Regulation of function by dimerization through the amino-terminal membrane-spanning domain of human ABCC1/MRP1

Youyun Yang, Yang Liu, Zizheng Dong, Junkang Xu, Hui Peng, Zhaoqian Liu, Jian-Ting Zhang

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)8821-8830
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number12
DOIs
StatePublished - Mar 23 2007

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ATP-Binding Cassette Transporters
Dimerization
Membranes
Chemotherapy
Nucleotides
Dimers
Drug Therapy
Membrane Transport Proteins
Multiple Drug Resistance
P-Glycoprotein
Drug Resistance
Neoplasms
Adenosine Triphosphate
Monomers
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of function by dimerization through the amino-terminal membrane-spanning domain of human ABCC1/MRP1. / Yang, Youyun; Liu, Yang; Dong, Zizheng; Xu, Junkang; Peng, Hui; Liu, Zhaoqian; Zhang, Jian-Ting.

In: Journal of Biological Chemistry, Vol. 282, No. 12, 23.03.2007, p. 8821-8830.

Research output: Contribution to journalArticle

Yang, Youyun ; Liu, Yang ; Dong, Zizheng ; Xu, Junkang ; Peng, Hui ; Liu, Zhaoqian ; Zhang, Jian-Ting. / Regulation of function by dimerization through the amino-terminal membrane-spanning domain of human ABCC1/MRP1. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 12. pp. 8821-8830.
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