ABCG2 explained

ATP-binding cassette super-family G member 2 is a protein that in humans is encoded by the ABCG2 gene.^{[1] [2]} 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.^[3]

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.

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.

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. Additionally, many ABC transporters have conserved NBD regions showing the strict conformation needed to bind ATP molecules.

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.^[4] 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,^[5] and it has been shown to have a role in protecting the fetus from xenobiotics in the maternal circulation.^[6]

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,^[6] the blood–brain barrier,^[6] 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.^[6] Xenobiotic toxins compete for the substrate binding domain of ABCG2 potentially causing toxins to concentrate in the breast milk. 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.^[7]

Interactive pathway map

Inhibition

It is inhibited by some calcium channel blockers such as amlodipine, felodipine and nifedipine.^[8] 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.^[9]

See also

• ATP-binding cassette transporter

Further reading

• Hazai E, Bikádi Z . Homology modeling of breast cancer resistance protein (ABCG2) . Journal of Structural Biology . 162 . 1 . 63–74 . April 2008 . 18249138 . 10.1016/j.jsb.2007.12.001 .
• Abbott BL . ABCG2 (BCRP): a cytoprotectant in normal and malignant stem cells . Clinical Advances in Hematology & Oncology . 4 . 1 . 63–72 . January 2006 . 16562373 .
• Schmitz G, Langmann T, Heimerl S . Role of ABCG1 and other ABCG family members in lipid metabolism . Journal of Lipid Research . 42 . 10 . 1513–1520 . October 2001 . 11590207 . 10.1016/S0022-2275(20)32205-7 . free .
• Ejendal KF, Hrycyna CA . Multidrug resistance and cancer: the role of the human ABC transporter ABCG2 . Current Protein & Peptide Science . 3 . 5 . 503–511 . October 2002 . 12369998 . 10.2174/1389203023380521 .
• Doyle L, Ross DD . Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2) . Oncogene . 22 . 47 . 7340–7358 . October 2003 . 14576842 . 10.1038/sj.onc.1206938 . 9648841 .
• Sugimoto Y, Tsukahara S, Ishikawa E, Mitsuhashi J . Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics . Cancer Science . 96 . 8 . 457–465 . August 2005 . 16108826 . 10.1111/j.1349-7006.2005.00081.x . 20734576 . 11158713 .
• Ishikawa T, Tamura A, Saito H, Wakabayashi K, Nakagawa H . Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design . Die Naturwissenschaften . 92 . 10 . 451–463 . October 2005 . 16160819 . 10.1007/s00114-005-0019-4 . 2005NW.....92..451I . 22151149 .
• Krishnamurthy P, Schuetz JD . Role of ABCG2/BCRP in biology and medicine . Annual Review of Pharmacology and Toxicology . 46 . 381–410 . 2006 . 16402910 . 10.1146/annurev.pharmtox.46.120604.141238 .
• Robey RW, Polgar O, Deeken J, To KW, Bates SE . ABCG2: determining its relevance in clinical drug resistance . Cancer and Metastasis Reviews . 26 . 1 . 39–57 . March 2007 . 17323127 . 10.1007/s10555-007-9042-6 . 11293439 .

Notes and References

1. Allikmets R, Gerrard B, Hutchinson A, Dean M . 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 . October 1996 . 8894702 . 10.1093/hmg/5.10.1649 . free .
2. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD . 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 . December 1998 . 9861027 . 28101 . 10.1073/pnas.95.26.15665 . 1998PNAS...9515665D . free .
3. Taylor NM, Manolaridis I, Jackson SM, Kowal J, Stahlberg H, Locher KP . Structure of the human multidrug transporter ABCG2 . Nature . 546 . 7659 . 504–509 . June 2017 . 28554189 . 10.1038/nature22345 . 2017Natur.546..504T . 20.500.11850/233014 . 4461745 . free .
4. Robey RW, To KK, Polgar O, Dohse M, Fetsch P, Dean M, Bates SE . ABCG2: a perspective . Advanced Drug Delivery Reviews . 61 . 1 . 3–13 . January 2009 . 19135109 . 3105088 . 10.1016/j.addr.2008.11.003 .
5. Web site: Entrez Gene: ABCG2 ATP-binding cassette, sub-family G (WHITE), member 2.
6. Vlaming ML, Lagas JS, Schinkel AH . Physiological and pharmacological roles of ABCG2 (BCRP): recent findings in Abcg2 knockout mice . Advanced Drug Delivery Reviews . 61 . 1 . 14–25 . January 2009 . 19118589 . 10.1016/j.addr.2008.08.007 .
7. Web site: OMIM entry # 614490 – BLOOD GROUP, JUNIOR SYSTEM; JR . Kniffin CL . . 2013 . 1 September 2019 .
8. Ghosh S, Sircar M . Calcium channel blocker overdose: experience with amlodipine . Indian Journal of Critical Care Medicine . 12 . 4 . 190–193 . October 2008 . 19742263 . 2738322 . 10.4103/0972-5229.45080 . Jaypee Brothers Medical Publishing . free .
9. Jackson SM, Manolaridis I, Kowal J, Zechner M, Taylor NM, Bause M, Bauer S, Bartholomaeus R, Bernhardt G, Koenig B, Buschauer A, Stahlberg H, Altmann KH, Locher KP . 6 . Structural basis of small-molecule inhibition of human multidrug transporter ABCG2 . Nature Structural & Molecular Biology . 25 . 4 . 333–340 . April 2018 . 29610494 . 10.1038/s41594-018-0049-1 . 20.500.11850/256191 . 4617388 . free .