ABCB1 p.His61Lys
| Predicted by SNAP2: | A: D (59%), C: N (57%), D: D (85%), E: D (85%), F: D (85%), G: D (75%), I: D (80%), K: D (85%), L: D (71%), M: D (85%), N: N (82%), P: D (91%), Q: D (75%), R: D (85%), S: N (66%), T: N (66%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Alteration of substrate specificity by mutations a... Biochemistry. 1997 Jul 22;36(29):8883-9. Taguchi Y, Kino K, Morishima M, Komano T, Kane SE, Ueda K
Alteration of substrate specificity by mutations at the His61 position in predicted transmembrane domain 1 of human MDR1/P-glycoprotein.
Biochemistry. 1997 Jul 22;36(29):8883-9., 1997-07-22 [PMID:9220975]
Abstract [show]
In CFTR, a member of the ABC superfamily and a chloride channel, amino acid substitutions in its transmembrane domains 1 and 6 (TM1, TM6) have been reported to modulate the anion selectivity or ion conductance of the ion channel. In P-glycoprotein, no amino acid substitution in TM1, but some in TM6, have been reported to modify the substrate specificity of this protein. In this work, we demonstrated the involvement of His61, which is in the middle of the predicted TM1, in the function of P-glycoprotein. His61 was replaced by all other amino acid residues, and each of the mutant cDNAs was introduced into drug-sensitive human carcinoma cells, KB3-1. The drug-resistance profile of cells stably expressing each mutated P-glycoprotein was investigated by comparing their relative resistance to vinblastine, colchicine, VP16, and adriamycin. The resistance to vinblastine was increased by replacing His61 by amino acids with smaller side chains, while it was lowered by replacing by amino acids with bulkier side chains. The reverse effect was observed for resistance to colchicine and VP16. The resistance to adriamycin was increased by replacing by amino acids with bulkier side chains except Lys or Arg, which have a basic side chain. We also showed that the replacement of His61 by Phe and Lys greatly impaired the efflux of calcein AM, while the replacement had no effect on the efflux of rhodamine 123. These results suggest that an amino acid residue at position 61 in TM1 is important in deciding the substrate specificity of P-glycoprotein.
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No. Sentence Comment
8 We also showed that the replacement of His61 by Phe and Lys greatly impaired the efflux of calcein AM, while the replacement had no effect on the efflux of rhodamine 123.
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ABCB1 p.His61Lys 9220975:8:39
status: NEW92 The replacement of His61 by Lys or Arg, which have a bulkier and basic side chain, reduced resistance to Vbl and Adr and increased resistance to Col and VP16, resulting in a resistance order of Col > VP16 ≈ Vbl > Adr.
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ABCB1 p.His61Lys 9220975:92:19
status: NEW136 The ability to confer resistance to Adr of mutant P-glycoproteins showed a characteristic dependence on the nature of the amino acids: although cells expressing mutants in which His61 was replaced by amino acids with side chains larger than His showed higher (more than 2-fold than that of the wild-type) resistance to Adr, cells expressing mutants in which His61 was replaced by Lys or Arg showed markedly lower resistance to Adr.
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ABCB1 p.His61Lys 9220975:136:358
status: NEW