Oligomerization domain of the multidrug resistance-associated transporter ABCG2 and its dominant inhibitory activity.
Overexpression of human ATP-binding cassette transporter ABCG2 in cancer cells causes multidrug resistance by effluxing anticancer drugs. ABCG2 is considered as a half transporter and is thought to function as a homodimer. However, recent evidence suggests that it may exist as a higher form of oligomer consisting of 12 subunits. In this study, we mapped the oligomerization domain of human ABCG2 to its transmembrane domain consisting of TM5-loop-TM6. This oligomerization domain, when expressed alone in HEK293 cells, also forms a homododecamer. Furthermore, this domain has activity that inhibits drug efflux and resistance function of the full-length ABCG2 likely by disrupting the formation of the homo-oligomeric full-length ABCG2. These findings suggest that human ABCG2 may exist and work as a homo-oligomer by interactions located in TM5-loop-TM6, and that ABCG2 oligomerization may be used as a target for therapeutic development to circumvent ABCG2-mediated drug resistance in cancer treatment.
Xu
Junkang
J
Department of Pharmacology and Toxicology, Indiana University Cancer Center, Walther Oncology Center/Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Peng
Hui
H
Chen
Qun
Q
Liu
Yang
Y
Dong
Zizheng
Z
Zhang
Jian-Ting
JT
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D010449:Peptide Mapping; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins