ABCC1 p.Thr556Ala
| Predicted by SNAP2: | A: N (87%), C: D (63%), D: D (75%), E: D (85%), F: D (75%), G: D (71%), H: D (80%), I: D (63%), K: D (85%), L: D (71%), M: D (75%), N: D (59%), P: D (80%), Q: D (80%), R: D (85%), S: N (87%), V: D (63%), W: D (85%), Y: D (80%), |
| Predicted by PROVEAN: | A: N, C: N, D: D, E: N, F: D, G: N, H: D, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, V: N, W: D, Y: D, |
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[hide] Mutational analysis of polar amino acid residues w... Drug Metab Dispos. 2006 Apr;34(4):539-46. Epub 2006 Jan 13. Zhang DW, Nunoya K, Vasa M, Gu HM, Cole SP, Deeley RG
Mutational analysis of polar amino acid residues within predicted transmembrane helices 10 and 16 of multidrug resistance protein 1 (ABCC1): effect on substrate specificity.
Drug Metab Dispos. 2006 Apr;34(4):539-46. Epub 2006 Jan 13., [PMID:16415113]
Abstract [show]
Human multidrug resistance protein 1 (MRP1) has a total of 17 transmembrane (TM) helices arranged in three membrane-spanning domains, MSD0, MSD1, and MSD2, with a 5 + 6 + 6 TM configuration. Photolabeling studies indicate that TMs 10 and 11 in MSD1 and 16 and 17 in MSD2 contribute to the substrate binding pocket of the protein. Previous mutational analyses of charged and polar amino acids in predicted TM helices 11, 16, and 17 support this suggestion. Mutation of Trp(553) in TM10 also affects substrate specificity. To extend this analysis, we mutated six additional polar residues within TM10 and the remaining uncharacterized polar residue in TM16, Asn(1208). Although mutation of Asn(1208) was without effect, two of six mutations in TM10, T550A and T556A, modulated the drug resistance profile of MRP1 without affecting transport of leukotriene C4, 17beta-estradiol 17-(beta-d-glucuronide) (E(2)17betaG), and glutathione. Mutation T550A increased vincristine resistance but decreased doxorubicin resistance, whereas mutation T556A decreased resistance to etoposide (VP-16) and doxorubicin. Although conservative mutation of Tyr(568) in TM10 to Phe or Trp had no apparent effect on substrate specificity, substitution with Ala decreased the affinity of MRP1 for E(2)17betaG without affecting drug resistance or the transport of other substrates tested. These analyses confirm that several amino acids in TM10 selectively alter the substrate specificity of MRP1, suggesting that they interact directly with certain substrates. The location of these and other functionally important residues in TM helices 11, 16, and 17 is discussed in the context of an energy-minimized model of the membrane-spanning domains of MRP1.
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No. Sentence Comment
6 Although mutation of Asn1208 was without effect, two of six mutations in TM10, T550A and T556A, modulated the drug resistance profile of MRP1 without affecting transport of leukotriene C4, 17beta-estradiol 17-(beta-D-glucuronide) (E217betaG), and glutathione.
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ABCC1 p.Thr556Ala 16415113:6:89
status: NEW7 Mutation T550A increased vincristine resistance but decreased doxorubicin resistance, whereas mutation T556A decreased resistance to etoposide (VP-16) and doxorubicin.
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ABCC1 p.Thr556Ala 16415113:7:103
status: NEW48 Mutations T550A, T552A, T556A, Y568A, Y568S, Y568F, Y568W, T570A, and N1208A were generated using the Quikchange Site-Directed Mutagenesis kit (Stratagene, La Jolla, CA).
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ABCC1 p.Thr556Ala 16415113:48:24
status: NEW50 Oligonucleotides bearing mismatched bases at the residues to be mutated (underlined) were synthesized by ACGT Corp. with the following sequences: T550A, 5Ј-GTCAGCCGTGGG- CGCCTTCACCTGGGT-3Ј; T552A, 5Ј-CGTGGGCACCTTCGCCTGGGTC- TGCAC-3Ј; T556A, 5Ј-CACCTGGGTCTGCGCGCCCTTTCTGGT-3Ј; Y568A, 5Ј-TGCACATTTGCCGTCGCCGTGACCATTGACGA-3Ј; Y568S, 5Ј-TGCACATTTGCCGTCTCCGTGACCATTGACGA-3Ј; Y568F, 5Ј-TGC- ACATTTGCCGTCTTCGTGACCATTGACGA-3Ј; Y568W, 5Ј-TGCACAT- TTGCCGTCTGGGTGACCATTGACGA-3Ј; T570A, (5Ј-TGCCGTCTACG- TGGCCATTGACGAGAACAAC-3Ј; and N1208A, 5Ј-GCCGTGCGGCTG- GAGTGTGTGGGCGCC-3Ј.
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ABCC1 p.Thr556Ala 16415113:50:258
status: NEW148 In contrast, mutation T556A reduced the resistance to both VP-16 and doxorubicin approximately 2-fold without affecting vincristine resistance.
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ABCC1 p.Thr556Ala 16415113:148:22
status: NEW151 We have shown that mutations T550A and T556A both affect the ability of MRP1 to confer drug resistance, whereas mutation Y568A only influenced the transport of E217betaG.
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ABCC1 p.Thr556Ala 16415113:151:39
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
111 The P557A mutation in TM10 also exhibited significantly reduced transport of five organic anion substrates [75], whereas the other two mutations in TM10, T550A and T556A, modulate the drug resistance profile of MRP1 [78].
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ABCC1 p.Thr556Ala 17295059:111:164
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
104 Mutations of C43S in TM1 (112); P343A, K332L and K332D in TM6 (113, 114); W445A and P448A in TM8 (113, 115); T550A, T556A and P557A in TM10 (113, 116); N590A, F594A, P595A, N597A, S604A and S605A in TM11 (113, 117, 118); E1089Q, E1089A, E1089L, E1089N, K1092, S1097 and N1100 in TM14 (119, 120); R1197K in TM16 (121); Y1236F, T1241A, T1242A, T1242C, T1242S, T1242L, Y1243F, N1245A, W1246C, W1246A, W1246F, W1246Y or R1249K in TM17 (121-124) significantly affect MRP1 function.
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ABCC1 p.Thr556Ala 19949927:104:116
status: NEW[hide] Transverse and tangential orientation of predicted... Eur Biophys J. 2011 Sep;40(9):1043-60. Epub 2011 Jun 24. de Foresta B, Vincent M, Garrigos M, Gallay J
Transverse and tangential orientation of predicted transmembrane fragments 4 and 10 from the human multidrug resistance protein (hMRP1/ABCC1) in membrane mimics.
Eur Biophys J. 2011 Sep;40(9):1043-60. Epub 2011 Jun 24., [PMID:21701864]
Abstract [show]
The human multidrug-resistance-associated protein 1 (hMRP1/ABCC1) belongs to the large ATP-binding cassette transporter superfamily. In normal tissues, hMRP1 is involved in tissue defense, whereas, in cancer cells, it is overproduced and contributes to resistance to chemotherapy. We previously investigated the folding properties of the predicted transmembrane fragments (TM) TM16, and TM17 from membrane-spanning domain 2 (MSD2). These TMs folded only partially as an alpha-helix and were located in the polar headgroup region of detergent micelles used as membrane mimics (Vincent et al. in Biochim Biophys Acta 1768:538-552, 2007; de Foresta et al. in Biochim Biophys Acta 1798:401-414, 2010). We have now extended these studies to TM4 and TM10, from MSD0 and MSD1, respectively. TM10 may be involved in the substrate translocation pathway whereas the role of TM4 is less predictable, because few studies have focused on MSD0, a domain present in some hMRP1 homologs only. Each TM contained a single Trp residue (W142 or W553) acting as an intrinsic fluorescent probe. The location and dynamics of the TMs in dodecylphosphocholine (DPC) or n-dodecyl-beta-D: -maltoside (DDM) micelles were studied by Trp steady-state and time-resolved fluorescence, including quenching experiments. Overall TM structure was analyzed by far-UV circular dichroism studies in detergent micelles and TFE. TM10 behaved similarly to TM16 and TM17, with an interfacial location in micelles consistent with a possible role in lining the transport pore. By contrast, TM4 behaved like a classical TM fragment with a high alpha-helical content, and its transmembrane insertion did not require its interaction with other TMs.
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No. Sentence Comment
61 Mutations resulting in the replacement of two of its threonine residues (T550A and T556A) modulated the drug-resistance profile of hMRP1 and a mutation affecting the tyrosine residue (Y568A) reduced the affinity of hMRP1 for E217bG (Zhang et al. 2006).
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ABCC1 p.Thr556Ala 21701864:61:83
status: NEW[hide] Bindings of hMRP1 transmembrane peptides with dode... Biochim Biophys Acta. 2014 Jan;1838(1 Pt B):493-509. doi: 10.1016/j.bbamem.2013.10.012. Epub 2013 Oct 21. Abel S, Lorieau A, de Foresta B, Dupradeau FY, Marchi M
Bindings of hMRP1 transmembrane peptides with dodecylphosphocholine and dodecyl-beta-d-maltoside micelles: a molecular dynamics simulation study.
Biochim Biophys Acta. 2014 Jan;1838(1 Pt B):493-509. doi: 10.1016/j.bbamem.2013.10.012. Epub 2013 Oct 21., [PMID:24157718]
Abstract [show]
In this paper, we describe molecular dynamics simulation results of the interactions between four peptides (mTM10, mTM16, TM17 and KTM17) with micelles of dodecylphosphocholine (DPC) and dodecyl-beta-d-maltoside (DDM). These peptides represent three transmembrane fragments (TM10, 16 and 17) from the MSD1 and MSD2 membrane-spanning domains of an ABC membrane protein (hMRP1), which play roles in the protein functions. The peptide-micelle complex structures, including the tryptophan accessibility and dynamics were compared to circular dichroism and fluorescence studies obtained in water, trifluoroethanol and with micelles. Our work provides additional results not directly accessible by experiments that give further support to the fact that these peptides adopt an interfacial conformation within the micelles. We also show that the peptides are more buried in DDM than in DPC, and consequently, that they have a larger surface exposure to water in DPC than in DDM. As noted previously by simulations and experiments we have also observed formation of cation-pi bonds between the phosphocholine DPC headgroup and Trp peptide residue. Concerning the peptide secondary structures (SS), we find that in TFE their initial helical conformations are maintained during the simulation, whereas in water their initial SS are lost after few nanoseconds of simulation. An intermediate situation is observed with micelles, where the peptides remain partially folded and more structured in DDM than in DPC. Finally, our results show no sign of beta-strand structure formation as invoked by far-UV CD experiments even when three identical peptides are simulated either in water or with micelles.
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No. Sentence Comment
36 For example, mutations of two threonine (T550A and T556A), a tryptophan (W553A), and a proline (P557A) in TM10 modify the drug-resistance profile of the protein or decrease the transport of various organic substrates [32-35].
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ABCC1 p.Thr556Ala 24157718:36:51
status: NEW