ABCB1 p.Pro1194Ala
| Predicted by SNAP2: | A: D (63%), C: D (71%), D: D (85%), E: D (80%), F: D (80%), G: D (80%), H: D (71%), I: D (66%), K: D (80%), L: D (75%), M: D (71%), N: D (75%), Q: D (75%), R: D (80%), S: D (66%), T: D (71%), V: D (75%), W: D (85%), Y: D (80%), |
| 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, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Superfolding of the partially unfolded core-glycos... J Biol Chem. 1998 Jun 12;273(24):14671-4. Loo TW, Clarke DM
Superfolding of the partially unfolded core-glycosylated intermediate of human P-glycoprotein into the mature enzyme is promoted by substrate-induced transmembrane domain interactions.
J Biol Chem. 1998 Jun 12;273(24):14671-4., 1998-06-12 [PMID:9614062]
Abstract [show]
Misprocessed mutants of human P-glycoprotein accumulate as core-glycosylated intermediates in the endoplasmic reticulum and are rapidly degraded. Trypsin digestion was used to test for structural differences between mature and core-glycosylated forms of P-glycoprotein. We found that the core-glycosylated wild-type and mutant P-glycoproteins were both 100-fold more sensitive to trypsin compared with the mature form of the wild-type enzyme. This result suggested that the core-glycosylated forms of both wild-type and mutant P-glycoproteins have similar unfolded structures, whereas the mature enzyme is folded into a more compact structure. The core-glycosylated mutant P-glycoproteins could be converted to the mature trypsin-resistant form by synthesis in the presence of drug substrate. Addition of proteasome inhibitor MG-132 to stabilize the core-glycosylated intermediate resulted in the accumulation but not maturation of the mutant protein. Further analysis showed that the second transmembrane domain TMD2 also became more resistant to trypsin digestion only after coexpression with TMD1 in the presence of substrate. Taken together, these results suggest that simply stabilizing the core-glycosylated intermediate is not sufficient to promote maturation of the processing mutants and that drug substrates induce maturation by promoting superfolding of the transmembrane domains.
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No. Sentence Comment
48 Misprocessing mutations are located throughout the molecule; these include the transmembrane domains (e.g. A123L), intracellular (e.g. E243A) and extracellular (e.g. Y853C) loops, the linker region (e.g. E707A), and both nucleotide-binding domains (e.g. G427C, P1194A).
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ABCB1 p.Pro1194Ala 9614062:48:261
status: NEW[hide] Thapsigargin or curcumin does not promote maturati... Biochem Biophys Res Commun. 2004 Dec 10;325(2):580-5. Loo TW, Bartlett MC, Clarke DM
Thapsigargin or curcumin does not promote maturation of processing mutants of the ABC transporters, CFTR, and P-glycoprotein.
Biochem Biophys Res Commun. 2004 Dec 10;325(2):580-5., [PMID:15530432]
Abstract [show]
Misprocessed plasma membrane proteins of CFTR and P-glycoprotein (P-gp) are retained in the endoplasmic reticulum (ER) by molecular chaperones. Depletion of the calcium stores in the ER by the SERCA calcium pump inhibitors thapsigargin or curcumin inhibits these interactions and allows the protein to be trafficked to the plasma membrane [Nat. Med. 8 (2002) 485; Science 304 (2004) 600]. We tested this hypothesis by treating various cell lines expressing misprocessed mutants of CFTR or P-gp with thapsigargin or curcumin. Conversion of the immature core-glycosylated protein to mature product was detected by immunoblot analysis of whole cell extracts. Mature product was not detected in any of the misprocessed mutants. By contrast, all misprocessed P-gp mutants were rescued by the chemical chaperone/drug substrate cyclosporin A in a dose-dependent manner. These results show that thapsigargin or curcumin is not effective in rescuing misprocessed mutants of P-gp and CFTR.
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No. Sentence Comment
69 A processing mutation in NBD2 is P1194A, while P709G is in the linker region.
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ABCB1 p.Pro1194Ala 15530432:69:33
status: NEW70 Although the processing mutations (G251V, G300V, DY490, P709A, G722A, F804A, and P1194A) are located in different segments of P-gp, all the mutants could be rescued when expressed with drug substrates such as cyclosporin A.
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ABCB1 p.Pro1194Ala 15530432:70:81
status: NEW90 We then compared the abilities of cyclosporin A, thapsigargin, and curcumin to induce maturation of P-gp processing mutants G251V, G300V, DY490, P709A, G722A, F804A, and P1194A.
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ABCB1 p.Pro1194Ala 15530432:90:170
status: NEW