ABCC1 p.Asp792Asn
| Predicted by SNAP2: | A: D (95%), C: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: 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, Y: D, |
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[hide] Functional interactions between nucleotide binding... Mol Pharmacol. 2005 Jun;67(6):1944-53. Epub 2005 Mar 8. Payen L, Gao M, Westlake C, Theis A, Cole SP, Deeley RG
Functional interactions between nucleotide binding domains and leukotriene C4 binding sites of multidrug resistance protein 1 (ABCC1).
Mol Pharmacol. 2005 Jun;67(6):1944-53. Epub 2005 Mar 8., [PMID:15755910]
Abstract [show]
Multidrug resistance protein 1 (MRP1) is a member of the "C" branch of the ATP-binding cassette transporter superfamily. The NH(2)-proximal nucleotide-binding domain (NBD1) of MRP1 differs functionally from its COOH-proximal domain (NBD2). NBD1 displays intrinsic high-affinity ATP binding and little ATPase activity. In contrast, ATP binding to NBD2 is strongly dependent on nucleotide binding by NBD1, and NBD2 is more hydrolytically active. We have demonstrated that occupancy of NBD2 by ATP or ADP markedly decreased substrate binding by MRP1. We have further explored the relationship between nucleotide and substrate binding by examining the effects of various ATP analogs and ADP trapping, as well as mutations in conserved functional elements in the NBDs, on the ability of MRP1 to bind the photoactivatable, high-affinity substrate cysteinyl leukotriene C(4) (LTC(4))(.) Overall, the results support a model in which occupancy of both NBD1 and NBD2 by ATP results in the formation of a low-affinity conformation of the protein. However, nonhydrolyzable ATP analogs (beta,gamma-imidoadenosine 5'-triphosphate and adenylylmethylene diphosphonate) failed to substitute for ATP or adenosine 5'-O-(thiotriphosphate) (ATPgammaS) in decreasing LTC(4) photolabeling. Furthermore, mutations of the signature sequence in either NBD that had no apparent effect on azido-ATP binding abrogated the formation of a low-affinity substrate binding state in the presence of ATP or ATPgammaS. We suggest that the effect of these mutations, and possibly the failure of some ATP analogs to decrease LTC(4) binding, may be attributable to an inability to elicit a conformational change in the NBDs that involves interactions between the signature sequence and the gamma-phosphate of the bound nucleotide.
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No. Sentence Comment
67 The forward primers for the D792N and D1454N mutations of the Walker B motifs were 5Ј-CATTTACCTCT- TCAATGATCCCCTC-3Ј and 5Ј-ATCCTTGTGTTGAATGAGGCCA- CG-3Ј, respectively.
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ABCC1 p.Asp792Asn 15755910:67:28
status: NEW189 The D792N mutation diminished transport activity by approximately 65%, whereas the D1454N mutation essentially inactivated the protein (Fig. 5B).
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ABCC1 p.Asp792Asn 15755910:189:4
status: NEW190 As observed with the NBD1 Walker A mutations, the D792N mutation drastically decreased binding by NBD1 and, to a lesser extent, binding by NBD2.
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ABCC1 p.Asp792Asn 15755910:190:50
status: NEW192 The D792N mutation also strongly decreased ADP trapping by both NBD1 and NBD2, although the D1454N mutation eliminated trapping by NBD2 but only modestly decreased trapping by NBD1 (Fig. 6B).
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ABCC1 p.Asp792Asn 15755910:192:4
status: NEW193 Despite the partial retention of vanadate-dependent trapping at NBD2 of the D792N mutant, we were unable to detect an ATP/vanadate-dependent decrease in LTC4 binding with either mutant (Fig. 6C).
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ABCC1 p.Asp792Asn 15755910:193:76
status: NEW228 The relative expression levels of wt and mutant half-molecules were evaluated by densitometry and are indicated on the figure. B, effect of D792N and D1454N mutations on ATP-dependent LTC4 transport activity.
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ABCC1 p.Asp792Asn 15755910:228:140
status: NEW229 Membrane vesicles (2 g) containing wt and the D792N and D1454N mutant MRP1 half-molecules or control beta-gus were assayed for ATP-dependent LTC4 transport activity by incubation in transport buffer containing [3 H]LTC4 (50 nM, 0.13 Ci) at 23°C for 2 min in the presence and absence of ATP (4 mM) as described under Materials and Methods. Results shown are means Ϯ S.D. of triplicate determinations in a single experiment.
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ABCC1 p.Asp792Asn 15755910:229:54
status: NEW230 Similar results were obtained in three additional independent experiments. C, effect of D792N and D1454N mutations on photolabeling with 8-azido-[␣-32 P]ATP.
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ABCC1 p.Asp792Asn 15755910:230:88
status: NEW242 The effect of the MRP1 Walker B D792N and D1454N mutations on ATP binding and ADP trapping was similar to that of the Walker A lysine mutations; the level of transport activity of the NBD1 aspartic acid-to-asparagine mutation was comparable with that of the Walker A lysine-to-methionine mutation (Gao et al., 2000).
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ABCC1 p.Asp792Asn 15755910:242:32
status: NEW260 B, effect of D792N and D1454N mutations on vanadate-dependent nucleotide trapping.
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ABCC1 p.Asp792Asn 15755910:260:13
status: NEW265 C, effect of D792N and D1454N mutations on LTC4 photolabeling in the presence or absence of nucleotide.
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ABCC1 p.Asp792Asn 15755910:265:13
status: NEW266 Membrane vesicles (50 g of total protein) containing wt and the D792N and D1454N mutant MRP1 half-molecules were incubated in transport buffer at 23°C for 20 min in the absence or presence of ATP␥S (4 mM) or ATP (1 mM) plus vanadate (1 mM) before the addition of [3 H]LTC4 (200 nM, 0.13 Ci).
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ABCC1 p.Asp792Asn 15755910:266:72
status: NEW[hide] A molecular understanding of ATP-dependent solute ... Cancer Metastasis Rev. 2007 Mar;26(1):15-37. Chang XB
A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1.
Cancer Metastasis Rev. 2007 Mar;26(1):15-37., [PMID:17295059]
Abstract [show]
Over a million new cases of cancers are diagnosed each year in the United States and over half of these patients die from these devastating diseases. Thus, cancers cause a major public health problem in the United States and worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Numerous mechanisms of MDR exist in cancer cells, such as intrinsic or acquired MDR. Overexpression of ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (P-gp or ABCB1), breast cancer resistance protein (BCRP or ABCG2) and/or multidrug resistance-associated protein (MRP1 or ABCC1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs. In addition to their roles in MDR, there is substantial evidence suggesting that these drug transporters have functions in tissue defense. Basically, these drug transporters are expressed in tissues important for absorption, such as in lung and gut, and for metabolism and elimination, such as in liver and kidney. In addition, these drug transporters play an important role in maintaining the barrier function of many tissues including blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier. Thus, these ATP-dependent drug transporters play an important role in the absorption, disposition and elimination of the structurally diverse array of the endobiotics and xenobiotics. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
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No. Sentence Comment
241 Indeed, several mutations, such as K684E, K1333E, K684R, K1333R, D792N, D1454N, G771A and G1433A, significantly diminished ATP binding and Vi-dependent ADP trapping at NBD2 and lost the ability to shift the substrate binding from a high to low affinity site [61].
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ABCC1 p.Asp792Asn 17295059:241:65
status: NEW[hide] Molecular mechanism of ATP-dependent solute transp... Methods Mol Biol. 2010;596:223-49. Chang XB
Molecular mechanism of ATP-dependent solute transport by multidrug resistance-associated protein 1.
Methods Mol Biol. 2010;596:223-49., [PMID:19949927]
Abstract [show]
Millions of new cancer patients are diagnosed each year and over half of these patients die from this devastating disease. Thus, cancer causes a major public health problem worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Over-expression of ATP-binding cassette transporters, such as P-glycoprotein, breast cancer resistance protein and/or multidrug resistance-associated protein 1 (MRP1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs across the cell membrane barrier. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
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No. Sentence Comment
157 Indeed, several mutations, such as K684E, K1333E, K684R, K1333R, D792N, D1454N, G771A and G1433A, significantly diminished ATP binding and lost the ability to shift the bound substrate from high to low affinity site (99).
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ABCC1 p.Asp792Asn 19949927:157:65
status: NEW