ABCMdb

ABCG2 p.Gly553Leu

Predicted by SNAP2:	A: D (75%), C: D (80%), D: D (95%), E: D (91%), F: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (91%), M: D (95%), N: D (85%), P: D (95%), Q: D (95%), R: D (95%), S: D (85%), T: D (85%), V: D (91%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Mutational studies of G553 in TM5 of ABCG2: a resi... Biochemistry. 2006 Apr 25;45(16):5251-60. Polgar O, Ozvegy-Laczka C, Robey RW, Morisaki K, Okada M, Tamaki A, Koblos G, Elkind NB, Ward Y, Dean M, Sarkadi B, Bates SE
Mutational studies of G553 in TM5 of ABCG2: a residue potentially involved in dimerization.
Biochemistry. 2006 Apr 25;45(16):5251-60., 2006-04-25 [PMID:16618113]

Abstract [show]
ABCG2 is an ATP-binding cassette half-transporter conferring resistance to chemotherapeutic agents such as mitoxantrone, irinotecan, and flavopiridol. With its one transmembrane and one ATP-binding domain, ABCG2 is thought to homodimerize for function. One conserved region potentially involved in dimerization is a three-amino acid sequence in transmembrane segment 5 (residues 552-554). Mutations in the corresponding residues in the Drosophila white protein (an orthologue of ABCG2) are thought to disrupt heterodimerization. We substituted glycine 553 with leucine (G553L) followed by stable transfection in HEK 293 cells. The mutant was not detectable on the cell surface, and markedly reduced protein expression levels were observed by immunoblotting. A deficiency in N-linked glycosylation was suggested by a reduction in molecular mass compared to that of the 72 kDa wild-type ABCG2. Similar results were observed with the G553E mutant. Confocal microscopy demonstrated mostly ER localization of the G553L mutant in HEK 293 cells, even when coexpressed with the wild-type protein. Despite its altered localization, the G553L and G553E mutants were cross-linked using amine-reactive cross-linkers with multiple arm lengths, suggesting that the monomers are in the proximity of each other but are unable to complete normal trafficking. Interestingly, when expressed in Sf9 insect cells, G553L moves to the cell membrane but is unable to hydrolyze ATP or transport the Hoechst dye. Still, when coexpressed, the mutant interferes with the Hoechst transport activity of the wild-type protein. These data show that glycine 553 is important for protein trafficking and are consistent with, but do not yet prove, its involvement in ABCG2 homodimerization.

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4 We substituted glycine 553 with leucine (G553L) followed by stable transfection in HEK 293 cells. Login to comment
8 Confocal microscopy demonstrated mostly ER localization of the G553L mutant in HEK 293 cells, even when coexpressed with the wild-type protein. Login to comment
9 Despite its altered localization, the G553L and G553E mutants were cross-linked using amine-reactive cross-linkers with multiple arm lengths, suggesting that the monomers are in the proximity of each other but are unable to complete normal trafficking. Login to comment
10 Interestingly, when expressed in Sf9 insect cells, G553L moves to the cell membrane but is unable to hydrolyze ATP or transport the Hoechst dye. Login to comment
48 The G553L and G553E mutants were generated by site-directed mutagenesis in the pcDNA3.1/ Myc-HisA(-) vector (Invitrogen) as previously described (23). Login to comment
82 N-Terminally GFP-tagged wild-type (wt) ABCG2 and ABCG2-G553L constructs were generated by cloning the XhoI-BamHI fragment of pAcUW21-L/wtABCG2 or pAcUW21-L/ABCG2-G553L into the corresponding site of the pEGFP vector (Clontech, Mountain View, CA). Login to comment
83 HEK 293 cells were transfected with the pEGFP-wtG2 or pEGFP-G553L vector using the FuGene reagent (Roche, Indianapolis, IN). Login to comment
86 Generation of Sf9 Cells Expressing the Wild Type or the K86M or G553L Mutant. Login to comment
88 The transfer vector carrying the G553L mutant was generated by cloning the SacI fragment of pcDNA 3.1/G553L into the corresponding site of the pAcUW21-L vector. Login to comment
101 To study the function of wt ABCG2 when coexpressed with the G553L mutant, 4 × 106 Sf9 cells were transfected with the combination of different volumes of recombinant baculoviruses (as indicated in Figure 9) containing wt ABCG2, G553L, K86M, or -galactosidase. Login to comment
108 Sf9 membranes containing wild-type ABCG2, G553L, or K86M were harvested, and membranes were isolated and stored at -80 °C according to the method of Sarkadi et al. (29). Login to comment
114 To begin to characterize the residue, HEK 293 cells were stably transfected with ABCG2 carrying a glycine to leucine substitution at amino acid 553 (G553L) using a pcDNA3 vector. Login to comment
118 unlike the wild-type protein, revealed no surface expression for the G553L mutant (Figure 2A, six of the 24 clones shown). Login to comment
122 As illustrated in panels B and C of Figure 2, the G553L mutant was represented by a double band on immunoblot with the majority of the protein running lower than the normal molecular mass of 72 kDa. To investigate whether this lower-molecular mass band was representative of the nonglycosylated protein, isolated membranes from cells bearing wild-type or mutant vectors were treated with the PNGase F enzyme to remove N-linked glycans. Login to comment
123 In the case of the G553L mutant, no significant shift in molecular mass was observed after PNGase F treatment (Figure 3), indicating that, indeed, the G553L mutant is underglycosylated, while a clear shift to a lower-molecular mass band was seen in membranes extracted from HEK 293 cells transfected with wild-type ABCG2 or from flavopiridol-selected MCF-7 cells used as controls (25). Login to comment
124 Since the G553L mutant did not demonstrate normal surface localization by flow cytometry with the 5D3 antibody, immunofluorescence studies were carried out with the BXP-21 antibody on the clone with the highest expression level (clone 2 in Figure 2B). Login to comment
125 Figure 4 demonstrates that wild-type ABCG2 is localized to the cell membrane, while the FIGURE 2: Surface expression and protein and RNA levels of the G553L mutant transfected to HEK 293 cells. Login to comment
126 (A) Flow cytometry with the 5D3 surface antibody for six of the G553L clones. Login to comment
128 The G553L mutant is not detectable on the cell surface, while the wild-type protein is localized to the surface. Login to comment
129 (B) Membrane proteins from the same G553L clones (25 µg/lane) were separated by SDS-PAGE, transferred onto a PVDF membrane, and probed with the monoclonal anti-ABCG2 antibody BXP-21. Login to comment
135 One hundred micrograms of membranes was incubated with 3 µL of PNGase F overnight at 37 °C followed by SDS-PAGE separation and immunoblotting with the BXP-21 monoclonal anti-ABCG2 antibody, resulting in a clear shift to a lower-molecular mass band in the wild-type ABCG2-transfected and the flavopiridol-selected MCF-7 control cell lines (MCF-7/FLV1000), while there is no significant shift in the case of the G553L mutant. Login to comment
136 G553L mutant is predominantly intracellular. Login to comment
137 Parallel staining with the anti-calnexin monoclonal antibody revealed that the G553L mutant colocalizes with the endoplasmic reticulum (ER) chaperone, calnexin. Login to comment
138 These results suggest that the G553L mutant is not able to complete normal folding or processing to move to the cell surface in mammalian cells. Login to comment
141 Unexpectedly, using the homobifunctional amine-reactive cross-linkers MBS (9.9 Å arm length) and DSG (7.7 Å arm length) on intact cells, the G553L mutant could be cross-linked as indicated by the appearance of higher-molecular mass bands corresponding to dimers and higher-order multimers of the 72 kDa ABCG2 monomer (Figure 5). Login to comment
145 As the lower protein expression levels seen upon immunoblotting and the lack of surface expression might be the result of abnormal folding and/or dimerization, using the baculovirus heterologous expression system, we expressed the G553L mutant in Sf9 insect cells (S. frugiperda ovarian cells), which might be more tolerant of an aberrant protein and typically yields higher levels of protein expression (34). Login to comment
146 Interestingly, we found that the G553L mutant migrates to the cell surface in the insect cells as demonstrated by flow cytometry with the 5D3 antibody (Figure 6A). Login to comment
149 FIGURE 4: Localization of the G553L mutant in HEK 293 cells. Confocal microscopy of stably transfected HEK 293 reveals that the G553L mutant colocalizes with the ER marker calnexin, while the wild-type protein localizes to the cell surface. Login to comment
154 Cross-linking is observed with both amine-reactive cross-linkers in HEK 293 cells transfected with either wild-type ABCG2 or the G553L mutant as suggested by dimers and higher-order multimers. Login to comment
155 The molecular mass of monomeric wild-type ABCG2 is 72 kDa. To further investigate whether the G553L mutation interferes with dimerization, we transiently expressed a GFP-tagged G553L mutant together with the wild-type protein in HEK 293 cells and performed confocal microscopy. Login to comment
157 As shown in Figure 7, the GFP-tagged G553L mutant is localized to the ER as before and the nontagged wild-type protein trafficked to the surface, suggesting that the mutant was unable to form competent dimers with the wild-type protein. Login to comment
159 Figure 8 represents Hoechst 33342 transport activities for Sf9 cells coinfected with a constant amount of recombinant baculovirus carrying wild-type ABCG2 together with varying amounts of the G553L and K86M mutants. Login to comment
160 In case of the 50:400 ratio, which represents approximately equal protein expression levels upon immunoblotting for the wild-type and the G553L mutant (data not shown), an ~35% decrease in transport activity is seen and suggests some interaction between the wild-type and mutant proteins. Login to comment
166 The G553E mutant, like the G553L mutant, is represented by a double band on immunoblots, suggestive of impaired glycosylation, and in fact, following treatment with PNGase F, only one lower-molecular mass band was visible upon immunoblotting (data not shown). Login to comment
169 We found that substitution of glycine 553 with either leucine (G553L) or glutamic acid (G553E) followed by transfection into HEK 293 cells resulted in a markedly reduced level of protein expression with impaired glycosylation and predominant ER retention. Login to comment
170 In SF9 insect cells, the G553L mutant trafficked to the cell surface but, nevertheless, was unable to hydrolyze ATP. Login to comment
171 Although the wild-type protein was unable to rescue the mutant from its ER localization in the mammalian cells, chemical cross-linking studies indicated that the two G553L monomers are FIGURE 6: G553L mutant in Sf9 insect cells. Login to comment
172 (A) Wild-type ABCG2 and the G553L mutant are detectable on the surface of Sf9 cells with the 5D3 monoclonal anti-ABCG2 antibody on flow cytometry (as detailed in Figure 2). Login to comment
173 (B) The G553L mutant displays basal ATPase activity similar to that of the nonfunctional K86M mutant in Sf9 membranes. Login to comment
177 When Sf9 insect cells were coinfected with the G553L mutant and the wild-type protein, the Hoechst transport activity was reduced by approximately 35%. Login to comment
190 The fact that the ABCG2 G553L mutant protein does not leave the ER in mammalian cells suggests that it is recognized by the ER`s quality control system and is degraded, explaining the low observed expression levels (38). Login to comment
192 In addition to the above-mentioned aberrant localization in the mammalian cells, the glycosylation pattern of the G553L and G553E mutants was also altered. Login to comment
193 Interestingly, FIGURE 7: Coexpression of wild-type ABCG2 and the G553L mutant in HEK 293 cells. Confocal microscopy results of HEK 293 cells transiently transfected with either the GFP-tagged G553L mutant (first row) or the GFP-tagged wild type (third row) or cotransfected with the GFP-tagged mutant and nontagged wild type (second row) are presented. Login to comment
195 The cotransfection images (second row) show that despite the presence of the wild-type protein the G553L mutant is retained intracellularly, while the wild-type protein localizes to the cell surface. Login to comment
198 In the case of ABCG2, previous studies have shown that the protein is glycosylated at asparagine 596 and that the glycosylation is not necessary for cell surface localization (39) or function, suggesting that the G553L mutant is not retained in the ER merely due to failure to undergo glycosylation. Login to comment
199 The fact that we found no evidence of colocalization on confocal microscopy when the G553L mutant was coexpressed with wild-type ABCG2 in HEK 293 cells suggests that there is no stable interaction between wild-type and mutant proteins in the ER of mammalian cells, as would be expected if the wild-type and mutant formed stable dimers. Login to comment
203 Sf9 cells were infected with a combination of the indicated volumes of recombinant baculoviruses containing wild-type ABCG2, G553L, K86M, or -galactosidase. Login to comment
209 The G553L mutant shows no transport of Hoechst 33342 (second column) and at the 50:400 ratio (fifth column), representing approximately equal protein expression levels for the mutant and the wild type, results in a 35% decrease in activity, while in case of the K86M mutant, the same ratio (last column) almost completely abrogates Hoechst transport. Login to comment
216 Though the G553L mutant is confined to the ER, it must be near another mutant protein because chemical cross-linking of two mutant proteins even at a distance of 7.7 Å was observed. Login to comment
223 In contrast to the results observed with the K86M mutant-wild-type dimer, a roughly 35% decrease was observed in the Sf9 cells expressing both the wild-type and the G553L mutant protein. Login to comment
224 This limited, but reproducible, effect of the G553L mutant on the wild-type protein argues that the mutant has a conformation that can associate with the wild-type protein, although that association must be relatively weak. Login to comment

[hide] Towards understanding the mechanism of action of t... J Mol Graph Model. 2007 Mar;25(6):837-51. Epub 2006 Aug 30. Li YF, Polgar O, Okada M, Esser L, Bates SE, Xia D
Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study.
J Mol Graph Model. 2007 Mar;25(6):837-51. Epub 2006 Aug 30., [PMID:17027309]

Abstract [show]
The ATP-binding cassette protein ABCG2 is a member of a broad family of ABC transporters with potential clinical importance as a mediator of multidrug resistance. We carried out a homology and knowledge-based, and mutationally improved molecular modeling study to establish a much needed structural framework for the protein, which could serve as guidance for further genetic, biochemical, and structural analyses. Based on homology with known structures of both full-length and nucleotide-binding domains (NBD) of ABC transporters and structural knowledge of integral membrane proteins, an initial model of ABCG2 was established. Subsequent refinement to conform to the lipophilic index distributions in the transmembrane domain (TMD) and to the results of site-directed mutagenesis experiments led to an improved model. The complete ABCG2 model consists of two identical subunits facing each other in a closed conformation. The dimeric interface in the nucleotide-binding domain (NBD) involves a characteristic nucleotide sandwich and the interface in the TMD consists of the TM helices 1-3 of one subunit and the helices 5 and 6 of the other. The interface between the NBD and the TMD is bridged by the conserved structural motif between TM2 and TM3, the intracellular domain 1 (ICD1), and the terminal beta-strand (S6) of the central beta-sheet in the NBD. The apparent flexibility of the ICD1 may play a role in transmitting conformational changes from the NBD to the TMD or from the TMD to the NBD.

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No. Sentence Comment
179 T mutant binds more tightly to Rhodamin123 and inhibits rhodamine123 transport [19,51,21] G553L, G553E TM5 In drosophila, mutation at this position yields monomer. Login to comment
244 Introducing a larger or charged residue at this position (G553L and G553E) would result in a clash of amino acid side chains and disrupt the dimer formation both in ABCG2 and in its Drosophila orthologue. Login to comment

[hide] Homology modeling of breast cancer resistance prot... J Struct Biol. 2008 Apr;162(1):63-74. Epub 2007 Dec 15. Hazai E, Bikadi Z
Homology modeling of breast cancer resistance protein (ABCG2).
J Struct Biol. 2008 Apr;162(1):63-74. Epub 2007 Dec 15., [PMID:18249138]

Abstract [show]
BCRP (also known as ABCG2, MXR, and ABC-P) is a member of the ABC family that transports a wide variety of substrates. BCRP is known to play a key role as a xenobiotic transporter. Since discovering its role in multidrug resistance, considerable efforts have been made in order to gain deeper understanding of BCRP structure and function. The recent study was aimed at predicting BCRP structure by creating a homology model. Based on sequence similarity with known structures of full-length, NB and TM domain of ABC transporters, TM, NB, and linker regions of BCRP were defined. The NB domain of BCRP was modeled using MalK as a template. Based on secondary structure prediction of BCRP and comparison of the transmembrane connecting regions of known structures of ABC transporters, the TM domain arrangement of BCRP was established and was found to resemble to that of the recently published crystal structure of Sav1866. Thus, an initial alignment of TM domain of BCRP was established using Sav1866 as a template. This alignment was subsequently refined using constrains derived from secondary structure and TM predictions and the final model was built. Finally, the complete homodimer ABCG2 model was generated using Sav1866 as template. Furthermore, known ligands of BCRP were docked to our model in order to define possible binding sites. The results of molecular dockings of known BCRP substrates to the BCRP model were in agreement with recently published experimental data indicating multiple binding sites in BCRP.

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No. Sentence Comment
245 However, in our model, R482 cannot form interaction with rhodamine, but L484 is in interacting distance Table 3 Mutations on BCRP and their effect on its function Mutation Effect/results Reference V12M Did not effect Hemato and MTX transport Tamura et al. (2006) G51C Did not effect Hemato and MTX transport Tamura et al. (2006) K86M Inactivates transporter (dominant negative effect on ATPase activity); alters subcellular distribution Henriksen et al. (2005a) K86M Transporter inactive, but still able to bind ATP Ozvegy et al. (2002) Q126stop Defective porphyrin transport Tamura et al. (2006) Q141K Did not effect Hemato and MTX transport Tamura et al. (2006) T153M Did not effect Hemato and MTX transport Tamura et al. (2006) Q166E Did not effect Hemato and MTX transport Tamura et al. (2006) I206L Did not effect Hemato and MTX transport Tamura et al. (2006) F208S Defective porphyrin transport Tamura et al. (2006) S248P Defective porphyrin transport Tamura et al. (2006) E334stop Defective porphyrin transport Tamura et al. (2006) F431L Effects MTX transport Tamura et al. (2006) S441N Defective porphyrin transport Tamura et al. (2006) E446-mutants No drug resistance Miwa et al. (2003) R482G, R482T Effects MTX transport Tamura et al. (2006) R482T Substrate drug transport and inhibitor efficiency is not mediated by changes in drug-binding Pozza et al. (2006) R482G, R482T Substitution influence the substrate specificity of the transporter Ozvegy et al. (2002) R482G, R482T Altered substrate specificity Honjo et al. (2001) R482G Methotrexate not transported Chen et al. (2003b) Mitomo et al. (2003) R482G Resistance to hydrophilic antifolates in vitro, G482-ABCG2 mutation confers high-level resistance to various hydrophilic antifolates Shafran et al., (2005) R482G Three distinct drug, binding sites Clark et al. (2006) R482G Altered substrate specificity, granulocyte maturation uneffected Ujhelly et al. (2003) R482 mutants Higher resistance to mitoxantrone and doxorubicin than wt Miwa et al. (2003) R482X Affects substrate transport and ATP hydrolysis but not substrate binding Ejendal et al. (2006) F489L Impaired porphyrin transport Tamura et al. (2006) G553L; G553E Impaired trafficing, expression, and N-linked glycosylation Polgar et al. (2006) L554P Dominant negative effect on drug sensitivity Kage et al. (2002) N557D Resistance to MTX, but decreased transport of SN-38; N557E no change in transport compared to wt Miwa et al. (2003) F571I Did not effect Hemato and MTX transport Tamura et al. (2006) N590Y Did not effect Hemato and MTX transport Tamura et al. (2006) C592A Impaired function and expression Henriksen et al. (2005b) C592A/C608A Restored plasma mb expression; MTX transport normal, BODIPY-prazosin impaired Henriksen et al. (2005b) C603A Disulfide bridge; no functional or membrane targeting change Henriksen et al. (2005b) C608A Impaired function and expression Henriksen et al. (2005b) D620N Did not effect Hemato and MTX transport Tamura et al. (2006) H630X No change in transport Miwa et al. (2003) Cand N-terminal truncated Impaired trafficing Takada et al. (2005) with the ligand. Login to comment

[hide] ABCG2: structure, function and role in drug respon... Expert Opin Drug Metab Toxicol. 2008 Jan;4(1):1-15. Polgar O, Robey RW, Bates SE
ABCG2: structure, function and role in drug response.
Expert Opin Drug Metab Toxicol. 2008 Jan;4(1):1-15., [PMID:18370855]

Abstract [show]
ABCG2 was discovered in multi-drug-resistant cancer cells, with the identification of chemotherapeutic agents, such as mitoxantrone, flavopiridol, methotrexate and irinotecan as substrates. Later, drugs from other therapeutic groups were also described as substrates, including antibiotics, antivirals, HMG-CoA reductase inhibitors and flavonoids. An expanding list of compounds inhibiting ABCG2 has also been generated. The wide variety of drugs transported by ABCG2 and its normal tissue distribution with highest levels in the placenta, intestine and liver, suggest a role in protection against xenobiotics. ABCG2 also has an important role in the pharmacokinetics of its substrates. Single nucleotide polymorphisms of the gene were shown to alter either plasma concentrations of substrate drugs or levels of resistance against chemotherapeutic agents in cell lines. ABCG2 was also described as the determinant of the side population of stem cells. All these aspects of the transporter warrant further research aimed at understanding ABCG2's structure, function and regulation of expression.

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No. Sentence Comment
155 When expressed in HEK cells, the glycine to leucine mutation at this position (G553L) results in significantly reduced protein expression levels, altered glycosylation, and retention in the ER, even when coexpressed with the wild-type protein. Login to comment
156 Yet, the G553L mutant can be chemically crosslinked. Login to comment
158 Indeed, the GFP-tagged G553L mutant was pulled down with the His-tagged wild-type ABCG2 in co-immunoprecipitation experiments following coexpression in Sf9 cells (Figure 2). Login to comment
161 Coimmunoprecipitation of the G553L mutant with the wild-type protein in Sf9 insect cells. Login to comment
162 Sf9 insect cells were coinfected with bacculovirus carrying His-tagged wt ABCG2 and GFP-tagged G553L mutant followed by membrane preparation. Login to comment
171 wt-His/wt-GFP 1 2 3 4 5 6 7 8 wt-His/G553L-GFP Figure 1. Login to comment

[hide] Posttranslational negative regulation of glycosyla... Biochem Biophys Res Commun. 2011 Jan 21;404(3):853-8. Epub 2010 Dec 22. Sugiyama T, Shuto T, Suzuki S, Sato T, Koga T, Suico MA, Kusuhara H, Sugiyama Y, Cyr DM, Kai H
Posttranslational negative regulation of glycosylated and non-glycosylated BCRP expression by Derlin-1.
Biochem Biophys Res Commun. 2011 Jan 21;404(3):853-8. Epub 2010 Dec 22., 2011-01-21 [PMID:21184741]

Abstract [show]
Human breast cancer resistance protein (BCRP)/MXR/ABCG2 is a well-recognized ABC half-transporter that is highly expressed at the apical membrane of many normal tissues and cancer cells. BCRP facilitates disposition of endogenous and exogenous harmful xenobiotics to protect cells/tissues from xenobiotic-induced toxicity. Despite the enormous impact of BCRP in the physiological and pathophysiological regulation of the transport of a wide variety of substrates, little is known about the factors that regulate posttranslational expression of BCRP. Here, we identified Derlin-1, a member of a family of proteins that bears homology to yeast Der1p, as a posttranslational regulator of BCRP expression. Overexpression of Derlin-1 suppressed ER to Golgi transport of wild-type (WT) BCRP that is known to be efficiently trafficked to the plasma membrane. On the other hand, protein expression of N596Q variant of BCRP, N-linked glycosylation-deficient mutant that preferentially undergoes ubiquitin-mediated ER-associated degradation (ERAD), was strongly suppressed by the overexpression of Derlin-1, whereas knockdown of Derlin-1 stabilized N596Q protein, suggesting a negative regulatory role of Derlin-1 for N596Q protein expression. Notably, knockdown of Derlin-1 also stabilized the expression of tunicamycin-induced deglycosylated WT BCRP protein, implying the importance of glycosylation state for the recognition of BCRP by Derlin-1. Thus, our data demonstrate that Derlin-1 is a negative regulator for both glycosylated and non-glycosylated BCRP expression and provide a novel posttranslational regulatory mechanism of BCRP by Derlin-1.

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163 Further, we could also assess the impact of Der- lin-1 on the expression of other BCRP variants such as R383A, G553L and G553E variants, which are also shown to be impaired N-linked glycosylation like N596Q BCRP [27,28]. Login to comment