ABCMdb

ABCC1 p.Phe594Tyr

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Publications

PMID: 14561746 [PubMed] Campbell JD et al: "Molecular modeling correctly predicts the functional importance of Phe594 in transmembrane helix 11 of the multidrug resistance protein, MRP1 (ABCC1)."

No. Sentence Comment

7 On the other hand, the conservatively substituted F594W and F594Y mutants remained transport competent, although significant substrate- and substitution-specific changes were observed. Login to comment
69 Phe594 substitutions were generated in the pBluescriptSK(ϩ) plasmid above according to the manufacturer`s instructions with the following mutagenic primers (substituted nucleotides are underlined): F594A, 5Ј-G TTC AAC ATC CTC CGG GCT CCC CTG AAC ATT CTC C-3Ј; F594W, 5Ј-C TTG TTC AAC ATC CTC CGC TGG CCC CTG AAC ATT CTC CCC-3Ј; and F594Y, 5Ј-G TTC AAC ATC CTC CGC TAT CCC CTG AAC ATT CTC C-3Ј. Login to comment
99 LTC4 Transport and Photo-labeling Is Eliminated by Ala Substitution of Phe594 -As shown in Fig. 2A, all three mutants generated (F594A, F594W, and F594Y) were expressed at levels 60-100% of those of wild-type MRP1 in transfected HEK cells. Login to comment
102 After correcting for differences in MRP1 protein expression levels, ATP-dependent LTC4 uptake by the F594A mutant was reduced by more than 90%, whereas uptake by the F594W and F594Y mutants was comparable with that by wild-type MRP1. Login to comment
111 A, representative immunoblot of membrane vesicles prepared from HEK293T cells transfected with empty vector (pcDNA3.1(-)), wild-type (WT-MRP1), and mutant (F594A, F594W, and F594Y) MRP1 cDNAs. Login to comment
123 The conservatively substituted Phe594 mutants F594W and F594Y could still be photolabeled by [3 H]LTC4, although photolabeling was reduced, by ϳ50% when corrected for differences in MRP1 protein expression. Login to comment
128 For some substrates, uptake by the F594W mutant was up to 1.5-fold higher than that by wild-type MRP1 (GSH) and substantially higher than that by the F594Y mutant (E13SO4 and GSH). Login to comment
129 For other substrates the opposite effects were observed, i.e. vesicular uptake by the F594Y mutant was higher than that by wild-type MRP1 (E217betaG and MTX) and even higher than that by the F594W mutant (E217betaG and MTX). Login to comment
130 For example, E217betaG uptake by F594W was ϳ30% of wild-type MRP1, whereas vesicular uptake of this glucuronide conjugate by F594Y was ϳ1.4-fold higher than that by wild-type MRP1 (Fig. 3A). Login to comment
131 In contrast, GSH uptake by the F594Y mutant was just 15% of that of wild-type MRP1, whereas uptake of this tripeptide by the F594W mutant was ϳ1.6-fold higher than that of wild-type MRP1. Login to comment
161 On the other hand, conservative substitutions of Phe594 with either Tyr or Trp had little effect on LTC4 transport but, in some cases, caused some significant changes in the transport of at least two of the four other MRP1 organic anion substrates tested. Login to comment
162 Thus, although the aromatic properties of the residue at position 594 are critical for retaining overall activity (i.e. F594 (wild-type), F594W, and F594Y are active but F594A is not), the addition of hydrogen bonding capacity to the amino acid side chain (as in F594W and F594Y) also influences substrate specificity, as shown previously for the polar aromatic residues at positions 553, 1198, 1243, and 1246. Login to comment

PMID: 15260484 [PubMed] Zhang DW et al: "Transmembrane helix 11 of multidrug resistance protein 1 (MRP1/ABCC1): identification of polar amino acids important for substrate specificity and binding of ATP at nucleotide binding domain 1."

No. Sentence Comment

287 However, unlike Asn590 , conservative substitution of Phe594 with Tyr or Trp altered the substrate specificity of the protein, suggesting that the latter residue may interact directly with substrate (35). Login to comment

PMID: 16816140 [PubMed] Deeley RG et al: "Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins."

No. Sentence Comment

847 Conservative substitutions of Phe594 with Tyr or Trp had selective effects on substrate specificity, suggesting that it may be involved in direct interaction of MRP1 with its substrates (52). Login to comment
846 Conservative substitutions of Phe594 with Tyr or Trp had selective effects on substrate specificity, suggesting that it may be involved in direct interaction of MRP1 with its substrates (52). Login to comment
848 Similarly, only Ala substitution of Asn590 (a "cavity"-creating substitution) adversely affected MRP1 activity, while replacing this residue with Asp or Gln had no effect, suggesting that the polar side chain of Asn590 may be involved in interhelical interactions that influence the conformation of the protein in the vicinity of the binding pocket (570). Login to comment

PMID: 16820223 [PubMed] Cole SP et al: "Transport of glutathione and glutathione conjugates by MRP1."

No. Sentence Comment

150 TM6 is also predicted to be adjacent to TM11, in which a conservative Tyr substitution of Phe594 adversely affects only GSH transport, whereas non-conservative Ala substitution of this residue eliminates the transport of multiple organic anions [38]. 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

156 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