Regulation of function by dimerization through the amino-terminal membrane-spanning domain of human ABCC1/MRP1.
Overexpression of some ATP-binding cassette (ABC) membrane transporters such as ABCB1/P-glycoprotein/MDR1 and ABCC1/MRP1 causes multidrug resistance in cancer chemotherapy. It has been thought that half-ABC transporters with one nucleotide-binding domain and one membrane-spanning domain (MSD) likely work as dimers, whereas full-length transporters with two nucleotide-binding domains and two or three MSDs function as monomers. In this study, we examined the oligomeric status of the human full-length ABC transporter ABCC1/MRP1 using several biochemical approaches. We found 1) that it is a homodimer, 2) that the dimerization domain is located in the amino-terminal MSD0L0 (where L0 is loop 0) region, and 3) that MSD0L0 has a dominant-negative function when coexpressed with wild-type ABCC1/MRP1. These findings suggest that ABCC1/MRP1 may exist and function as a dimer and that MSD0L0 likely plays some structural and regulatory functions. It is also tempting to propose that the MSD0L0-mediated dimerization may be targeted for therapeutic development to sensitize ABCC1/MRP1-mediated drug resistance in cancer chemotherapy.
Yang
Youyun
Y
Department of Pharmacology and Toxicology, Indiana University Cancer Center, IN 46202, USA.
Liu
Yang
Y
Dong
Zizheng
Z
Xu
Junkang
J
Peng
Hui
H
Liu
Zhaoqian
Z
Zhang
Jian-Ting
JT
D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002850:Chromatography, Gel; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019281:Dimerization; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013395:Sucrose / Q000494:pharmacology; D014162:Transfection
D003432:Cross-Linking Reagents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013395:Sucrose; C421109:multidrug resistance-associated protein 1