ABCB1 p.Leu175Cys
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PMID: 21589945
[PubMed]
Klepsch F et al: "Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein."
No.
Sentence
Comment
138
In addition, a recent cross-linking study further strengthened this by showing that an M1M cross-link between L175C and N820C did not prevent verapamil and rhodamine B to be transported [46].
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ABCB1 p.Leu175Cys 21589945:138:110
status: NEW
PMID: 22700974
[PubMed]
Loo TW et al: "The ATPase activity of the P-glycoprotein drug pump is highly activated when the N-terminal and central regions of the nucleotide-binding domains are linked closely together."
No.
Sentence
Comment
10
It was found that cross-linking of cysteines that lie close to the LSGGQ (P517C) and Walker A (I1050C) sites of NBD1 and NBD2, respectively, as well as the cytoplasmic extensions of TM segments 3 (D177C or L175C) and 9 (N820C) with a short cross-linker activated ATPase activity over 10-fold.
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ABCB1 p.Leu175Cys 22700974:10:206
status: NEW129 A, model showing predicted orientations of Leu175 , Asp177 , andAsn820 intheclosedconformation.B,membranespreparedfromHEK293 cells expressing the ICL1/ICL3 mutants D177C/N820C or L175C/N820C were treated with cross-linkers M1M, M4M, or M17M or no cross-linker (Control).
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ABCB1 p.Leu175Cys 22700974:129:47
status: NEWX
ABCB1 p.Leu175Cys 22700974:129:179
status: NEW132 C, membranes expressing mutants D177C/N820C or L175C/N820C were treated with or without (None) cross-linker and histidine-tagged P-gp isolated by nickel-chelate chromatography.
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ABCB1 p.Leu175Cys 22700974:132:47
status: NEW143 In this study, we also observed that the majority of mutant L175C/N820C was cross-linked when the mutant was treated with 0.02 mM M1M at 20 °C while only a low level of cross-linking (about 25%) was observed when D177C/N820C was treated under the same conditions.
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ABCB1 p.Leu175Cys 22700974:143:35
status: NEWX
ABCB1 p.Leu175Cys 22700974:143:60
status: NEW144 Since D177C is predicted to have a more favorable orientation toward N820C compared with L175C (Fig. 3A), it would be expected that cross-linking of D177C/N820C would be more efficient than L175C/N820C.
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ABCB1 p.Leu175Cys 22700974:144:89
status: NEWX
ABCB1 p.Leu175Cys 22700974:144:190
status: NEW146 We previously observed that mutant L175C/N820 only showed efficient cross-linking with a narrow concentration range of M1M (about 10-20 M).
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ABCB1 p.Leu175Cys 22700974:146:35
status: NEWX
ABCB1 p.Leu175Cys 22700974:146:85
status: NEW150 We tested the effects of M4M and M17M cross-linking on the ATPase activity of mutant L175C/N820C and found that the effects were similar to those observed with mutant D177C/ N820C (Fig. 3C).
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ABCB1 p.Leu175Cys 22700974:150:85
status: NEW151 Cross-linking of L175C/N820C with M4M highly activated the basal ATPase activity of the mutant while cross-linking with M17M caused little activation.
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ABCB1 p.Leu175Cys 22700974:151:17
status: NEW152 The ATPase activity of M17M cross-linked L175C/N820C could still be highly activated when assayed in the presence of verapamil.
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ABCB1 p.Leu175Cys 22700974:152:41
status: NEW158 In previous studies we showed that mutants C137/A935C (39) and L443C/ S909C (27) had verapamil-stimulated ATPase activities similar to Cys-less P-gp.
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ABCB1 p.Leu175Cys 22700974:158:136
status: NEW163 These results indicate that stimulation of ATPase activity observed in M4M cross-linked mutants P517C/I1050C (Fig. 2B), D177C/N820C, or L175C/N820C (Fig. 3C) was likely a specific effect of trapping the protein in the closed conformation.
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ABCB1 p.Leu175Cys 22700974:163:136
status: NEW236 The observation that cross-linked mutants P517C/I1050C, D177C/N820C, and L175C/N820C showed high levels of ATPase activity indicates that the protein does not have to adopt an inward-facing conformation with separation of the NBDs for ATP hydrolysis to continue after the first two hydrolysis steps.
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ABCB1 p.Leu175Cys 22700974:236:73
status: NEW264 We predict that covalent attachment of thiol-reactive drug substrates to cysteines in the TMDs (or M4M cross-linking of mutants P517C/I1050C, D177C/N820C, or L175C/N820C) traps P-gp in states IV-VI (Fig. 8) that show a high rate of ATP hydrolysis.
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ABCB1 p.Leu175Cys 22700974:264:158
status: NEW126 A, model showing predicted orientations of Leu175 , Asp177 , andAsn820 intheclosedconformation.B,membranespreparedfromHEK293 cells expressing the ICL1/ICL3 mutants D177C/N820C or L175C/N820C were treated with cross-linkers M1M, M4M, or M17M or no cross-linker (Control).
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ABCB1 p.Leu175Cys 22700974:126:179
status: NEW140 In this study, we also observed that the majority of mutant L175C/N820C was cross-linked when the mutant was treated with 0.02 mM M1M at 20 &#b0;C while only a low level of cross-linking (about 25%) was observed when D177C/N820C was treated under the same conditions.
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ABCB1 p.Leu175Cys 22700974:140:60
status: NEW141 Since D177C is predicted to have a more favorable orientation toward N820C compared with L175C (Fig. 3A), it would be expected that cross-linking of D177C/N820C would be more efficient than L175C/N820C.
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ABCB1 p.Leu175Cys 22700974:141:89
status: NEWX
ABCB1 p.Leu175Cys 22700974:141:190
status: NEW147 Cross-linking of L175C/N820C with M4M highly activated the basal ATPase activity of the mutant while cross-linking with M17M caused little activation.
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ABCB1 p.Leu175Cys 22700974:147:17
status: NEW148 The ATPase activity of M17M cross-linked L175C/N820C could still be highly activated when assayed in the presence of verapamil.
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ABCB1 p.Leu175Cys 22700974:148:41
status: NEW229 The observation that cross-linked mutants P517C/I1050C, D177C/N820C, and L175C/N820C showed high levels of ATPase activity indicates that the protein does not have to adopt an inward-facing conformation with separation of the NBDs for ATP hydrolysis to continue after the first two hydrolysis steps.
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ABCB1 p.Leu175Cys 22700974:229:73
status: NEW257 We predict that covalent attachment of thiol-reactive drug substrates to cysteines in the TMDs (or M4M cross-linking of mutants P517C/I1050C, D177C/N820C, or L175C/N820C) traps P-gp in states IV-VI (Fig. 8) that show a high rate of ATP hydrolysis.
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ABCB1 p.Leu175Cys 22700974:257:158
status: NEW
PMID: 20394729
[PubMed]
Loo TW et al: "Human P-glycoprotein is active when the two halves are clamped together in the closed conformation."
No.
Sentence
Comment
7
Only mutant L175C/N820C was cross-linked.
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ABCB1 p.Leu175Cys 20394729:7:12
status: NEW58 The majority of mutant L175C/N820C was cross-linked after treatment with M1M cross-linker (Fig. 2A).
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ABCB1 p.Leu175Cys 20394729:58:23
status: NEW59 Cross-linked product was not observed in the other 11 mutants (Fig. 2A) or in the single cysteine mutants L175C and N820C (data not shown).
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ABCB1 p.Leu175Cys 20394729:59:106
status: NEW60 When mutant L175C/N820C was treated with various concentrations of M1M, it was found that the highest amount of cross-linked product was obtained in the presence of about 0.01-0.02 mM cross-linker and decreased with higher concentrations of cross-linker (Fig. 2B).
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ABCB1 p.Leu175Cys 20394729:60:12
status: NEW62 To test whether mutant L175C/N820C was still active, the histidine-tagged version of mutant L175C/N820C was isolated by nickel-chelate chromatography and assayed for drug-stimulated ATPase activity.
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ABCB1 p.Leu175Cys 20394729:62:23
status: NEWX
ABCB1 p.Leu175Cys 20394729:62:92
status: NEW64 It was found that activation and apparent affinity of mutant L175C/N820C for the drug substrates verapamil, vinblastine, rhodamine B, and colchicine were not significantly different from the Cys-less parent (data not shown).
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ABCB1 p.Leu175Cys 20394729:64:61
status: NEW65 For example, mutant L175C/N820C showed 50% stimulation of ATPase activity (S50) in the presence of 12.6 ± 1.0 lM verapamil, 44 ± 7 lM rhodamine B, 450 ± 40 lM colchicine, and 2.2 ± 0.4 lM vinblastine.
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ABCB1 p.Leu175Cys 20394729:65:20
status: NEW67 Therefore, the mutant was selected for further analysis. Cross-linking of mutant L175C/N820C with M1M (Fig. 2A) suggested that these residues were in close proximity.
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ABCB1 p.Leu175Cys 20394729:67:81
status: NEW
PMID: 24523403
[PubMed]
Loo TW et al: "Identification of the distance between the homologous halves of P-glycoprotein that triggers the high/low ATPase activity switch."
No.
Sentence
Comment
10
To determine the distance that show high or low ATPase activity, we cross-linked reporter cysteines L175C (N-half) and N820C (C-half) with cross-linkers of various lengths that separated the halves between 6 and 30 &#c5; (ॷ-carbons).
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ABCB1 p.Leu175Cys 24523403:10:100
status: NEW12 The results suggest that the ATPase activation switch appears to be turned on or off when L175C/N820 are clamped at distances less than or greater than 20 &#c5;, respectively.
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ABCB1 p.Leu175Cys 24523403:12:90
status: NEW47 To address these questions, we used cross-linkers of various lengths to cross-link a P-gp mutant that contained reporter cysteines at positions L175C (N-half) and N820 (C-half) in a Cys-less background.
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ABCB1 p.Leu175Cys 24523403:47:144
status: NEW48 The L175C and N820C reporter cysteines were selected because they are located at positions predicted to undergo large changes in distance between the closed (12 &#c5; between ॷ-carbons) and open (about 30 &#c5; between ॷ-carbons) conformations.
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ABCB1 p.Leu175Cys 24523403:48:4
status: NEW49 In addition, modifications to L175C and N820C are not expected to have a major impact on activity because they reside outside the drug- and ATP-binding sites.
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ABCB1 p.Leu175Cys 24523403:49:30
status: NEW50 We previously showed that L175C/N820C could be efficiently cross-linked with the short cross-linker 1,4-butanediyl bismethanethiosulfonate (M4M) that can span a distance of 7.5 &#c5; (about 13 &#c5; between ॷ-carbons) to activate ATPase activity (40).
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ABCB1 p.Leu175Cys 24523403:50:26
status: NEW51 Here, we tested the effects of cross-linking mutant L175C/ N820C at 10 different distances between the halves.
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ABCB1 p.Leu175Cys 24523403:51:52
status: NEW52 It was found that linkage of L175C to N820C with cross-linkers predicted to span a distance of less than 20 &#c5; highly activated P-gp ATPase activity (over 10-fold), but cross-linking with longer cross-linkers yielded P-gps with low ATPase activity.
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ABCB1 p.Leu175Cys 24523403:52:29
status: NEW55 Mutations L175C and N820C were introduced into Cys-less P-gp as described previously (42).
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ABCB1 p.Leu175Cys 24523403:55:10
status: NEW60 Disulfide Cross-linking Analysis-The double cysteine mutant L175C/N820C was transiently expressed in HEK 293 cells.
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ABCB1 p.Leu175Cys 24523403:60:60
status: NEW66 Intramolecular disulfide cross-linking between L175C and N820C can be detected because the cross-linked product migrates with a slower mobility on SDS-polyacrylamide gels (47).
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ABCB1 p.Leu175Cys 24523403:66:47
status: NEW68 Cross-linking of L175C/N820C with M1M or oxidant (copper phenanthroline) was performed using P-gp isolated by nickel-chelate chromatography.
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ABCB1 p.Leu175Cys 24523403:68:17
status: NEW81 P-gp ATPase Activity Is Highly Activated When Residues L175C and N820C Are Cross-linked in Close Proximity-In a previous study, we found that cross-linking the two homologous halves through formation of a direct disulfide bond between A259C in intracellular helix 2 (IH2) and W803C in IH3 inhibited activity (49).
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ABCB1 p.Leu175Cys 24523403:81:55
status: NEW83 Because cysteines at positions L175C and N820C are located away from the IH TMD/NBD contact points (Fig. 1), cross-linking L175C and N820C in close proximity might not disrupt TMD/NBD interactions.
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ABCB1 p.Leu175Cys 24523403:83:31
status: NEWX
ABCB1 p.Leu175Cys 24523403:83:123
status: NEW84 The L175C or N820C mutations did not appear to affect activity of P-gp because the drug-stimulated ATPase activity of the L175C/N820C mutant was very similar to the Cys-less parent (42).
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ABCB1 p.Leu175Cys 24523403:84:4
status: NEWX
ABCB1 p.Leu175Cys 24523403:84:122
status: NEW86 Cross-linking of mutant L175C/N820C was low (b0d;50% cross-linking) when membranes prepared from transfected cells were treated with oxidant (copper phenanthroline) even at 37 &#b0;C (data not shown).
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ABCB1 p.Leu175Cys 24523403:86:24
status: NEW88 Accordingly, histidine-tagged mutant L175C/N820C was expressed in HEK 293 cells, isolated by nickel chelate chromatography and treated with oxidant.
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ABCB1 p.Leu175Cys 24523403:88:37
status: NEW89 In the presence of dodecyl maltoside detergent, mutant L175C/ N820C could be efficiently cross-linked with copper phenanthroline (Fig. 2, A and B).
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ABCB1 p.Leu175Cys 24523403:89:55
status: NEW101 Cross-linking of L175C and N820C in close proximity highly activates P-gp basal ATPase activity.
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ABCB1 p.Leu175Cys 24523403:101:17
status: NEW102 A, purified histidine-tagged mutant L175C/N820C was treated with (af9;) or without (afa;) copper phenanthroline (CuP) or M1M cross-linker.
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ABCB1 p.Leu175Cys 24523403:102:36
status: NEW105 B, amount of cross-linked protein relative to total P-gp was quantitated from three different transfections afe; S.D. C, ATPase activities of mutant L175C/N820C were determined in the absence (afa;) or presence (af9;) of verapamil (Ver) before (None) and after cross-linking with copper phenanthroline or M1M.
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ABCB1 p.Leu175Cys 24523403:105:152
status: NEW107 To test for the effects of cross-linking on activity, isolated L175C/N820C was treated with or without 0.5 mM copper phenanthroline or 0.009 mM M1M.
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ABCB1 p.Leu175Cys 24523403:107:63
status: NEW112 Activation of mutant L175C/N820C basal ATPase activity with M1M was higher than previously observed using membranes (42) suggesting that the efficiency of cross-linking was improved using purified P-gp.
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ABCB1 p.Leu175Cys 24523403:112:21
status: NEW115 P-gp ATPase Activity Is Not Highly Activated When Residues L175C and N820C Are Cross-linked with Long Cross-linkers- The next step was to test the effects of cross-linking with MTS cross-linkers that could span longer distances such as M2M (5.2 &#c5;), M4M (7.8 &#c5;), M5M (8.8 &#c5;), M6M (10.4 &#c5;), M8M (13 &#c5;), M11M (16.9 &#c5;), M14M (19 &#c5;) and M17M (22 &#c5;) (45).
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ABCB1 p.Leu175Cys 24523403:115:59
status: NEW117 For example, we used 0.009 mM M1M to treat L175C/N820C because we previously showed that cross-linking efficiency was sharply reduced at lower concentrations (0.003 mM) or higher concentrations (0.027 mM) (42).
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ABCB1 p.Leu175Cys 24523403:117:43
status: NEW118 Accordingly, membranes prepared from cells expressing mutant L175C/N820C were treated with various concentrations of MTS cross-linkers with various lengths of spacer arms for 10 min at 20 &#b0;C, and samples were subjected to immunoblot analysis.
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ABCB1 p.Leu175Cys 24523403:118:61
status: NEW127 Membranes prepared from cells expressing mutant L175C/ N820C were first treated for 10 min at 20 &#b0;C in the absence or presence of 0.027 mM MTS cross-linkers of different lengths.
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ABCB1 p.Leu175Cys 24523403:127:48
status: NEW129 Because mutant L175C/N820C was efficiently cross-linked with the MTS cross-linkers, we tested whether cross-linking affected activity.
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ABCB1 p.Leu175Cys 24523403:129:15
status: NEW131 Cross-linking of L175C/N820C P-gp with various concentrations of M2M and M17M cross-linker.
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ABCB1 p.Leu175Cys 24523403:131:17
status: NEW132 Membranes prepared from HEK 293 cells expressing mutant L175C/N820C were treated with various concentrations (0-2.2 mM) of M2M (A and B) or M17M (C and D) cross-linker.
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ABCB1 p.Leu175Cys 24523403:132:56
status: NEW136 Activation Switch for P-gp ATPase Activity MARCH 21, 2014ߦVOLUME 289ߦNUMBER 12 JOURNAL OF BIOLOGICAL CHEMISTRY 8487 membranes and assayed for ATPase activity in the presence or absence of saturating concentrations (0.4 mM) of verapamil. Fig. 5 shows that untreated mutant L175C/N820C isolated from membranes exhibited about a 12-fold increase in verapamil-stimulated ATPase activity.
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ABCB1 p.Leu175Cys 24523403:136:285
status: NEW139 By contrast, treatment of mutant L175C/ N820C with the intermediate size MTS cross-linkers (M2M, M4M, M5M, M6M, and M8M) that span maximum distances of about 5.2-13 &#c5; (distance of about 10.6-18.6 &#c5; between the ॷ-carbons) highly activated ATPase activity in the absence of verapamil.
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ABCB1 p.Leu175Cys 24523403:139:33
status: NEW142 It appeared that cross-linking of mutant L175C/N820C with the intermediate size cross-linkers locked P-gp in an activated state resulting in high levels of ATPase activity in the absence or presence of drug substrates.
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ABCB1 p.Leu175Cys 24523403:142:41
status: NEW143 A quite different effect was observed when mutant L175C/ N820C was treated with the long cross-linkers M11M, M14M, and M17M that could span maximum distances of about 16.9, 19, and 22 &#c5; in length, respectively (span distances of about 22 to 28 &#c5; between the ॷ-carbons) (Fig. 5).
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ABCB1 p.Leu175Cys 24523403:143:50
status: NEW145 Cross-linking of mutant L175C/N820C with the intermediate size MTS cross-linkers like M2M increased the basal ATPase activity of the mutant (Fig. 5).
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ABCB1 p.Leu175Cys 24523403:145:24
status: NEW147 To test these possibilities, a series of control experiments were carried out with L175C/N820C using M2M.
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ABCB1 p.Leu175Cys 24523403:147:83
status: NEW150 We compared the effects of treating mutant L175C/N820C with low (0.027 mM; promotes cross-linking) or high (3 mM; likely labels each cysteine with a separate M2M molecule) concentrations of M2M on ATPase activity.
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ABCB1 p.Leu175Cys 24523403:150:43
status: NEW154 Next, mutant histidine-tagged P-gps were constructed that contained only the L175C or N820C mutation alone to test if modification of only one cysteine had an impact on ATPase activity.
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ABCB1 p.Leu175Cys 24523403:154:77
status: NEW159 Cross-linking of mutant L175C/N820C with cross-linkers of various lengths.
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ABCB1 p.Leu175Cys 24523403:159:24
status: NEW160 A, membranes prepared from HEK 293 cells expressing mutant L175C/N820C were treated without (None) or with MTS cross-linkers of various lengths (MXM).
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ABCB1 p.Leu175Cys 24523403:160:59
status: NEW164 ATPase activity of mutant L175C/N820C cross-linked with various MXM cross-linkers.
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ABCB1 p.Leu175Cys 24523403:164:26
status: NEW165 Membranes were prepared from HEK 293 cells expressing mutant histidine-tagged L175C/N820C and cross-linked with various MXM cross-linkers (X afd; 2-17).
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ABCB1 p.Leu175Cys 24523403:165:78
status: NEW169 These results show that activation of mutant L175C/N820C basal ATPase activity by M2M was due to cross-linking between the two cysteines.
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ABCB1 p.Leu175Cys 24523403:169:45
status: NEW173 In agreement with the EPR and simulation studies (55), we found that the presence of ATP did not promote the formation of a more closed structure as it did not promote L175C/N820C cross-linking (42).
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ABCB1 p.Leu175Cys 24523403:173:168
status: NEW174 We also found that verapamil did not promote or inhibit cross-linking of L175C/N820C (42).
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ABCB1 p.Leu175Cys 24523403:174:73
status: NEW179 The experiments presented here show that human L175C/ N820C P-gp remains active when it is trapped in conformations with a wide range of separations between the halves (about 6-30 &#c5;).
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ABCB1 p.Leu175Cys 24523403:179:47
status: NEW192 Activity of L175C/N820C, Cys-less, L175C, and N820C P-gp treated with various concentrations of M2M.
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ABCB1 p.Leu175Cys 24523403:192:12
status: NEWX
ABCB1 p.Leu175Cys 24523403:192:35
status: NEW193 A, histidine-tagged mutant L175C/N820C was isolated from membranes treated was treated without (None), low (0.027 mM), or high (3 mM) concentrations of M2M and ATPase activity determined in the absence (afa;) or presence (af9;) of verapamil (Ver).
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ABCB1 p.Leu175Cys 24523403:193:27
status: NEW194 B, membranes expressing histidine-tagged mutant L175C/N820C, Cys-less, L175C, or N820C P-gp were treated without (afa;) or with (af9;) 0.027 mM M2M.
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ABCB1 p.Leu175Cys 24523403:194:48
status: NEWX
ABCB1 p.Leu175Cys 24523403:194:71
status: NEW197 Correlation of ATPase activity of L175C/N820C treated with cross-linkers of various lengths and the distance between the ॷ-carbons of L175C and N820C.
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ABCB1 p.Leu175Cys 24523403:197:34
status: NEWX
ABCB1 p.Leu175Cys 24523403:197:140
status: NEW198 The activity of mutant L175C/N820C cross-linked with MXM cross-linker (M1M (2), M2M (3), M4M (4), M5M (5), M6M (6), M8M (7), M11M (8), M14M (9), or M17M (10)) was compared with that treated with copper phenanthroline (1).
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ABCB1 p.Leu175Cys 24523403:198:23
status: NEW211 Could P-gp still transport drug substrates when L175C/ N820C is cross-linked with short (M2M to M8M) cross-linkers?
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ABCB1 p.Leu175Cys 24523403:211:48
status: NEW212 Unfortunately, it was not possible to use whole cell transport or drug resistance assays because cross-linking could not be detected when cells expressing the L175C/N820C mutant were treated with the MTS cross-linkers.3 The lack of cross-linking in whole cells could be due to the presence of intracellular thiol reductants such as glutathione that would not only react with the MTS cross-linkers but also reduce any disulfide bond.
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ABCB1 p.Leu175Cys 24523403:212:159
status: NEW214 We predict, however, that P-gp cross-linked at L175C/ N820C with short cross-linkers should be able to bind substrates with relatively high affinity because it was reported that P-gp trapped in the closed vanadate-trapped transition state had similar affinity for the drug substrates verapamil, Hoechst 33342, cyclosporin A, vinblastine, colchicine, rhodamine B, and doxorubicin as in the relaxed (open) state (66).
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ABCB1 p.Leu175Cys 24523403:214:47
status: NEW
PMID: 25053414
[PubMed]
Loo TW et al: "Cysteines introduced into extracellular loops 1 and 4 of human P-glycoprotein that are close only in the open conformation spontaneously form a disulfide bond that inhibits drug efflux and ATPase activity."
No.
Sentence
Comment
257
Direct cross-linking of the cysteines L175C and N820C (23) or cross-linking of mutant P571C/I1050C with the short 1,4-butanediyl bismethanethiosulfonate cross-linker (7.8 &#c5;) (24) highly activated P-gp ATPase activity over 10-fold in the absence of drug substrates.
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ABCB1 p.Leu175Cys 25053414:257:38
status: NEW258 Cysteines L175C/N820C are located in the intracellular loops (Fig. 1, C and D), whereas cysteines P517C/I1050C are located in the NBDs (Fig. 1, C and D).
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ABCB1 p.Leu175Cys 25053414:258:10
status: NEW259 An explanation for the difference is that linkage of the homologous halves at the L175C/N820C or P517C/I1050C sites would tend to favor the closed conformation (Fig. 1C) to FIGURE 9.
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ABCB1 p.Leu175Cys 25053414:259:82
status: NEW