ABCC8 p.Leu1260Trp
| Predicted by SNAP2: | A: N (72%), C: N (72%), D: D (66%), E: D (71%), F: N (78%), G: N (57%), H: D (66%), I: N (57%), K: D (75%), M: N (66%), N: D (66%), P: D (71%), Q: D (63%), R: D (71%), S: N (57%), T: N (82%), V: N (72%), W: D (63%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D, |
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[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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No. Sentence Comment
7 Mutation of Leu1260 to Gly, Ile, Trp, Lys, or Glu also resulted in the expression of the 150-kDa immature protein.
X
ABCC8 p.Leu1260Trp 15542593:7:12
status: NEW109 Residue Leu1260 was mutated to Gly, Ile, Trp, Lys, or Glu, whereas residue Tyr1267 was mutated to Leu, Trp, Phe, or Lys.
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ABCC8 p.Leu1260Trp 15542593:109:8
status: NEW