ABCC1 p.Lys1333Glu
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: 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, D: D, E: D, F: D, G: D, H: D, I: 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
65 The forward primers for creating K684R, K684E, K1333R, and K1333E mutations of Walker A motifs were 5Ј-GGCTGCGGAAGGTCGTC- CCTGC-3Ј, 5Ј-GGGCTGCGGAGAGTCGTCCCTGC-3Ј, 5Ј-GGGAGC- TGGGAGGTCGTCCCTGA-3Ј, and 5Ј-GGGAGCTGGGGAGTCGTC- CCTGA-3Ј, respectively.
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ABCC1 p.Lys1333Glu 15755910:65:59
status: NEW131 Densitometry of immunoblots of vesicle proteins indicated that levels of the K684R, K684E, K1333R, and K1333E MRP1 mutants ranged from 30 to 60% those of wt MRP1 (Fig. 3A).
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ABCC1 p.Lys1333Glu 15755910:131:103
status: NEW158 Membrane vesicles (1 g of total protein) prepared from Sf21 cells expressing a combination of a wt and mutant half-molecule containing a K684E, K684R, K1333E, or K1333R mutation were separated by SDS-PAGE on gradient gels and transferred to Immobilon-P membranes.
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ABCC1 p.Lys1333Glu 15755910:158:159
status: NEW163 The relative expression levels of wt and mutant proteins evaluated by densitometry are indicated in the figure. B, effect of K684E, K684R, K1333E, and K1333R mutations on ATP-dependent LTC4 transport activity.
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ABCC1 p.Lys1333Glu 15755910:163:139
status: NEW176 In contrast, both the K1333R and the K1333E mutations essentially eliminated binding at NBD2 but had little or no effect on the labeling of NBD1 (Fig. 3C).
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ABCC1 p.Lys1333Glu 15755910:176:37
status: NEW179 Likewise, both the K1333R and K1333E mutations eliminated trapping by the mutant NBD2 (Fig. 3D).
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ABCC1 p.Lys1333Glu 15755910:179:30
status: NEW204 Membrane vesicles (50 g of total protein) containing wt and the K684R, K684E, K1333R, and K1333E 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.Lys1333Glu 15755910:204:98
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.Lys1333Glu 17295059:241:42
status: NEW259 In contrast, mutation of the Walker A motif K1333 residue in NBD2, such as K1333L [40, 141, 148], K1333M [16, 63, 118], K1333R [61] or K1333E [61], mainly affected ATP binding (at 4°C) at the mutated NBD2 [61, 148] and significantly decreased the ATP hydrolysis at the mutated NBD2 [61, 148].
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ABCC1 p.Lys1333Glu 17295059:259:135
status: NEW[hide] Interaction between the bound Mg.ATP and the Walke... Biochemistry. 2008 Aug 12;47(32):8456-64. Epub 2008 Jul 18. Yang R, Scavetta R, Chang XB
Interaction between the bound Mg.ATP and the Walker A serine residue in NBD2 of multidrug resistance-associated protein MRP1 plays a crucial role for the ATP-dependent leukotriene C4 transport.
Biochemistry. 2008 Aug 12;47(32):8456-64. Epub 2008 Jul 18., 2008-08-12 [PMID:18636743]
Abstract [show]
Structural analysis of human MRP1-NBD1 revealed that the Walker A S685 forms a hydrogen bond with the Walker B D792 and interacts with the Mg (2+) cofactor and the beta-phosphate of the bound Mg.ATP. We have found that substitution of the S685 with an amino acid that potentially prevents the formation of the hydrogen bond resulted in misfolding of the protein and significantly affect the ATP-dependent leukotriene C4 (LTC4) transport. In this report we tested whether the corresponding substitution in NBD2 would also result in misfolding of the protein. In contrast to the NBD1 mutations, none of the mutations in NBD2, including S1334A, S1334C, S1334D, S1334H, S1334N, and S1334T, caused misfolding of the protein. However, elimination of the hydroxyl group at S1334 in mutations including S1334A, S1334C, S1334D, S1334H, and S1334N drastically reduced the ATP binding and the ATP-enhanced ADP trapping at the mutated NBD2. Due to this low efficient ATP binding at the mutated NBD2, the inhibitory effect of ATP on the LTC4 binding is significantly decreased. Furthermore, ATP bound to the mutated NBD2 cannot be efficiently hydrolyzed, leading to almost completely abolishing the ATP-dependent LTC4 transport. In contrast, S1334T mutation, which retained the hydroxyl group at this position, exerts higher LTC4 transport activity than the wild-type MRP1, indicating that the hydroxyl group at this position plays a crucial role for ATP binding/hydrolysis and ATP-dependent solute transport.
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No. Sentence Comment
182 The reduced nucleotide binding at the mutated NBD2, such as S1334A, S1334C, S1334D, S1334H, and S1334N, significantly decreased the ability to inhibit the LTC4 binding (Figure 7), similar to the mutations of K684E, G771A, or K1333E (19).
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ABCC1 p.Lys1333Glu 18636743:182:225
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.Lys1333Glu 19949927:157:42
status: NEW