ABCMdb

ABCC7 p.Ser1118Cys

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Publications

PMID: 19381710 [PubMed] Fatehi M et al: "Novel residues lining the CFTR chloride channel pore identified by functional modification of introduced cysteines."

No. Sentence Comment

66 An example is S1118C (Fig. 2c, d). Login to comment
71 As described previously for modification of cysteines introduced into TM6 (Fatehi and Linsdell 2008) and the extracellular loop between TMs 1 and 2 (Zhou et al. 2008), MTSET and MTSES altered the IREL-V shape in S1118C, T1121C, T1122C, G1127C, V1129C, I1131C and I1132C. Login to comment
72 Of 21 cysteine mutants studied, only six significantly altered I-V relationship shape in the absence of external MTS reagents (Fig. 3a), with S1118C, T1121C, T1122C, G1127C and A1136C all causing significant inward rectification and V1129C showing outward rectification. Login to comment
84 Unitary currents at depolarized voltages were significantly decreased in S1118C, T1121C, T1122C and G1127C and significantly increased in V1129C (Fig. 5b). Login to comment
85 This resulted in changes in the shape of the i-V relationship, causing inward rectification in the case of S1118C, T1121C, T1122C and G1127C and outward rectification in the case of V1129C (Figs. 4b, 5c). Login to comment
91 Indeed, changes in unitary current amplitude were observed in S1118C, T1121C, T1122C, G1127C, V1129C, I1131C and I1132C, but not wild-type, when MTS reagents were included in the pipette solution (Fig. 6). Login to comment
98 c, d Example I-V relationships and mean rectification ratios for S1118C under the same conditions. Login to comment
118 Four mutations (S1118C, T1121C, T1122C, G1127C) led to significant decreases in unitary current amplitude (Fig. 5b), which were relatively strongly affected by MTS modification-in each case conductance was further decreased by reaction with MTSES and increased to near wild-type levels by MTSET (Fig. 9a). Login to comment
124 Under these conditions, SCN- block was significantly strengthened in I1132C (at hyperpolarized and depolarized voltages), S1118C (at hyperpolarized voltages), T1121C and V1129C (at depolarized voltages) and I1131C (at very depolarized voltages only) Fig. 4 Single-channel currents carried by cysteine mutant forms of CFTR. Login to comment
125 a Example single-channel currents carried by wild-type, S1118C, T1121C, T1122C and V1129C, at membrane potentials of ?60 (top) and -60 (bottom) mV. Login to comment
133 Under these conditions, SCN- permeability was significantly increased in S1118C and (to a lesser extent) T1122C and G1127C and unaltered in T1121C, V1129C, I1131C and I1132C (Fig. 11). Login to comment
158 Of the seven mutants that were functionally modified by MTS reagents, five (S1118C, T1121C, T1122C, G1127C, V1129C) also showed significantly altered unitary current amplitude in the absence of MTS modification (Figs. 4, 5). Login to comment
161 a S1118C (d), T1121C (j), T1122C (), G1127C (h); b V1129C (m), I1131C (r), I1132C (.). Login to comment
183 We speculate that one group of reactive mutants (S1118C, T1121C, T1122C, G1127C) is located relatively deep in the pore from the outside and that the other (V1129C, Fig. 11 Thiocyanate permeability of mutants. Login to comment
185 In these examples, the current reversal potential is ?36.4 mV for wild-type and ?47.8 mV for S1118C (shown by arrows), suggesting an increased PSCN/PCl in this mutant. Login to comment
188 In this scenario, charge-neutral mutations deeper in the pore (S1118C, T1121C, T1122C, G1127C) (Fig. 9a) disrupt Cl- movement in the pore in a nonelectrostatic fashion, leading to reduced unitary currents at depolarized voltages, as described previously for TM6 mutations (McDonough et al. 1994; Linsdell et al. 1998; Linsdell 2001a). Login to comment
200 Mutations S1118C, T1122C and G1127C also altered the anion selectivity of CFTR, significantly increasing SCN- per- meability (Fig. 11), which is consistent with changes in pore structure and function. Login to comment
214 It should be stressed that, in some cases, the cysteine mutations we used in the present study represent rather conservative mutations (especially S1118C, which effectively changes one oxygen atom to sulfur). Login to comment

PMID: 20059485 [PubMed] Dorfman R et al: "Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene?"

No. Sentence Comment

64 Mutations in the CFTR gene grouped by clinical category Cystic fibrosis CFTR-related disease No disease T338I D614G L320V V920L L90S M470V H199R S1251N I203M G550R P111A I148T Q1291H R560K L1388Q L183I R170H I1027T S549R D443Y P499A L1414S T908N R668C S549N A455E E1401K Q151K G27E I1234L Y563N R347P C866R S1118C P1290S R75Q A559T V520F P841R M469V E1401G P67L G85E S50Y E1409K R933G G458V G178R Y1032C R248T I980K G85V V392G L973P L137H T351S R334W I444S V938G R792G R560T R555G L1339F D1305E P574H V1240G T1053I D58G G551D L1335P I918M F994C S945L L558S F1337V R810G D1152H G1247R P574S R766M D579G W1098R H949R F200I R352Q L1077P K1351E M244K L206W M1101K D1154G L375F N1303K R1066C E528D D110Y R347H R1070Q A800G P1021S S549K A1364V V392A damaging` (is supposed to affect protein function or structure) and 'probably damaging` (high confidence of affecting protein function or structure). Login to comment

PMID: 23955087 [PubMed] Wang W et al: "Relative contribution of different transmembrane segments to the CFTR chloride channel pore."

No. Sentence Comment

4 Two accessible residues in TM11 (T1115C and S1118C) were found to be more readily modified from the extracellular solution in closed channels, but more readily modified from the intracellular solution in open channels, as previously reported for T338C in TM6. Login to comment
77 Note that while MTSES caused rapid inhibition of macroscopic current amplitude in T1115C and S1118C, inhibition of I1112C current was much slower (note different time scale for this mutant). Login to comment
111 b Example whole cell currents recorded continuously at +30 mV for constitutively active T1115C/ E1371Q and S1118C/E1371Q channels. Login to comment
112 In contrast to currents carried by T1115C and S1118C channels (see Fig. 3), these whole cell currents were not significantly affected by addition of 200 bc;M MTSES to the extracellular solution (black bars), even though these currents were positively identified as being carried by CFTR by sensitivity to GlyH-101 (50 bc;M, hatched bars). Login to comment
117 Application of MTSES (200 bc;M) following channel activation with PKA and ATP caused a decrease in macroscopic current amplitude in I1112C, T1115C and S1118C, but not in T1121C (Fig. 2a, b) or in I1109C, F1110C, F1111C, A1113C, V1114C, F1116C, or I1117C (Fig. 2c). Login to comment
122 Previously it was shown that S1118C, T1121C, and T1122C-but not F1116C, I1117C, I1119C, or L1120C-are accessible to externally applied MTS reagents [10]. Login to comment
123 Figure 3 confirms that application of external MTSES (200 bc;M) following channel activation with cAMP-stimulatory cocktail caused a decrease in whole cell current amplitude in T1115C, S1118C, and T1121C, but not in I1112C. Login to comment
124 Together, these results (Figs. 2b, 3b) suggest that S1118C represents the outermost extent of internal MTSES penetration into the pore, and T1115 the innermost extent of external MTSES penetration. Login to comment
127 State-dependent accessibility of T1115C and S1118C in TM11 Modification of T1115C and S1118C by both internal and external MTSES is reminiscent of the accessibility pattern observed for TM6 cysteine mutant T338C [42]. Login to comment
128 This similarity is perhaps not surprising since a disulfide bond can be formed between the two cysteine side chains of T338C and S1118C in open channels [43], indicating close physical proximity of these pore-exposed side chains. Login to comment
137 As shown in Fig. 4a, c, the E1371Q mutation significantly accelerated the rate of modification of both T1115C and S1118C by intracellular MTSES, suggesting that these cysteines are more readily modified from the inside in open channels. Login to comment
141 This suggestion is consistent with data that S1118C can form a disulfide bond with T338C in open channels [43]. Login to comment
152 Previously it was shown that the S1118C mutation reduced single channel conductance at depolarized membrane potentials [10]. Login to comment
161 In each case, the single channel I-V relationship remained linear (e.g., Fig. 5b), in contrast to the strongly inwardly rectified I-V relationship previously observed for S1118C [10]. Login to comment
169 As observed at the single channel level (Fig. 5), the macroscopic I-V relationships for all mutants remained linear (e.g., Fig. 6a), in contrast to the strongly inwardly rectifying relationship previously observed for S1118C [10]. Login to comment
187 The proposed relative alignment of TMs 6 and 11 presented in Fig. 9a is consistent not only with the pattern of MTSES accessibility from different sides of the membrane, but also with previous data showing that disulfide bonds can form between T338C and S1118C, and between R334C and T1122C, in open channels [43]. Login to comment
199 Furthermore, using the same approach used previously to study side-dependent modification of T338C [42], we found that T1115C and S1118C were more readily modified from the extracellular solution in closed channels, but more readily modified from the intracellular solution in open channels (Fig. 4). Login to comment
219 Previously, the S1118C mutation was shown to decrease conductance at positive voltages, leading to inward rectification of both the single channel and macroscopic current-voltage relationships [10], and although this would be considered a very conservative mutation (one oxygen atom replaced by sulfur) this effect was not reproduced in S1118A, S1118Q or S1118 (Fig. 5). Login to comment
220 Given that the effects of the S1118C mutation on single channel conductance and rectification were exacerbated by modification by external MTSES, and mostly reversed by modification with positively charged MTSET [10], these effects might reflect partial negative charge of the introduced cysteine side chain rather than a change in side chain volume. Login to comment