ABCMdb

ABCC3 p.Thr1237Ser

Predicted by SNAP2:	A: D (75%), C: D (75%), D: D (85%), E: D (85%), F: D (80%), G: D (75%), H: D (80%), I: D (75%), K: D (91%), L: D (80%), M: D (66%), N: D (63%), P: D (91%), Q: D (80%), R: D (91%), S: N (61%), V: D (75%), W: D (85%), Y: 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, V: D, W: D, Y: D,

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Publications
[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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Sentences [show]
No. Sentence Comment
75 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'). Login to comment
189 Effect of Mutations T1237G, T1237S, and T1237L on VP-16 Resistance. Login to comment
210 Effects of Mutations T1237G, T1237S, and T1237L on the Transport Profile of MRP3. Login to comment
212 Thus, the effects of the mutations T1237G, T1237S, and T1237L on the ability of MRP3 to transport these three substrates were also examined by in vitro transport assays (Figure 8B-D). Login to comment
278 Although the majority of mutations that eliminated hydrogen-bonding potential had a negative effect on the activity FIGURE 8: Effect of mutations T1237S, T1237L, and T1237G on ATP-dependent [3H]methotrexate (panel B), [3H]E217βG (panel C), and [3H]taurocholate (panel D) uptake by wild-type MRP3. Login to comment
289 The effect of replacement of Thr1237 with Ser was more complex. Login to comment