ABCG2

File:ABCG2 with plasma membrane.jpg

ABCG2 with simulated plasma membrane

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ATP-binding cassette subfamily G member 2 is a protein that in humans is encoded by the ABCG2 gene. 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.

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, also known as subfamily G. 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. 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, and it has been shown to have a role in protecting the fetus from xenobiotics in the maternal circulation.

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, the blood–brain barrier, 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. 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.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [[File: [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] ]] Fluorouracil (5-FU) Activity edit

Click on genes, proteins and metabolites below to link to respective articles. [[File: [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] [[ ]] ]] Irinotecan Pathway edit

Inhibition

It is inhibited by some calcium channel blockers such as amlodipine, felodipine and nifedipine. 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.

See also

• ATP-binding cassette transporter

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. PMC 11158713. 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)
• Template:UCSC gene info
• Template:PDBe-KB2

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