ABCMdb

PMID: 17295059

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., [PubMed]

Sentences

No. Mutations Sentence Comment

109 ABCC1 p.Lys332Asp ABCC1 p.Lys332Leu ABCC1 p.Pro343Ala P343A, K332L and K332D mutations in TM6 resulted in significantly reduced transport of some organic anion substrates [75, 76]. Login to comment 110 ABCC1 p.Trp445Ala ABCC1 p.Pro448Ala W445A and P448A mutations in TM8 substantially reduced the ATP-dependent transport of some MRP1 substrates, including LTC4, GSH, MTX, E217βG or E13SO4 [75, 77]. Login to comment 111 ABCC1 p.Pro557Ala ABCC1 p.Thr556Ala ABCC1 p.Thr550Ala 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]. Login to comment 112 ABCC1 p.Phe594Ala ABCC1 p.Asn597Ala ABCC1 p.Ser605Ala ABCC1 p.Ser604Ala ABCC1 p.Asn590Ala Many mutations in TM11, such as N590A, F594A, N597A, S604A and S605A, also modulate the drug resistance profile of MRP1 [79, 80]. Login to comment 113 ABCC1 p.Pro595Ala In addition, the P595A mutation in TM11 exhibited significantly reduced transport of five organic anion substrates [75]. Login to comment 114 ABCC1 p.Glu1089Gln ABCC1 p.Glu1089Ala ABCC1 p.Glu1089Asn ABCC1 p.Glu1089Leu E1089Q, E1089A, E1089L or E1089N mutations in TM14 markedly decreased resistance to anthracyclines without affecting LTC4 and E217βG transport [81]. Login to comment 116 ABCC1 p.Arg1197Lys The R1197K mutation within or near TM16 almost completely abolished LTC4 binding and ATP-dependent LTC4 transport [83]. Login to comment 117 ABCC1 p.Trp1246Cys ABCC1 p.Trp1246Ala ABCC1 p.Trp1246Phe ABCC1 p.Trp1246Tyr ABCC1 p.Thr1242Ala ABCC1 p.Thr1242Cys ABCC1 p.Thr1242Ser ABCC1 p.Asn1245Ala ABCC1 p.Tyr1243Phe ABCC1 p.Tyr1236Phe ABCC1 p.Thr1241Ala ABCC1 p.Arg1249Lys ABCC1 p.Thr1242Leu Many mutations in TM17, such as Y1236F, T1241A, T1242A, T1242C, T1242S, T1242L, Y1243F, N1245A, W1246C, W1246A, W1246F, W1246Y, or R1249K, significantly affect MRP1 function [83-86]. Login to comment 142 ABCC1 p.Glu1089Gln Consistent with these results, converting human E1089 to mouse Q at the corresponding position (human MRP1/E1089Q) markedly decreased resistance to anthracycline, but without affecting LTC4 and E217βG transport [81], suggesting that anthracycline, LTC4 and E217βG might bind to slightly different regions within MRP1 protein. Login to comment 143 ABCC5 p.Ala1239Thr Converting the mouse Mrp1 A1239 to human T at the corresponding position (mouse Mrp1/ A1239T) created a protein that increased E217βG transport 3-fold, but decreased resistance to vincristine and VP-16 without affecting anthracycline resistance [85]. Login to comment 144 ABCC5 p.Ala1239Thr ABCC5 p.Ala1239Thr Interestingly, substitution of a second murine sequence in Mrp1/ A1239T with a human MRP1 codon to generate the Mrp1/ A1239T/Q1086E double mutant restored the resistance to both vincristine and VP-16 [85]. Login to comment 146 ABCC1 p.Glu1089Gln ABCC1 p.Thr1242Ala ABCC1 p.Thr1242Ala Introduction of a second mutation based on mouse Mrp1 sequence into human MRP1/T1242A to generate a double mutant MRP1/ E1089Q/T1242A created a protein similar to mouse wild-type Mrp1 that restored resistance to vicristine and VP-16 but not to doxorubicin and epirubicin [85]. Login to comment 151 ABCC1 p.Glu1089Lys Mutation of E1089K completely eliminated resistance to anthracyclines and vincristine without affecting LTC4 and E217βG transport [81]. Login to comment 153 ABCC1 p.Asn1100Ala ABCC1 p.Ser1097Ala In addition, S1097A and N1100A selectively decreased the transport of E217βG but not to LTC4 [82]. Login to comment 154 ABCC1 p.Lys332Asp ABCC1 p.Lys332Arg Mutations in TM6, such as K332D or K332R, significantly reduced ATP-dependent LTC4 or GSH transport, but did not have any effect on ATP-dependent E217βG or E13SO4 transport [94]. Login to comment 156 ABCC1 p.Phe594Trp ABCC1 p.Phe594Tyr In addition, the LTC4, GSH, E217βG or E13SO4 transport activities of conservatively substituted F594W and F594Y mutants located in TM11 were significantly different from each other [80], suggesting that they bind to different regions or different conformations of the MRP1 protein. Login to comment 157 ABCC1 p.Trp1246Cys Hela cells transfected with W1246C mutated MRP1 are not resistant to vincristine, doxorubicin, daunorubicin, or VP-16 [84]. Login to comment 158 ABCC1 p.Trp1246Cys In contrast, the resistance to sodium arsenite of Hela cells transfected with W1246C mutated MRP1 is partially diminished whereas resistance to potassium antimony tartrate remained comparable to that of cells expressing wild-type MRP1 [84]. Login to comment 160 ABCC1 p.Trp1246Cys W1246C-mutated MRP1 eliminated E217βG transport while leaving the capacity for LTC4 and verapamil-stimulated GSH transport intact [84]. Login to comment 161 ABCC1 p.Trp1246Cys In addition, in contrast to wild-type MRP1, LTC4 transport by W1246C-mutated MRP1 was no longer inhibited by E217βG, indicating that the mutant MRP1 had lost the ability to bind the E217βG whole molecule or the glucuronide portion. Login to comment 181 ABCC1 p.Leu768Arg ABCC1 p.Leu1430Arg Mutation of the first residue in LSGGQ signature sequence to an R residue, L768R in NBD1 or L1430R in NBD2, retained both ATPase activity and ATP-dependent solute transport activity [116], indicating that this L residue is not crucial for the NBD1·ATP2·NBD2 sandwich structure formation. Login to comment 182 ABCC1 p.Gly1433Asp ABCC1 p.Gly771Asp However, mutations of the conserved glycine residue at the fourth position of the signature sequence with aspartic acid to generate G771D in NBD1 or G1433D in NBD2 of MRP1 resulted in the loss of ability to hydrolyze ATP and to uptake solute [116]. Login to comment 183 ABCC1 p.Gly1433Asp ABCC1 p.Gly771Asp ABCC1 p.Gly1433Ala ABCC1 p.Gly771Ala Accordingly, the mutants at these positions, such as G771D, G771A, G1433D or G1433A, did not lose their ability to bind ATP, but significantly reduced their Vi-dependent nucleotide trapping at 37°C [61, 116, 117]. Login to comment 184 ABCC1 p.Gly771Asp Interestingly, in another report, the G771D mutant in the ABC signature motif of NBD1 enhanced the [α-32 P]-ATP binding on ice at the mutated NBD1, but completely inhibited the Vi-dependent ATP hydrolysis product ADP trapping at the intact NBD2 at 37°C [118]. Login to comment 185 ABCC1 p.Gly1433Asp In contrast, the G1433D mutation in the signature sequence of NBD2 enhanced the [α-32 P]-ATP binding on ice at the mutated NBD2, but completely inhibited the Vi-dependent ADP trapping at the intact NBD1 at 37°C [118], implying that the LSGGQ signature sequence in NBD1 may be involved in ATP binding/hydrolysis at the NBD2, whereas the LSVGQ signature sequence in NBD2 may be involved in ATP binding/hydrolysis at the NBD1. Login to comment 241 ABCC1 p.Lys684Arg ABCC1 p.Lys1333Arg ABCC1 p.Lys1333Glu ABCC1 p.Lys684Glu ABCC1 p.Gly1433Ala ABCC1 p.Gly771Ala ABCC1 p.Asp1454Asn ABCC1 p.Asp792Asn 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]. Login to comment 242 ABCC1 p.Glu1455Asp In contrast, mutation of the putative catalytic residue E1455 to a short chain D residue, E1455D, markedly increased the affinity of the mutated NBD2 for ATP while decreasing its ability to hydrolyze ATP [62], leading to significantly increased α-32 P-ATP labeling regardless of whether Vi is present or not [62]. Login to comment 243 ABCC1 p.Glu1455Asp Binding of ATP, ATP + Vi, or ATPγS to E1455D significantly inhibited the LTC4 labeling [62], further supporting the above hypothesis that occupancy of both NBD1 and NBD2 by nucleotide binding without hydrolysis may be sufficient to transport the bound substrate across membrane bilayer. Login to comment 245 ABCC1 p.Glu1455Leu ABCC1 p.Asp793Glu ABCC1 p.Glu1455Asp ABCC1 p.Glu1455Asp ABCC1 p.Glu1455Asp For example, although ATPγS binding to wild-type or E1455D-mutated MRP1 significantly inhibited LTC4 labeling [62], ATPγS itself did not support the ATP-dependent LTC4 or E217βG transport [33, 47]; ATP can efficiently bind to E1455D, D793E/ E1455D or E1455L [62, 144], but mutation of this putative catalytic residue abolished the ATP-dependent solute transport [62, 144]. Login to comment 256 ABCC1 p.Lys684Met ABCC1 p.Lys684Leu ABCC1 p.Lys684Arg ABCC1 p.Lys684Glu Mutation of the Walker A motif K684 residue in NBD1, such as K684L [40, 141, 148], K684M [16, 63, 118], K684R [61] or K684E [61], significantly reduced ATP binding (at 4°C) at the mutated NBD1 and the intact NBD2 and Vi dependent ADP trapping at 37°C, but never completely abolished ATP-dependent solute transport. Login to comment 257 ABCC1 p.Lys684Arg In addition, these mutations, such as K684R [61], did not affect LTC4 binding and ATPγS or ATP + Vi did not inhibit LTC4 labeling. Login to comment 259 ABCC1 p.Lys1333Met ABCC1 p.Lys1333Leu ABCC1 p.Lys1333Arg ABCC1 p.Lys1333Glu 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]. Login to comment 261 ABCC1 p.Glu1455Leu ABCC1 p.Glu1455Asp ABCC1 p.Glu1455Ser ABCC1 p.Glu1455Gln ABCC1 p.Glu1455Asn This conclusion is further supported by mutation of the putative catalytic residue E1455 in NBD2 that all the mutants, including E1455S, E1455Q, E1455N, E1455L and E1455D, lost their abilities to transport LTC4 across membrane bilayer [62, 144]. Login to comment 262 ABCC1 p.Asp793Leu ABCC1 p.Asp793Asn Interestingly, substitution of the corresponding putative catalytic residue D793 in NBD1 with a non-acidic residue, such as D793L or D793N, increased the rate of ATP-dependent LTC4 transport [139, 144]. Login to comment 266 ABCC1 p.Trp653Cys ABCC1 p.Tyr1302Cys Interestingly, substitution of the aromatic residue W653, which was predicted [150] and proved [151] to interact with the adenine ring of the bound ATP, with a polar C residue, such as W653C or Y1302C, decreased the affinity for ATP, resulting in greatly increased Kd values for ATP binding or Km values for ATP-dependent LTC4 transport, but significantly increased the rate of ATP-dependent LTC4 transport [152]. Login to comment