ABCMdb

ABCC1 p.Ser1097Ala

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Publications

PMID: 12954620 [PubMed] Zhang DW et al: "Functional importance of polar and charged amino acid residues in transmembrane helix 14 of multidrug resistance protein 1 (MRP1/ABCC1): identification of an aspartate residue critical for conversion from a high to low affinity substrate binding state."

No. Sentence Comment

5 In addition, mutations S1097A and N1100A selectively decreased transport of 17beta-estradiol 17-(beta-D-glucuronide) (E217betaG) but not cysteinyl leukotriene 4 (LTC4), demonstrating the importance of multiple residues in this helix in determining substrate specificity. Login to comment
51 They are as follows: T1082A (5Ј-C TCC AAG GAG CTC GAC GCA GTG GAC TCC-3Ј), D1084N (5Ј-CTG GAC ACA GTG AAT TCC ATG ATC CCG-3Ј), D1084A (5Ј-CTG GAC ACA GTG AAA TCG ATG ATC CCG-3Ј), D1084E (5Ј-CTG GAC ACA GTG GAC TCG ATG ATC CCG-3Ј), D1084V (5Ј-CTG GAC ACA GTG GTA TCG ATG ATC CCG-3Ј), S1085A (5Ј-CTG GAC ACA GTC GAC GCC ATG ATC CCG G-3Ј), K1092M (5Ј-C CCG GAG GTC ATC ATG ATG TTC ATG GGC-3Ј), K1092A (5Ј-C CCG GAG GTC ATC GCG ATG TTC ATG GGC-3Ј), K1092E (5Ј-C CCG GAG GTC ATC GAG ATG TTC ATG GGC-3Ј), K1092R (5Ј-C CCG GAG GTC ATC AGG ATG TTC ATG GGC-3Ј), S1097A (5Ј-G ATG TTC ATG GGC GCC CTG TTC AAC-3Ј), N1100A (5Ј-TTC ATG GGC TCG CTC TTC GCC GTC ATT GGT G-3Ј), N1100S (5Ј-TTC ATG GGC TCG CTC TTC AGT GTC ATT GGT G-3Ј). Login to comment
136 The levels of LTC4 uptake by vesicles prepared from HEK transfectants expressing either wild type MRP1 or mutations T1082A, S1085A, K1092M, S1097A, and N1100A were proportional to the relative expression levels of the wild type and mutant proteins. Login to comment
138 ATP-dependent transport of [3 H]E217betaG was unaffected by the T1082A, S1085A and K1092M mutations (Fig. 3, D-F), but substitution of Ser1097 with Ala and conversion of Asp1084 to Asn both dramatically decreased transport. Login to comment
140 Thus, mutations S1097A and N1100A only affected transport of the estrogen conjugate, whereas mutation D1084N decreased the ability of MRP1 to transport both LTC4 and E217betaG. Login to comment
147 Transport of [3 H]GSH by Wild Type and Mutant MRP1-The studies described above indicated that mutations S1097A and D1084N affected the ability of MRP1 to confer drug resistance and to transport conjugated organic anions, whereas the K1092M mutation influenced only the drug resistance profile of MRP1. Login to comment
164 Other mutations, including mutations S1097A and K1092M that altered the drug resistance profile of MRP1, had no effect. Login to comment
165 These findings suggest that the effects of mutations S1097A and K1092M on MRP1-mediated drug resistance appear to result primarily from changes in the ability to interact with the drug substrate rather than GSH. Login to comment
176 The values shown represent the mean (ϮS.D.) of relative resistance values determined from three independent experiments. Resistance factors normalized for differences in the levels of mutant proteins expressed in the transfectant populations used are shown in parentheses. Transfectant Drug (relative resistance factor) Vincristine VP-16 Doxorubicin HEKMRP1 15.9 Ϯ 2.0 (15.9) 15.9 Ϯ 3.1 (15.9) 7.4 Ϯ 1.3 (7.4) HEKMRP1T082A 16.6 Ϯ 2.9 (19.5) 14.3 Ϯ 2.7 (16.8) 7.1 Ϯ 2.8 (8.4) HEKMRP1D1084N 1.4 Ϯ 0.4 (1.4) 4.4 Ϯ 0.6 (4.4) 1.1 Ϯ 0.1 (1.1) HEKMRP1S1085A 13.5 Ϯ 1.5 (17.5) 15.4 Ϯ 2.3 (20.0) 6.2 Ϯ 1.3 (8.1) HEKMRP1K1092M 40.1 Ϯ 8.1 (50.1) 12.5 Ϯ 3.0 (15.6) 15.3 Ϯ 3.2 (19.1) HEKMRP1S1097A 7.9 Ϯ 1.1 (9.9) 3.7 Ϯ 0.9 (4.6) 1.8 Ϯ 0.2 (2.3) HEKMRP1N1100A 14.6 Ϯ 2.1 (19.5) 11.4 Ϯ 4.0 (15.2) 6.7 Ϯ 1.5 (8.9) Mutational and Functional Analysis of Mutant Human MRP146056 affected the ability of the protein to transport both LTC4 and E217betaG whereas mutations S1097A and N1100A selectively decreased the transport of only E217betaG, we compared their effect on the kinetic parameters of transport of both substrates (Fig. 5). Login to comment
177 For E217betaG transport, the normalized Vmax values for mutations D1084N, S1097A, and N1100A were lower than that for wild type MRP1 (3207 pmol/mg/min for wild type MRP1, versus 151, 2279, and 1852 pmol/mg/min for mutations D1084N, S1097A and N1100A, respectively) (Fig. 5A and Table II). Login to comment
180 On the other hand, mutation S1097A significantly increased the Km value (28.4 ␮M) (Fig. 5A and Table II). Login to comment
181 Thus, although mutations D1084N, S1097A, and N1100A all decreased the conjugated estrogen transport, the three mutations had different effects on the apparent Km values for E217betaG uptake. Login to comment
182 For LTC4 uptake, the Km values for wild type MRP1 and mutant MRP1S1097A and MRP1N1100A were essentially identical (146, 141, and 138 nM for wild type MRP1 and mutations S1097A and N1100A, respectively) and the normalized Vmax values for mutations S1097A and N1100A were also very similar with that of wild type MRP1 (223, 208, and 242 pmol/mg/ min for mutations S1097A, N1100A, and wild type MRP1, respectively) (Table II). Login to comment
278 On the other hand, mutations S1097A, N1100A, and N1100S reduced E217betaG but not LTC4 or GSH transport activity. Login to comment
279 Mutation S1097A also reduced resistance to all three classes of drugs tested. Login to comment
283 Consistent with this possibility, mutation S1097A significantly increased the Km value for E217betaG transport without affecting transport of LTC4, suggesting that the hydrogen bonding capability of Ser1097 may be involved specifically in the interac- FIG. 8. Login to comment
292 Substitution of Ser1097 with Ala also dramatically decreased resistance to all three drugs tested. Login to comment
294 However, in the present study, we did not observed any effect of mutation S1097A on verapamil-stimulated GSH transport by MRP1. Login to comment
296 In addition, in contrast to the effect of mutation S1097A on E217betaG transport, mutation N1100A, which only affected the transport of E217betaG, decreased the Vmax without significantly affecting Km, suggesting that the mutation affects a step in the transport process subsequent to initial binding of this substrate. Login to comment

PMID: 17295059 [PubMed] Chang XB et al: "A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1."

No. Sentence Comment

153 In addition, S1097A and N1100A selectively decreased the transport of E217βG but not to LTC4 [82]. Login to comment