ABCMdb

ABCC1 p.Glu1089Asp

Predicted by SNAP2:	A: D (53%), C: D (71%), D: D (66%), F: D (85%), G: D (75%), H: D (85%), I: D (75%), K: D (71%), L: D (75%), M: D (80%), N: D (66%), P: D (85%), Q: D (75%), R: D (85%), S: D (59%), T: D (63%), V: D (71%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: N, C: D, D: N, F: D, G: N, H: N, I: D, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N,

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Publications
[hide] Identification of an amino acid residue in multidr... J Biol Chem. 2001 Apr 20;276(16):13231-9. Epub 2001 Jan 23. Zhang DW, Cole SP, Deeley RG
Identification of an amino acid residue in multidrug resistance protein 1 critical for conferring resistance to anthracyclines.
J Biol Chem. 2001 Apr 20;276(16):13231-9. Epub 2001 Jan 23., 2001-04-20 [PMID:11278596]

Abstract [show]
Murine multidrug resistance protein 1 (mrp1), unlike human MRP1, does not confer resistance to anthracyclines. Previously, we have shown that a human/murine hybrid protein containing amino acids 959-1187 of MRP1 can confer resistance to these drugs. We have now examined the functional characteristics of mutant proteins in which we have converted individual amino acids in the comparable region of mrp1 to those present at the respective locations in MRP1. These mutations had no effect on the drug resistance profile conferred by mrp1 with the exception of converting glutamine 1086 to glutamate, as it is in the corresponding position (1089) in MRP1. This mutation created a protein that conferred resistance to doxorubicin without affecting vincristine resistance, or the ability of mrp1 to transport leukotriene C(4) (LTC(4)) and 17beta-estradiol 17-(beta-d-glucuronide) (E(2)17betaG). Furthermore, mutation Q1086D conferred the same phenotype as mutation Q1086E while the mutation Q1086N did not detectably alter the drug resistance profile of mrp1, suggesting that an anionic side chain was required for anthracycline resistance. To confirm the importance of MRP1 E1089 for conferring resistance to anthracyclines, we mutated this residue to Gln, Asp, Ala, Leu, and Lys in the human protein. The mutation E1089D showed the same phenotype as MRP1, while the E1089Q substitution markedly decreased resistance to anthracyclines without affecting LTC(4) and E(2)17betaG transport. Conversion of Glu-1089 to Asn, Ala, or Leu had a similar effect on resistance to anthracyclines, while conversion to a positive amino acid, Lys, completely eliminated resistance to anthracyclines and vincristine without affecting transport of LTC(4), E(2)17betaG, and the GSH-dependent substrate, estrone-3-sulfate. These results demonstrate that an acidic amino acid residue at position 1089 in predicted TM14 of MRP1 is critical for the ability of the protein to confer drug resistance particularly to the anthracyclines, but is not essential for its ability to transport conjugated organic anions such as LTC(4) and E(2)17betaG.

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No. Sentence Comment
7 The mutation E1089D showed the same phenotype as MRP1, while the E1089Q substitution markedly decreased resistance to anthracyclines without affecting LTC4 and E217betaG transport. Login to comment
110 Thus, glutamate 1089 was mutated to aspartate, glutamine, alanine, leucine, and lysine and chemosensitivity assays were carried out. Login to comment
116 Typical survival curves for transfectants expressing wild type MRP1 and the mutant proteins E1089Q, E1089D, and E1089K are shown in Fig. 4. Login to comment
146 In view of the effect of mutations of glutamate 1089 in the human protein on resistance to vincristine and VP-16 in addition to the anthracyclines, we also examined LTC4 and E217betaG transport by wild type and mutant human MRP1, including MRP1, E1089Q, E1089D, and E1089K. Login to comment
231 This was supported by the results obtained by substitution of glutamate 1089 with aspartate, which resulted in no detectable change in resistance profile, and by conversion to lysine, which essentially eliminated resistance to both anthracyclines and vincristine, and substantially decreased resistance to VP-16. Login to comment

[hide] The Drosophila melanogaster multidrug-resistance p... Gene. 2003 Mar 27;307:41-50. Grailles M, Brey PT, Roth CW
The Drosophila melanogaster multidrug-resistance protein 1 (MRP1) homolog has a novel gene structure containing two variable internal exons.
Gene. 2003 Mar 27;307:41-50., [PMID:12706887]

Abstract [show]
Drosophila melanogaster has a gene very similar to human MRP1 that encodes a full ABC-transporter containing three membrane-spanning domains and two nucleotide-binding domains. This 19 exon insect gene, dMRP (FBgn0032456), spans slightly more than 22 kb. The cDNA SD07655 representing this gene was sequenced and found to contain sequences from 12 exons including single copies of two exons having multiple genomic copies. The gene contains two variant copies of exon 4 and seven of exon 8. While a cDNA contains only one version of each variable exon, all forms of these variable exons were detected in adult fly mRNA. These results predict that Drosophila could make 14 different MRP isoforms from a single gene by substituting different variable exons. This is the first report of any organism using differential splicing of alternative, internal exons, to produce such a large array of MRP isoforms having the same size, but with limited and defined internal variations. Defining the functional differences in the dMRP isoforms should provide clues to the structure/function relationships of the amino acids in these MRP domains, both for the insect enzyme and for those of other species.

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Sentences [show]
No. Sentence Comment
155 Site directed mutagenesis was used to change Glu 1089 to Gln, Asp, Ala, Leu or Lys. Login to comment
153 Site directed mutagenesis was used to change Glu 1089 to Gln, Asp, Ala, Leu or Lys. Login to comment