ABCC3 p.Ser1231Ala
| Predicted by SNAP2: | A: D (66%), C: D (66%), D: D (80%), E: D (80%), F: D (75%), G: D (66%), H: D (75%), I: D (71%), K: D (85%), L: D (75%), M: D (66%), N: D (71%), P: D (85%), Q: D (66%), R: D (85%), T: N (78%), V: D (66%), W: D (85%), Y: D (80%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, T: N, V: D, W: D, Y: D, |
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[hide] Characterization of the role of polar amino acid r... Biochemistry. 2003 Aug 26;42(33):9989-10000. Zhang DW, Gu HM, Vasa M, Muredda M, Cole SP, Deeley RG
Characterization of the role of polar amino acid residues within predicted transmembrane helix 17 in determining the substrate specificity of multidrug resistance protein 3.
Biochemistry. 2003 Aug 26;42(33):9989-10000., [PMID:12924948]
Abstract [show]
Human multidrug resistance protein (MRP) 3 is the most closely related homologue of MRP1. Like MRP1, MRP3 confers resistance to etoposide (VP-16) and actively transports 17 beta-estradiol 17-(beta-D-glucuronide) (E(2)17 beta G), cysteinyl leukotriene 4 (LTC(4)), and methotrexate, although with generally lower affinity. Unlike MRP1, MRP3 also transports monovalent bile salts. We have previously demonstrated that hydrogen-bonding residues predicted to be in the inner-leaflet spanning segment of transmembrane (TM) 17 of MRP1 are important for drug resistance and E(2)17 beta G transport. We have now examined the importance of the hydrogen-bonding potential of residues in TM17 of MRP3 on both substrate specificity and overall activity. Mutation S1229A reduced only methotrexate transport. Mutations S1231A and N1241A decreased resistance to VP-16 and transport of E(2)17 beta G and methotrexate but not taurocholate. Mutation Q1235A also reduced resistance to VP-16 and transport of E(2)17beta G but increased taurocholate transport without affecting transport of methotrexate. Mutations Y1232F and S1233A reduced resistance to VP-16 and the transport of all three substrates tested. In contrast, mutation T1237A markedly increased VP-16 resistance and transport of all substrates. On the basis of the substrates analyzed, residues Ser(1229), Ser(1231), Gln(1235), and Asn(1241) play an important role in determining the specificity of MRP3, while mutation of Tyr(1232), Ser(1233), and Thr(1237) affects overall activity. Unlike MRP1, the involvement of polar residues in determining substrate specificity extends throughout the TM helix. Furthermore, elimination of the hydrogen-bonding potential of a single amino acid, Thr(1237), markedly enhanced the ability of the protein to confer drug resistance and to transport all substrates examined.
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No. Sentence Comment
6 Mutations S1231A and N1241A decreased resistance to VP-16 and transport of E217βG and methotrexate but not taurocholate.
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ABCC3 p.Ser1231Ala 12924948:6:10
status: NEW75 They are as follows: S1229A (5'-GGG CTG GTG GGG CTA GCT GTG TCC TAC TCC-3'), S1231A (5'-GC CTT TCT GTG GCC TAC TCC CTG CAG GTG ACA-3'), Y1232F (5'-T TCT GTG TCC TTC TCC TTA CAG GTG ACA TTT G-3'), S1233A (5'-CT GTG TCC TAC GCC CTG CAG GTG ACA TTT G-3'), Q1235A (5'-G TCC TAC TCC TTG GCG GTG ACA TTT GCT C-3'), T1237A (5'-CC TTG CAG GTG GCA TTC GCT CTG AAC TGG-3'), T1237S (5'-CC TTG CAG GTG TCC TTC GCT CTG AAC TGG-3'), T1237G (5'-CC TTG CAG GTG GGA TTC GCT CTG AAC TGG-3'), T1237L (5'-CC TTG CAG GTG CTA TTC GCT CTG AAC TGG-3'), and N1241A (5'-GTG ACA TTT GCG CTA GCC TGG ATG ATA C-3').
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ABCC3 p.Ser1231Ala 12924948:75:77
status: NEW138 Replacement of Ser1229 with Ala had no significant effect on MRP3-mediated E217βG uptake, whereas mutations S1231A, Y1232F, S1233A, Q1235A, and N1241A all decreased the transport activity.
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ABCC3 p.Ser1231Ala 12924948:138:114
status: NEW146 However, mutations S1229A, S1231A, Y1232F, S1233A, and N1241A all reduced methotrexate transport activity.
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ABCC3 p.Ser1231Ala 12924948:146:27
status: NEW149 Mutations S1229A, S1231A, and N1241A did not significantly influence transport activity.
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ABCC3 p.Ser1231Ala 12924948:149:18
status: NEW186 However, mutation of five hydrophilic amino acid residues (S1231A, Y1232F, S1233A, Q1235A, and N1241A) caused approximately a 2-3-fold reduction of resistance to VP-16.
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ABCC3 p.Ser1231Ala 12924948:186:59
status: NEW188 Thus, on the basis of the substrates tested in this study, mutations S1229A, S1231A, Q1235A, and N1241A affected substrate specificity of MRP3, whereas mutations Y1232F, S1233A, and T1237A influenced the overall activity of the protein.
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ABCC3 p.Ser1231Ala 12924948:188:77
status: NEW