ABCB1 p.Ala841Leu
| Predicted by SNAP2: | C: N (78%), D: D (85%), E: D (75%), F: D (53%), G: D (71%), H: D (80%), I: N (57%), K: D (71%), L: D (63%), M: N (53%), N: D (75%), P: D (75%), Q: D (66%), R: D (80%), S: N (82%), T: N (87%), V: N (78%), W: D (85%), Y: D (75%), |
| Predicted by PROVEAN: | C: N, 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: N, T: N, V: N, W: D, Y: D, |
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[hide] Insight in eukaryotic ABC transporter function by ... FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19. Frelet A, Klein M
Insight in eukaryotic ABC transporter function by mutation analysis.
FEBS Lett. 2006 Feb 13;580(4):1064-84. Epub 2006 Jan 19., 2006-02-13 [PMID:16442101]
Abstract [show]
With regard to structure-function relations of ATP-binding cassette (ABC) transporters several intriguing questions are in the spotlight of active research: Why do functional ABC transporters possess two ATP binding and hydrolysis domains together with two ABC signatures and to what extent are the individual nucleotide-binding domains independent or interacting? Where is the substrate-binding site and how is ATP hydrolysis functionally coupled to the transport process itself? Although much progress has been made in the elucidation of the three-dimensional structures of ABC transporters in the last years by several crystallographic studies including novel models for the nucleotide hydrolysis and translocation catalysis, site-directed mutagenesis as well as the identification of natural mutations is still a major tool to evaluate effects of individual amino acids on the overall function of ABC transporters. Apart from alterations in characteristic sequence such as Walker A, Walker B and the ABC signature other parts of ABC proteins were subject to detailed mutagenesis studies including the substrate-binding site or the regulatory domain of CFTR. In this review, we will give a detailed overview of the mutation analysis reported for selected ABC transporters of the ABCB and ABCC subfamilies, namely HsCFTR/ABCC7, HsSUR/ABCC8,9, HsMRP1/ABCC1, HsMRP2/ABCC2, ScYCF1 and P-glycoprotein (Pgp)/MDR1/ABCB1 and their effects on the function of each protein.
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No. Sentence Comment
519 Loo et al. [256] demonstrated that mutations affecting the processing and targeting of Pgp disrupted interactions between the NBDs such as in DY490, G269V (ICL2), P709G (linker), G722A (TM7) and A841L (TM9).
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ABCB1 p.Ala841Leu 16442101:519:195
status: NEW[hide] Rescue of folding defects in ABC transporters usin... J Bioenerg Biomembr. 2005 Dec;37(6):501-7. Loo TW, Bartlett MC, Clarke DM
Rescue of folding defects in ABC transporters using pharmacological chaperones.
J Bioenerg Biomembr. 2005 Dec;37(6):501-7., [PMID:16691490]
Abstract [show]
The ATP-binding cassette (ABC) family of membrane transport proteins is the largest class of transporters in humans (48 members). The majority of ABC transporters function at the cell surface. Therefore, defective folding and trafficking of the protein to the cell surface can lead to serious health problems. The classic example is cystic fibrosis (CF). In most CF patients, there is a deletion of Phe508 in the CFTR protein (DeltaF508 CFTR) that results in defective folding and intracellular retention of the protein (processing mutant). A potential treatment for most patients with CF would be to use a ligand(s) of CFTR that acts a pharmacological chaperone to correct the folding defect. The feasibility of such an approach was first demonstrated with the multidrug transporter P-glycoprotein (P-gp), an ABC transporter, and a sister protein of CFTR. It was found that P-gps with mutations at sites equivalent to those found in CFTR processing mutants were rescued when they were expressed in the presence of drug substrates or modulators of P-gp. These compounds acted as pharmacological chaperones and functioned by promoting interactions among the various domains in the protein during the folding process. Several groups have attempted to identify compounds that could rescue the folding defect in DeltaF508 CFTR. The best compound identified through high-throughout screening is a quinazoline derivative (CFcor-325). Expression of DeltaF508 CFTR as well as other CFTR processing mutants in the presence of 1 muM CFcor-325 promoted folding and trafficking of the mutant proteins to the cell surface in an active conformation. Therefore, CFcor-325 and other quinazoline derivates could be important therapeutic compounds for the treatment of CF.
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No. Sentence Comment
76 The presence of a processing mutation in either half-molecule (N-half (G268V) or COOH-half (A841L)) resulted in the loss of interactions between the half-molecules.
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ABCB1 p.Ala841Leu 16691490:76:92
status: NEW[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.Ala841Leu 8995353:64:208
status: NEW[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
97 We then tested the effect of a misprocessing mutation located in the C-half of P-glycoprotein (A841L), on the ability of the two halves to associate.
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ABCB1 p.Ala841Leu 9614062:97:95
status: NEW99 Wild-type N-Half-A52 was coexpressed in HEK 293 cells with either wild-type C-Half-His or mutant (A841L) C-Half-His, in the presence or absence of CsA.
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ABCB1 p.Ala841Leu 9614062:99:98
status: NEW100 Fig. 3A shows that CsA had a dramatic effect on the association of A841L C-Half-His and wild-type N-Half-A52.
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ABCB1 p.Ala841Leu 9614062:100:67
status: NEW117 A, wild-type N-Half-A52 was coexpressed with wild-type C-Half-His or with mutant (A841L) C-Half-His in the presence (ϩ) or absence (-) of 10 M CsA.
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ABCB1 p.Ala841Leu 9614062:117:82
status: NEW