Mo, WeiQi, JingZhang, Jian-Ting2023-01-182023-01-182012-05Mo W, Qi J, Zhang JT. Different roles of TM5, TM6, and ECL3 in the oligomerization and function of human ABCG2. Biochemistry. 2012;51(17):3634-3641. doi:10.1021/bi300301ahttps://hdl.handle.net/1805/30947ABCG2 is a member of the ATP-binding cassette transporter superfamily, and its overexpression causes multidrug resistance (MDR) in cancer chemotherapy. ABCG2 may also protect cancer stem cells by extruding cytotoxic materials. ABCG2 has previously been shown to exist as a high-order homo-oligomer consisting of possibly 8-12 subunits, and the oligomerization domain was mapped to the C-terminal domain, including TM5, ECL3, and TM6. In this study, we further investigate this domain in detail for the role of each segment in the oligomerization and drug transport function of ABCG2 using domain swapping and site-directed mutagenesis. We found that none of the three segments (TM5, TM6, and ECL3) is essential for the oligomerization activity of ABCG2 and that any one of these three segments in the full-length context is sufficient to support ABCG2 oligomerization. While TM5 plays an important role in the drug transport function of ABCG2, TM6 and ECL3 are replaceable. Thus, each segment in the TM5-ECL3-TM6 domain plays a distinctive role in the oligomerization and function of ABCG2.en-USPublisher PolicyATP-binding cassette transportersExtracellular spaceNeoplasm proteinsProtein multimerizationProtein subunitsArticle