ABCC1 p.Thr1242Asp
| Predicted by SNAP2: | A: N (82%), C: N (66%), D: N (72%), E: N (66%), F: N (78%), G: N (82%), H: N (82%), I: N (72%), K: N (53%), L: N (72%), M: N (78%), N: N (87%), P: N (53%), Q: N (78%), R: N (53%), S: N (87%), V: N (72%), W: N (61%), Y: N (78%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, V: N, W: N, Y: N, |
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[hide] Identification of a nonconserved amino acid residu... J Biol Chem. 2001 Sep 14;276(37):34966-74. Epub 2001 Jun 27. Zhang DW, Cole SP, Deeley RG
Identification of a nonconserved amino acid residue in multidrug resistance protein 1 important for determining substrate specificity: evidence for functional interaction between transmembrane helices 14 and 17.
J Biol Chem. 2001 Sep 14;276(37):34966-74. Epub 2001 Jun 27., 2001-09-14 [PMID:11429411]
Abstract [show]
Murine multidrug resistance protein 1 (mrp1), differs from its human ortholog (MRP1) in that it fails to confer anthracycline resistance and transports the MRP1 substrate, 17beta-estradiol 17-(beta-d-glucuronide) (E(2)17betaG), very poorly. By mutating variant residues in mrp1 to those present in MRP1, we identified Glu(1089) of MRP1 as being critical for anthracycline resistance. However, Glu(1089) mutations had no effect on E(2)17betaG transport. We have now identified a nonconserved amino acid within the highly conserved COOH-proximal transmembrane helix of MRP1/mrp1 that is important for transport of the conjugated estrogen. Converting Ala(1239) in mrp1 to Thr, as in the corresponding position (1242) in MRP1, increased E(2)17betaG transport 3-fold. Any mutation of mrp1 Ala(1239), including substitution with Thr, decreased resistance to vincristine and VP-16 without altering anthracycline resistance. However, introduction of a second murine to human mutation, Q1086E, which alone selectively increases anthracycline resistance, into mrp1A1239T restored resistance to both vincristine and VP-16. To confirm the importance of MRP1 Thr(1242) for E(2)17betaG transport and drug resistance, we mutated this residue to Ala, Cys, Ser, Leu, and Lys. These mutations decreased E(2)17betaG transport 2-fold. Conversion to Asp eliminated transport of the estrogen conjugate and also decreased leukotriene C(4) transport approximately 2-fold. The mutations also reduced the ability of MRP1 to confer resistance to all drugs tested. As with mrp1, introduction of a second mutation based on the murine sequence to create MRP1E1089Q/T1242A restored resistance to vincristine and VP-16, but not anthracyclines, without affecting transport of leukotriene C(4) and E(2)17betaG. These results demonstrate the important role of Thr(1242) for E(2)17betaG transport. They also reveal a highly specific functional relationship between nonconserved amino acids in TM helices 14 and 17 of both mrp1 and MRP1 that enables both proteins to confer similar levels of resistance to vincristine and VP-16.
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No. Sentence Comment
239 The consequences of mutating mrp1A1239 and MRP1T1242, with the exception of the T1242D mutation, are qualitatively similar to those we observed following mutation of the highly conserved Trp1246 , which abolished drug resistance and E217betaG transport (30).
X
ABCC1 p.Thr1242Asp 11429411:239:80
status: NEW266 Only substitution of Thr1242 with Asp affected transport of both E217betaG transport and, albeit to a lesser extent, LTC4.
X
ABCC1 p.Thr1242Asp 11429411:266:21
status: NEW