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3.A.1.204.2
Drug resistance transporter, ABCG2 (MXR; ABCP) (human breast cancer resistance protein, BCRP) (Moitra et al., 2011). It exports urate and haem in haempoietic cells (Latunde-Dada et al., 2006) as well as cytotoxic agents (mitoxantrone, flavopiridol, methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, topotecan, and resveratrol), fluorescent dyes (Hoechst 33342) and other toxic substances (PhIP and pheophorbide a) (Özvegy-Laczka et al., 2005). It also transports folate and sterols: estradiol, and probably cholesterol, progesterone, testosterone and tamoxifen (Janvilisri et al., 2003; Breedveld et al., 2007). It is a homotetramer (Xu et al., 2004). It forms a homodimer bound via a disulfide bond at Cys-603 which stabilizes the protein against ubiquitin-mediated degradation in proteosomes (Wakabayashi et al., 2007), and can for dodecamers with 12 subunits (Xu et al. 2007). It has 6 established TMSs with the N- and C- termini inside (Wang et al., 2008). The following drugs are exported from human breast cancer cell line MCF-7: miloxantrone, daunorubicin, doxorubicin and rhodamine123). Also transports reduced folates and mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006). It is an active glutathione efflux pump (Brechbuhl et al., 2010). Mutations in ABCG2 cause hyperuricemia and gout , which led to the identification of urate as a physiological subsrate for ABCG2; it catalyzes elimination of urate across the renal tubular apical membrane (Prestin et al. 2014). Zafirlukast antagonizes ABCG2 multidrug resistance (Sun et al., 2012). Inhibited by Sildenafil (Shi et al., 2011) and lapatinib derivatives (Sodani et al., 2012).  Mutation of basic residues can increase or decrease drug efflux activities (Cai et al. 2010).  A substrate of ABCG2 is d-luciferin, allowing bioluminescent immaging of drug efflux across the blood-brain barrier.  Inhibitors include Ko143, gefetinib and nilotinib (Bakhsheshian et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  Telabinib reverses chemotheraputic MDR mediated by ABCG2 (Sodani et al. 2014).  Residues involved in protein trafficking and drug transport activity have been identified (Haider et al. 2015).  The 3-d structure in the inward facing conformation has been solved (Rosenberg et al. 2015). Durmus et al. 2015 and Westover and Li 2015 have reviewed BCRP-mediated transport of cancer chemotheraputic agents.  A role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux has been proposed (Macalou et al. 2015).  Functions at the blood:placenta barrier of the mouse (Kumar et al. 2016). The Q141K variant exhibits decreased functional expression and thus increased drug accumulation and decreased urate secretion, and the R482 position, which plays a role the substrate specificity, is located in one of the substrate binding pockets (László et al. 2016). Naturally occurring single nucleotide polymorphisms in humans giving rise to amino acyl residue substitutions in the transmembrane domains result in impared transport of Lucifer Yellow and estrone sulfate (Sjöstedt et al. 2017). A cryoEM structure revealed two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between TMSs. A multidrug recognition and transport mechanism was proposed, and disease-causing single nucleotide polymorphisms were rationalized. The structural basis of cholesterol recognition by G-subfamily ABC transporters was also revealed (Taylor et al. 2017). Catalyzes efflux of ochratoxin A (OTA) (Qi et al. 2017).

Accession Number:Q9UNQ0
Protein Name:ATP-binding cassette sub-family G member 2
Length:655
Molecular Weight:72314.00
Species: [9606]
Number of TMSs:7
Location1 / Topology2 / Orientation3: Cell membrane1 / Multi-pass membrane protein2
Substrate methotrexate, topoteca, flavopiridol, Heme, Glutathione, mitoxantrone, Urate, resveratrol, Hoechst 33342, pheophorbide a, folate, estradiol, cholesterol, progesterone, testosterone, tamoxife, miloxantrone, daunorubicin, doxorubicin, rhodamine123

Cross database links:

Genevestigator: Q9UNQ0
eggNOG: prNOG06758
DIP: DIP-29162N
RefSeq: NP_004818.2   
Entrez Gene ID: 9429   
Pfam: PF01061    PF00005   
OMIM: 603756  gene
KEGG: hsa:9429   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005886 C:plasma membrane
GO:0005524 F:ATP binding
GO:0042803 F:protein homodimerization activity
GO:0008559 F:xenobiotic-transporting ATPase activity
GO:0042493 P:response to drug
GO:0006810 P:transport

References (17)

[1] “A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance.”  Allikmets R.et.al.   9850061
[2] “A multidrug resistance transporter from human MCF-7 breast cancer cells.”  Doyle L.A.et.al.   9861027
[3] “Identification of breast cancer resistant protein/mitoxantrone resistance/placenta-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088, topoisomerase I inhibitors with an indolocarbazole structure.”  Komatani H.et.al.   11306452
[4] “The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.”  Zhou S.et.al.   11533706
[5] “The expression and functional characterization of ABCG2 in brain endothelial cells and vessels.”  Zhang W.et.al.   12958161
[6] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[7] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[8] “Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes.”  Miyake K.et.al.   9892175
[9] “Role of ABCG1 and other ABCG family members in lipid metabolism.”  Schmitz G.et.al.   11590207
[10] “N-linked glycosylation of the human ABC transporter ABCG2 on asparagine 596 is not essential for expression, transport activity, or trafficking to the plasma membrane.”  Diop N.K.et.al.   15807535
[11] “Single amino acid (482) variants of the ABCG2 multidrug transporter: major differences in transport capacity and substrate recognition.”  Oezvegy-Laczka C.et.al.   15670731
[12] “Effect of Walker A mutation (K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2.”  Henriksen U.et.al.   15769853
[13] “Intramolecular disulfide bond is a critical check point determining degradative fates of ATP-binding cassette (ABC) transporter ABCG2 protein.”  Wakabayashi K.et.al.   17686774
[14] “Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8.”  Iida A.et.al.   12111378
[15] “Eight novel single nucleotide polymorphisms in ABCG2/BCRP in Japanese cancer patients administered irinotacan.”  Itoda M.et.al.   15618737
[16] “Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine.”  Zamber C.P.et.al.   12544509
[17] “Single nucleotide polymorphisms modify the transporter activity of ABCG2.”  Morisaki K.et.al.   15838659

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FASTA formatted sequence
1:	MSSSNVEVFI PVSQGNTNGF PATASNDLKA FTEGAVLSFH NICYRVKLKS GFLPCRKPVE 
61:	KEILSNINGI MKPGLNAILG PTGGGKSSLL DVLAARKDPS GLSGDVLING APRPANFKCN 
121:	SGYVVQDDVV MGTLTVRENL QFSAALRLAT TMTNHEKNER INRVIQELGL DKVADSKVGT 
181:	QFIRGVSGGE RKRTSIGMEL ITDPSILFLD EPTTGLDSST ANAVLLLLKR MSKQGRTIIF 
241:	SIHQPRYSIF KLFDSLTLLA SGRLMFHGPA QEALGYFESA GYHCEAYNNP ADFFLDIING 
301:	DSTAVALNRE EDFKATEIIE PSKQDKPLIE KLAEIYVNSS FYKETKAELH QLSGGEKKKK 
361:	ITVFKEISYT TSFCHQLRWV SKRSFKNLLG NPQASIAQII VTVVLGLVIG AIYFGLKNDS 
421:	TGIQNRAGVL FFLTTNQCFS SVSAVELFVV EKKLFIHEYI SGYYRVSSYF LGKLLSDLLP 
481:	MRMLPSIIFT CIVYFMLGLK PKADAFFVMM FTLMMVAYSA SSMALAIAAG QSVVSVATLL 
541:	MTICFVFMMI FSGLLVNLTT IASWLSWLQY FSIPRYGFTA LQHNEFLGQN FCPGLNATGN 
601:	NPCNYATCTG EEYLVKQGID LSPWGLWKNH VALACMIVIF LTIAYLKLLF LKKYS