ABCC2 p.Phe368Ala
| Predicted by SNAP2: | A: N (61%), C: N (82%), D: D (75%), E: D (66%), G: D (63%), H: D (63%), I: N (66%), K: D (66%), L: N (87%), M: N (78%), N: D (63%), P: D (71%), Q: D (59%), R: D (66%), S: N (53%), T: N (53%), V: N (66%), W: D (59%), Y: N (61%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, G: 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: N, |
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[hide] Phenylalanine 368 of multidrug resistance-associat... Biochem Pharmacol. 2012 Aug 1;84(3):366-73. Epub 2012 Apr 21. Wittgen HG, van den Heuvel JJ, Krieger E, Schaftenaar G, Russel FG, Koenderink JB
Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity.
Biochem Pharmacol. 2012 Aug 1;84(3):366-73. Epub 2012 Apr 21., [PMID:22542979]
Abstract [show]
Multidrug resistance-associated protein 4 (MRP4) is a membrane transporter that mediates the cellular efflux of a wide range of anionic drugs and endogenous molecules. MRP4 transport can influence the pharmacokinetics of drugs and their metabolites, therefore more knowledge about the molecular determinants important for its transport function would be of relevance. Here, we substituted amino acids Phe(368), Trp(995), and Arg(998) with conservative or non-conservative residues, and determined the effect on transport of the model substrates estradiol 17-beta-d-glucuronide (E(2)17betaG), cyclic guanosine monophosphate (cGMP), methotrexate (MTX), and folic acid into membrane vesicles isolated from baculovirus transduced HEK293 cells overexpressing the mutant MRP4 proteins. This revealed that all Arg(998) mutations appeared to be deleterious, whereas the effect of a Phe(368) or Trp(995) replacement was dependent on the amino acid introduced and the substrate studied. Substitution of Phe(368) with Trp (F368W) induced a gain-of-function of E(2)17betaG transport and a loss-of-function of MTX transport, which could not be attributed to an altered substrate binding. Moreover, we did not observe any modification in ATP or ADP handling for F368W. These results, in combination with docking of substrates in a homology model of MRP4 in the inward- and outward-facing conformation, suggest that Phe(368) and Trp(995) do not play an important role in the initial binding of substrates. They, however, might interact with the substrates during rearrangement of helixes for substrate translocation, funneling the substrates to the exit site in the outward-facing conformation.
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No. Sentence Comment
186 Mutation of Phe368 to Ala decreased transport of all substrates tested, whereas conservative substitutions with the aromatic Trp and Tyr residues caused substrate-dependent effects.
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ABCC2 p.Phe368Ala 22542979:186:12
status: NEW