ABCB1 p.Gly54Val
| Predicted by SNAP2: | A: D (80%), C: D (75%), D: D (91%), E: D (91%), F: D (91%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (91%), P: D (91%), Q: D (91%), R: D (95%), S: D (75%), T: D (85%), V: D (91%), W: D (91%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Correction of defective protein kinesis of human P... J Biol Chem. 1997 Jan 10;272(2):709-12. Loo TW, Clarke DM
Correction of defective protein kinesis of human P-glycoprotein mutants by substrates and modulators.
J Biol Chem. 1997 Jan 10;272(2):709-12., 1997-01-10 [PMID:8995353]
Abstract [show]
There is growing evidence that abnormal protein folding or trafficking (protein kinesis) leads to diseases. We have used P-glycoprotein as a model protein to develop strategies to overcome defects in protein kinesis. Misprocessed mutants of the human P-glycoprotein are retained in the endoplasmic reticulum as core-glycosylated biosynthetic intermediates and rapidly degraded. Synthesis of the mutant proteins in the presence of drug substrates or modulators such as capsaicin, cyclosporin, vinblastine, or verapamil, however, resulted in the appearance of a fully glycosylated and functional protein at the cell surface. These effects were dose-dependent and occurred within a few hours after the addition of substrate. The ability to facilitate processing of the misfolded mutants appeared to be independent of the cell lines used and location of the mutation. P-glycoproteins with mutations in transmembrane segments, extracellular or cytoplasmic loops, the nucleotide-binding domains, or the linker region were processed to the fully mature form in the presence of these substrates. These drug substrates or modulators acted as specific chemical chaperones for P-glycoprotein because they were ineffective on the deltaF508 mutant of cystic fibrosis transmembrane conductance regulator. Therefore, one possible strategy to prevent protein misfolding is to carry out synthesis in the presence of specific substrates or modulators of the protein.
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No. Sentence Comment
64 In addition to the mutants G268V and ⌬Y490, we were able to facilitate processing of P-glycoproteins with mutations in the predicted transmembrane segments (TM1, G54V; TM5, G300V; TM7, A718L; and TM9, A841L), in the extracellular loops between transmembrane segments (G854V), in the cytoplasmic loops (G251V and W803A), in the nucleotide-binding domains (G427C and S434C), and in the linker region connecting the two halves of the molecule (E707A) (data not shown).
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ABCB1 p.Gly54Val 8995353:64:169
status: NEW[hide] Amino acid substitutions in the first transmembran... FEBS Lett. 1997 Aug 11;413(1):142-6. Taguchi Y, Morishima M, Komano T, Ueda K
Amino acid substitutions in the first transmembrane domain (TM1) of P-glycoprotein that alter substrate specificity.
FEBS Lett. 1997 Aug 11;413(1):142-6., [PMID:9287132]
Abstract [show]
Recently, we showed that the amino acid at position 61 in TM1 of human P-glycoprotein is important in deciding the substrate specificity of this protein. In this work, we investigated whether the amino acids other than His61 in TM1 of P-glycoprotein are also essential in the function of this protein. Nine amino acids residues, from Ala57 to Leu65 in TM1, were independently substituted to Arg, and analyzed the drug resistance of cells stably expressing each of these mutant P-glycoproteins. The mutant P-glycoproteins Ile60 --> Arg, His61 --> Arg, Ala63 --> Arg, Gly64 --> Arg, and Leu65 --> Arg were normally processed and expressed in the plasma membrane. Substrate specificities of mutant P-glycoproteins Gly64 --> Arg and Leu65 --> Arg were quite different from that of the wild type, and similar to that of the His61 --> Arg mutant, while the Ile60 --> Arg and Ala63 --> Arg mutant P-glycoproteins showed similar substrate specificities to that of the wild-type P-glycoprotein, suggesting that not only the amino acid residue at position 61 but also those at position 64 and 65 are also important in deciding the substrate specificity of P-glycoprotein. These three amino acids His61, Gly64, and Leu65 would form a compact region on an alpha-helix arrangement of TM1. These results suggest that a region consisting of His61, Gly64, and Leu65 in TM1 would participate in the formation of the recognition site for substrates of P-glycoprotein.
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No. Sentence Comment
87 It was reported [21] that no Vbl- or Col-resistant colonies were obtained from cells transfected with either Gly54 -> Val, Ala58 -> Leu, or Gly62 -> Val mutant P-glycoprotein cDNA, and that the major products from these three mutant cDNAs were protein with an apparent mass of 150 kDa when their cDNAs were transiently expressed in HEK 293 cells, suggesting that these mutations in TMl affected the proper folding In this study, we examined whether the substitution of amino acids near His61 in TMl affect substrate specificity of P-glycoprotein.
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ABCB1 p.Gly54Val 9287132:87:109
status: NEW