in Figure 1 for wild type and R334Q and with the following parameters for other channel variants: R334C 4 mM external ClÀ , Kd(0) = 1362 lM, zd = À0.295; R334C 154 mM external ClÀ , Kd(0) = 836 lM, zd = À0.219; R334E 4 mM external ClÀ , Kd(0) = 759 lM, zd = À0.376; R334E 154 mM external ClÀ , Kd(0) = 564 lM, zd = À0.173; R334H 4 mM external ClÀ , Kd(0) = 140 lM, zd = À0.166; R334H 154 mM external ClÀ , Kd(0) = 119 lM, zd = À0.149; R334K 4 mM external ClÀ , Kd(0) = 143 lM, zd = À0.314; R334K 154 mM external ClÀ , Kd(0) = 317 lM, zd = À0.374; R334L 4 mM external ClÀ , Kd(0) = 176 lM, zd = À0.258; R334L 154 mM external ClÀ , Kd(0) = 284 lM, zd = À0.366 extracellular Pt(NO2)4 2À by normalizing current amplitude at the hyperpolarized extreme of the voltage range studied, -80 mV (Fig. 10b). Login to comment
159 These plots represent mean data from four to seven patches. Fitted lines are to equation 1 with the following parameters: wild type, Kd(0) = 2.51 lM, zd = À0.042; R334C, Kd(0) = 18.5 lM, zd = À0.056; R334E, Kd(0) = 25.0 lM, zd = À0.107; R334H, Kd(0) = 3.10 lM, zd = À0.085; R334K, Kd(0) = 6.31 lM, zd = À0.232; R334L, Kd(0) = 4.08 lM, zd = À0.061; R334Q, Kd(0) = 6.64 lM, zd = À0.239 with our previous suggestion that intracellular Au(CN)2 À blocks the channel by interacting directly with R334, several reasons prompt us to suggest that Pt(NO2)4 2À does not interact directly with the arginine side chain at this position. Login to comment
228 ), R334E (5), R334H (j), R334K (), R334L (h), R334Q (u); c wild type (d), K95Q (m), R303Q (Å). Login to comment

[hide] Cystic fibrosis transmembrane conductance regulato... Biophys J. 1998 Mar;74(3):1320-32. Mansoura MK, Smith SS, Choi AD, Richards NW, Strong TV, Drumm ML, Collins FS, Dawson DC
Cystic fibrosis transmembrane conductance regulator (CFTR) anion binding as a probe of the pore.
Biophys J. 1998 Mar;74(3):1320-32., [PMID:9512029]

Abstract [show]
We compared the effects of mutations in transmembrane segments (TMs) TM1, TM5, and TM6 on the conduction and activation properties of the cystic fibrosis transmembrane conductance regulator (CFTR) to determine which functional property was most sensitive to mutations and, thereby, to develop a criterion for measuring the importance of a particular residue or TM for anion conduction or activation. Anion substitution studies provided strong evidence for the binding of permeant anions in the pore. Anion binding was highly sensitive to point mutations in TM5 and TM6. Permeability ratios, in contrast, were relatively unaffected by the same mutations, so that anion binding emerged as the conduction property most sensitive to structural changes in CFTR. The relative insensitivity of permeability ratios to CFTR mutations was in accord with the notion that anion-water interactions are important determinants of permeability selectivity. By the criterion of anion binding, TM5 and TM6 were judged to be likely to contribute to the structure of the anion-selective pore, whereas TM1 was judged to be less important. Mutations in TM5 and TM6 also dramatically reduced the sensitivity of CFTR to activation by 3-isobutyl 1-methyl xanthine (IBMX), as expected if these TMs are intimately involved in the physical process that opens and closes the channel.

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No. Sentence Comment
229 Hipper et al. (1995) reported that the mutations R334E, R334H, K335E, K335H, R347E, and R347H did not alter CFTR conduction properties, but careful inspection of the data presented revealed that the level of CFTR expression was very low so that altered properties of mutant CFTRs might have been easily obscured. Login to comment

[hide] Mutations in the putative pore-forming domain of C... FEBS Lett. 1995 Nov 6;374(3):312-6. Hipper A, Mall M, Greger R, Kunzelmann K
Mutations in the putative pore-forming domain of CFTR do not change anion selectivity of the cAMP activated Cl- conductance.
FEBS Lett. 1995 Nov 6;374(3):312-6., [PMID:7589561]

Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR) apparently forms Cl- channels in apical membranes of secretory epithelial cells. A detailed model describes molecular structure and biophysical properties of CFTR and the impact of various mutations as they occur in cystic fibrosis. In the present report mutations were introduced into the putative 6th alpha-helical transmembrane pore forming domain of CFTR. The mutants were subsequently expressed in Xenopus oocytes by injection of the respective cRNAs. Whole cell (wc) conductances could be reversibly activated by IBMX (1 nmol/l) only in oocytes injected with wild-type (wt) or mutant CFTR but not in oocytes injected with water or antisense CFTR. The activated conductance was partially inhibited by (each 100 mumol/l) DIDS (27%) and glibenclamide (77%), but not by 10 mumol/l NPPB. The following mutations were examined: K335E, R347E, R334E, K335H, R347H, R334H. They did not measurably change the wt-CFTR anion permeability (P) and we conductance (G) sequence of: PCl- > PBr- > P1- and GCl- > GBr- > G1-, respectively. Moreover, anomalous mole fraction behavior for the cAMP activated current could not be detected: neither in wt-CFTR nor in R347E-CFTR. Various mutants for which positively charged amino acids were replaced by histidines (K335H, R347H, R334H) did not show pH sensitivity of the IBMX activated wc conductance. We, therefore, cannot confirm previous results. CFTR might have a different molecular structure than previously suggested or it might act as a regulator of ion conductances.

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6 The following mutations were examined: K335E, R347E, R334E, K335H, R347H, R334H. Login to comment
9 Various mutants for which positively charged amino acids were replaced by histidines (K335H, R347H, R334H) did not show pH sensitivity of the IBMX activated wc conductance. Login to comment
32 Synthesis of mutated CFTR-cDNA was induced by annealing of ampicillin repair oligonucleotide and oligonucleotide primers carrying the respective mutation changing positively charged to negatively charged amino acids (R334E, R347E, K335E) or replacing R and K at these positions by histidines (R334H, R347H, K335H). Login to comment
80 Next, positively charged amino acids R334, R347, K335 located in the putative 6th pore forming transmembrane a-helical domain of CFTR, were exchanged by histidines (R334H, R347H, K335H) or by the negatively charged glutamate (R334E, R347E, K335E). Login to comment
81 Wc conductances were activated significantly by IBMX in all 6 mutants but to variable degrees (AG in/.tS): 3.2 + 0.6 (R334E, n = 20), 2.7 + 0.6 (R334H, n = 13), 7.1 + 0.9 (K335E, n-- 20), 2.8 + 0.7 (K335H, n = 10), 3.2 + 0.04 (R347E, n = 32) and 1.8 + 0.3 (R347H, n = 10). Login to comment
91 Following previous experiments [7] wc C1- conductances were examined in mutants bearing a histidine mutation (K335H, R347H, R334H) at different extracellular pH values. Login to comment
94 aL IFEBS Letters 374 (1995) 312-316 - ~ - K335H (n=7) .... ~ .... R347H (n=8) 8 - • R334H (n=5) ...6- I~ ...L 25.5/6 7.5 8/8.5 opH Fig. 5. Summary of the conductances obtained from IBMX stimulated oocytes at different extracellular pH values. Login to comment
95 Experiments were performed with oocytes overexpressing three different CFTR mutants: K335H, R347H, R334H. Login to comment
108 In the present study we repeated some of the published (K335E, R347E, R347H) and performed additional mutations (R334E, R334H, K335H) which are all located in the putative sixth transmembrane domain and overexpressed the respective CFTRs in oocytes. Login to comment
117 Additional mutations were constructed in which positively charged lysine and two arginines in the sixth transmembrane domain were replaced by pH-sensitive histidines (R334H, K335H, R347H). Login to comment

[hide] Maximization of the rate of chloride conduction in... Arch Biochem Biophys. 2004 Jun 1;426(1):78-82. Gong X, Linsdell P
Maximization of the rate of chloride conduction in the CFTR channel pore by ion-ion interactions.
Arch Biochem Biophys. 2004 Jun 1;426(1):78-82., [PMID:15130785]

Abstract [show]
Multi-ion pore behaviour has been identified in many Cl(-) channel types but its biophysical significance is uncertain. Here, we show that mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel that disrupt anion-anion interactions within the pore are associated with drastically reduced single channel conductance. These results are consistent with models suggesting that rapid Cl(-) permeation in CFTR results from repulsive ion-ion interactions between Cl(-) ions bound concurrently inside the pore. Naturally occurring mutations that disrupt these interactions can result in cystic fibrosis.

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No. Sentence Comment
35 Results and discussion Previously we characterized the properties of six different R334 mutants (R334C, R334E, R334H, R334K, R334L, and R334Q) [19]. Login to comment
50 Comparison of unitary current amplitude at )100 mV showed that, compared to wild type, mean current was reduced by between 53 (in R334K) and 91% (in R334H) (Fig. 2B). Login to comment
65 (A) Unitary current-voltage relationships for each of the channel variants shown in Fig. 1: (d) wild type, (r) R334C, (j) R334E, (}) R334H, (s) R334K, () R334L, (.) Login to comment