ABCG2

ABCG2 with simulated plasma membrane

ABCG2
Identifiers
Aliases	ABCG2 , ATP-binding cassette, sub-family G (WHITE), member 2 (Junior blood group), ABC15, ABCP, BCRP, BCRP1, BMDP, CD338, CDw338, EST157481, GOUT1, MRX, MXR, MXR1, UAQTL1, MXR-1, ATP binding cassette subfamily G member 2 (Junior blood group)
External IDs	OMIM: 603756 MGI: 1347061 HomoloGene: 55852 GeneCards: ABCG2
Gene location (Human) Chr. Chromosome 4 (human) [2] Band 4q22.1 Start 88,090,150 bp [2] End 88,231,628 bp [2]
Gene location (Mouse) Chr. Chromosome 6 (mouse) [3] Band 6 B3|6 27.82 cM Start 58,561,508 bp [3] End 58,672,661 bp [3]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in jejunal mucosa endothelial cell seminal vesicula duodenum substantia nigra internal globus pallidus placenta inferior ganglion of vagus nerve subthalamic nucleus postcentral gyrus Top expressed in proximal tubule kidney ileum yolk sac jejunum sciatic nerve intestinal epithelium primitive streak intestinal villus abdominal wall More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding ABC-type xenobiotic transporter activity heme transmembrane transporter activity protein homodimerization activity transporter activity ATPase activity protein binding ATP binding ATPase-coupled transmembrane transporter activity cholesterol transfer activity identical protein binding xenobiotic transmembrane transporter activity Cellular component mitochondrial membranes membrane mitochondrion nucleus plasma membrane integral component of membrane apical plasma membrane receptor complex Biological process urate metabolic process cellular iron ion homeostasis heme transport xenobiotic transmembrane transport xenobiotic transport transmembrane transport cholesterol efflux cellular detoxification Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9429 26357 Ensembl ENSG00000118777 ENSMUSG00000029802 UniProt Q9UNQ0 Q7TMS5 RefSeq (mRNA) NM_001257386 NM_004827 NM_001348985 NM_001348986 NM_001348987 NM_001348988 NM_001348989 NM_011920 NM_001355477 NM_001381925 NM_001381926 NM_001381927 RefSeq (protein) NP_001244315 NP_004818 NP_001335914 NP_001335915 NP_001335916 NP_001335917 NP_001335918 NP_036050 NP_001342406 NP_001368854 NP_001368855 NP_001368856 Location (UCSC) Chr 4: 88.09 – 88.23 Mb Chr 6: 58.56 – 58.67 Mb PubMed search [4] [5]
Wikidata
View/Edit Human View/Edit Mouse

ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ABCG2 gene. ^{[6] [7]} ABCG2 has also been designated as CDw338 (cluster of differentiation w338). ABCG2 is a translocation protein used to actively pump drugs and other compounds against their concentration gradient using the bonding and hydrolysis of ATP as the energy source. ^[1]

ABCG2 forms into a homodimer to assume its active transport conformation. The dimer weighs approximately 144 kDa. The expression of this transport protein is highly conserved throughout the animal kingdom, pointing to its importance. ^[8]

Substrate binding with compounds occurs in the large central cavity. ABCG2 can bind to a broad range of compounds but binds strongest to flat, polycyclic chemicals with lots of hydrophobic character. ^[1]

Function

The membrane-associated protein encoded by this gene is included in the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. The active transport of chemicals requires a source of energy to catalyze the conformational changes the protein undergoes. The nucleotide-binding domains (NBDs) found towards the N-terminus allow binding to ATP molecules. The NBD and the transmembrane domain (TMD) are the most conserved region of the transporter in various animal groups, highlighting the importance of these regions for overall protein function. ^[8] Additionally, many ABC transporters have conserved NBD regions showing the strict conformation needed to bind ATP molecules. ^[1]

ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the White subfamily. Alternatively referred to as the breast cancer resistance protein (BCRP), this protein functions as a xenobiotic transporter which may play a role in multi-drug resistance to chemotherapeutic agents including mitoxantrone and camptothecin analogues. ^[8] Early observations of significant ABCG2-mediated resistance to anthracyclines were subsequently attributed mutations encountered in vitro but not in nature or the clinic. Significant expression of this protein has been observed in the placenta, ^[9] and it has been shown to have a role in protecting the fetus from xenobiotics in the maternal circulation. ^[10]

The transporter has been shown to play protective roles in blocking absorption at the apical membrane of the intestine, and at the blood–testis barrier, ^[10] the blood–brain barrier, ^[10] and the membranes of hematopoietic progenitor and other stem cells. At the apical membranes of the liver and kidney, it enhances excretion of xenobiotics. In the lactating mammary gland, it has a role on excreting vitamins such as riboflavin and biotin into milk. ^[10] Xenobiotic toxins compete for the substrate binding domain of ABCG2 potentially causing toxins to concentrate in the breast milk. ^[8] In the kidney and gastrointestinal tract, it has a role in urate excretion.

The protein also carries the Jr(a) antigen, which defines the Junior blood group system. ^[11]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1] [[File: [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] |alt=Fluorouracil (5-FU) Activity edit]] Fluorouracil (5-FU) Activity edit The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

Click on genes, proteins and metabolites below to link to respective articles. [§ 1] [[File: [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] |alt=Irinotecan Pathway edit]] Irinotecan Pathway edit The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

Inhibition

It is inhibited by some calcium channel blockers such as amlodipine, felodipine and nifedipine. ^[12] The fungal toxin fumitremorgin C (FTC) inhibits the protein but has neurotoxic side effects. A synthetic tetracyclic analog of FTC called Ko-143 inhibits ABCG2. ^[13]

See also

• ATP-binding cassette transporter

References

1. Taylor NM, Manolaridis I, Jackson SM, Kowal J, Stahlberg H, Locher KP (June 2017). "Structure of the human multidrug transporter ABCG2". Nature. 546 (7659): 504–509. Bibcode:2017Natur.546..504T. doi:10.1038/nature22345. hdl: 20.500.11850/233014 . PMID   28554189. S2CID   4461745.
2. GRCh38: Ensembl release 89: ENSG00000118777 - Ensembl, May 2017
3. GRCm38: Ensembl release 89: ENSMUSG00000029802 - Ensembl, May 2017
4. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
6. Allikmets R, Gerrard B, Hutchinson A, Dean M (October 1996). "Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database". Human Molecular Genetics. 5 (10): 1649–1655. doi: 10.1093/hmg/5.10.1649 . PMID   8894702.
7. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD (December 1998). "A multidrug resistance transporter from human MCF-7 breast cancer cells". Proceedings of the National Academy of Sciences of the United States of America. 95 (26): 15665–15670. Bibcode:1998PNAS...9515665D. doi: 10.1073/pnas.95.26.15665 . PMC   28101 . PMID   9861027.
8. Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M, Bates SE (January 2009). "ABCG2: a perspective". Advanced Drug Delivery Reviews. 61 (1): 3–13. doi:10.1016/j.addr.2008.11.003. PMC   3105088 . PMID   19135109.
9. "Entrez Gene: ABCG2 ATP-binding cassette, sub-family G (WHITE), member 2".
10. Vlaming ML, Lagas JS, Schinkel AH (January 2009). "Physiological and pharmacological roles of ABCG2 (BCRP): recent findings in Abcg2 knockout mice". Advanced Drug Delivery Reviews. 61 (1): 14–25. doi:10.1016/j.addr.2008.08.007. PMID   19118589.
11. Kniffin CL (2013). "OMIM entry # 614490 – BLOOD GROUP, JUNIOR SYSTEM; JR". Online Mendelian Inheritance in Man . Retrieved 1 September 2019.
12. Ghosh S, Sircar M (October 2008). "Calcium channel blocker overdose: experience with amlodipine". Indian Journal of Critical Care Medicine. Jaypee Brothers Medical Publishing. 12 (4): 190–193. doi: 10.4103/0972-5229.45080 . PMC   2738322 . PMID   19742263.
13. Jackson SM, Manolaridis I, Kowal J, Zechner M, Taylor NM, Bause M, et al. (April 2018). "Structural basis of small-molecule inhibition of human multidrug transporter ABCG2". Nature Structural & Molecular Biology. 25 (4): 333–340. doi:10.1038/s41594-018-0049-1. hdl: 20.500.11850/256191 . PMID   29610494. S2CID   4617388.

Further reading

• Hazai E, Bikádi Z (April 2008). "Homology modeling of breast cancer resistance protein (ABCG2)". Journal of Structural Biology. 162 (1): 63–74. doi:10.1016/j.jsb.2007.12.001. PMID   18249138.
• Abbott BL (January 2006). "ABCG2 (BCRP): a cytoprotectant in normal and malignant stem cells". Clinical Advances in Hematology & Oncology. 4 (1): 63–72. PMID   16562373.
• Schmitz G, Langmann T, Heimerl S (October 2001). "Role of ABCG1 and other ABCG family members in lipid metabolism". Journal of Lipid Research. 42 (10): 1513–1520. doi: 10.1016/S0022-2275(20)32205-7 . PMID   11590207.
• Ejendal KF, Hrycyna CA (October 2002). "Multidrug resistance and cancer: the role of the human ABC transporter ABCG2". Current Protein & Peptide Science. 3 (5): 503–511. doi:10.2174/1389203023380521. PMID   12369998.
• Doyle L, Ross DD (October 2003). "Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)". Oncogene. 22 (47): 7340–7358. doi:10.1038/sj.onc.1206938. PMID   14576842. S2CID   9648841.
• Sugimoto Y, Tsukahara S, Ishikawa E, Mitsuhashi J (August 2005). "Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics". Cancer Science. 96 (8): 457–465. doi:10.1111/j.1349-7006.2005.00081.x. PMID   16108826. S2CID   20734576.
• Ishikawa T, Tamura A, Saito H, Wakabayashi K, Nakagawa H (October 2005). "Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design". Die Naturwissenschaften. 92 (10): 451–463. Bibcode:2005NW.....92..451I. doi:10.1007/s00114-005-0019-4. PMID   16160819. S2CID   22151149.
• Krishnamurthy P, Schuetz JD (2006). "Role of ABCG2/BCRP in biology and medicine". Annual Review of Pharmacology and Toxicology. 46: 381–410. doi:10.1146/annurev.pharmtox.46.120604.141238. PMID   16402910.
• Robey RW, Polgar O, Deeken J, To KW, Bates SE (March 2007). "ABCG2: determining its relevance in clinical drug resistance". Cancer and Metastasis Reviews. 26 (1): 39–57. doi:10.1007/s10555-007-9042-6. PMID   17323127. S2CID   11293439.

External links

• ABCG2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ABCG2 genome location and ABCG2 gene details page in the UCSC Genome Browser .
• Overview of all the structural information available in the PDB for UniProt : Q9UNQ0 (Broad substrate specificity ATP-binding cassette transporter ABCG2) at the PDBe-KB .

This article incorporates text from the United States National Library of Medicine, which is in the public domain.