ABCMdb

ABCC1 p.Tyr1267Phe

Predicted by SNAP2:	A: D (80%), C: D (75%), D: D (91%), E: D (91%), F: D (59%), G: D (91%), H: D (85%), I: D (66%), K: D (91%), L: D (80%), M: D (80%), N: D (91%), P: D (95%), Q: D (91%), R: D (91%), S: D (91%), T: D (91%), V: D (75%), W: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: 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,

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Publications
[hide] The dileucine motif at the COOH terminus of human ... J Biol Chem. 2005 Jan 28;280(4):2522-8. Epub 2004 Nov 12. Loo TW, Bartlett MC, Clarke DM
The dileucine motif at the COOH terminus of human multidrug resistance P-glycoprotein is important for folding but not activity.
J Biol Chem. 2005 Jan 28;280(4):2522-8. Epub 2004 Nov 12., 2005-01-28 [PMID:15542593]

Abstract [show]
P-glycoprotein (P-gp, ABCB1) actively transports a broad range of cytotoxic compounds out of the cell. The COOH terminus of P-gp contains a dileucine motif (Leu(1260)-Leu(1261)) and a conserved phenylalanine (Phe(1268)). Similar residues in SUR1 (ABCC8) were reported to be important plasma membrane-targeting signals (Sharma, N., Crane, A., Clement, J. P. t., Gonzalez, G., Babenko, A. P., Bryan, J., and Aguilar-Bryan, L. (1999) J. Biol. Chem. 274, 20628-20632). Here, we used alanine-scanning mutagenesis to test whether these residues were essential for trafficking of P-gp to the cell surface. Mutant L1260A expressed a 150-kDa immature protein that did not reach the cell surface and was sensitive to digestion by Endo H(f). By contrast, mutants L1261A, F1268A, and wild-type P-gps expressed the 170-kDa mature proteins at the cell surface. Mutation of Leu(1260) to Gly, Ile, Trp, Lys, or Glu also resulted in the expression of the 150-kDa immature protein. All of the mutants, however, expressed the 170-kDa protein in the presence of the drug substrate/specific chemical chaperone cyclosporin A. Mutant L1260A P-gp exhibited drug-stimulated ATPase activities similar to that of wild-type enzyme after rescue with cyclosporin A. Deletion of the last 22 amino acids (Q(1259)-Q(1280)) also caused misprocessing. The mutant, however, was rescued by expression in the presence of cyclosporin A and conferred resistance to colchicine in transfected cells. These results show that the dileucine motif is not a plasma membrane targeting signal. The COOH terminus is required for proper folding of P-gp but not for activity.

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Sentences [show]
No. Sentence Comment
109 Residue Leu1260 was mutated to Gly, Ile, Trp, Lys, or Glu, whereas residue Tyr1267 was mutated to Leu, Trp, Phe, or Lys. Login to comment
114 Mutants Y1267L, Y1267W, and Y1267F were still able to mature, because the major product was FIG. 2. Login to comment