Ion transport by the human Breast Cancer Resistance Protein (ABCG2)

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Drug transporters, such as the Breast Cancer Resistance Protein (ABCG2), are recognized as key players in the distribution of drugs in human. The localization of this efflux pump in organs responsible for drug biotransformation and excretion gives ABCG2 an important gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. ABCG2 is also found in cancer cells, where it mediates the extrusion of drug to the cell's exterior. In doing so, it prevents entry of anticancer drugs into cells and, hence, impairs the chemotherapeutic treatment of this life-threatening disease. In this proposal, we will study fundamental aspects of the transport mechanism of human ABCG2. In particular, we will study the previously unknown ability of ABCG2 to transport ions such as protons. We are interested to learn which ions are transported (in addition to protons, for example sodium, potassium, chloride ions), how ABCG2 transports these ions, and why? What is the relationship between ion transport and drug transport? ABCG2 is thought to be active as a dimer, which we will test by mass spectrometry, and is likely to have drug binding sites that are alternately exposed to the inside surface of the membrane (where drugs bind) and outside surface of the membrane (where drugs are released). Based on the available crystal structures of multidrug binding proteins (transporters and transcriptional regulators), we hypothesize that (i) protons and other ions might displace drugs from binding sites in ABCG2 during drug release and/or (ii) their binding might support structural changes in the two ABCG2 units and their interface, that are associated with the reorientation of the drug binding sites. Fundamental knowledge about ABCG2 activity will allow the rational development of inhibitors (also termed modulators) of this efflux pump that could be used to target drugs to specific parts of the human body, and to improve chemotherapy of cancers.