ABCMdb

PMID: 19949927

Chang XB
Molecular mechanism of ATP-dependent solute transport by multidrug resistance-associated protein 1.
Methods Mol Biol. 2010;596:223-49., [PubMed]

Sentences

No. Mutations Sentence Comment

104 ABCC1 p.Cys43Ser ABCC1 p.Glu1089Gln ABCC1 p.Glu1089Ala ABCC1 p.Glu1089Asn ABCC1 p.Glu1089Leu 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.Lys332Asp ABCC1 p.Lys332Leu ABCC1 p.Trp445Ala ABCC1 p.Phe594Ala ABCC1 p.Pro448Ala ABCC1 p.Pro557Ala ABCC1 p.Pro595Ala ABCC1 p.Pro343Ala ABCC1 p.Arg1249Lys ABCC1 p.Arg1197Lys ABCC1 p.Asn597Ala ABCC1 p.Ser605Ala ABCC1 p.Ser604Ala ABCC1 p.Asn590Ala ABCC1 p.Thr556Ala ABCC1 p.Thr550Ala ABCC1 p.Thr1242Leu 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. Login to comment 110 ABCC1 p.Glu1089Gln In 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 E2 17bG transport (119), suggesting that anthracycline and hydrophobic portion of LTC4 or E2 17bG might bind to slightly different regions within MRP1 protein. Login to comment 145 ABCC1 p.Gly1433Asp ABCC1 p.Gly771Asp ABCC1 p.Gly1433Ala ABCC1 p.Gly771Ala However, substitution of the conserved glycine residue at the fourth position of LSGGQ motif with an A or a D residue in NBD1 (G771D or G771A) or in NBD2 (G1433D or G1433A) lost their abilities to transport substrate across the membrane (99, 151, 152). Login to comment 146 ABCC1 p.Gly771Asp Further analyses of these mutants indicated that G771D mutation enhanced the (a-32 P)-ATP binding on ice at the mutated NBD1, but completely inhibited the vanadate (Vi)-dependent ADP trapping at the intact NBD2 at 37 ºC (153). Login to comment 147 ABCC1 p.Gly1433Asp Conversely, the G1433D mutation in the ABC signature sequence of NBD2 enhanced the (a-32 P)-ATP binding on ice at the mutated NBD2, but completely inhibited the Vi-dependent ADP trapping at the intact NBD1 at 37 ºC (153), implying that the LSGGQ signature motif in NBD1 may be involved in ATP binding at the NBD2, whereas the LSVGQ signature motif in NBD2 may be involved in ATP binding at the NBD1. Login to comment 151 ABCC1 p.Glu1455Asp ABCC1 p.Glu1455Gln However, binding of poorly hydrolysable ATP analog ATPgS to wt MRP1 significantly inhibits the 3 H-LTC4 labeling (99, 100), implying that ATPgS binding might be sufficient to transport the bound LTC4 from high to low affinity site. This conclusion was further supported by the fact that ATPgS or ATP binding to the incompetent E1455D or E1455Q mutants, which were unable to hydrolyze the bound ATP, significantly inhibited the 3 H-LTC4 labeling (100, 156, 157). Login to comment 157 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 lost the ability to shift the bound substrate from high to low affinity site (99). Login to comment 158 ABCC1 p.Glu1455Asp Conversely, 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 decreased its ability to hydrolyze ATP (100), leading to significantly increase the a-32 P-ATP labeling regardless of whether Vi is present or not (100). Login to comment 159 ABCC1 p.Glu1455Asp Binding of ATP, ATP + Vi, or ATPgS to E1455D significantly inhibited the LTC4 labeling (100), further supporting the above hypothesis that occupancies of both NBD1 and NBD2 by nucleotide binding without hydrolysis may be sufficient to transport the bound substrate across membrane bilayer. Login to comment 212 ABCC1 p.His827Phe ABCC1 p.His827Leu We have found that substitution of the H residue in H-loop of MRP1-NBD1 with a residue, such as H827L or H827F, that avoids the interactions with the putative catalytic base D793 in NBD1 does not have a significant effect on the ATP-dependent LTC4 transport, whereas substitution of the H1486 residue in H-loop of NBD2 with the residues that potentially form hydrogen bond with the putative catalytic base E1455 has yielded functional MRP1 proteins with variant effects on the ATP-dependent LTC4 transport (186). Login to comment