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J. Biol. Chem., Vol. 281, Issue 41, 31152-31163, October 13, 2006

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The Amino Terminus of the Human Multidrug Resistance Transporter ABCC1 Has a U-shaped Folding with a Gating Function^*

Qun Chen^¶, Youyun Yang^¶1, Lang Li^||, and Jian-Ting Zhang^¶2

From the Department of Pharmacology and Toxicology, ^||Division of Biostatistics, Department of Medicine, Indiana University Cancer Center, and ^¶Walther Oncology Center/Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202

Multidrug resistance is a serious problem in successful cancer chemotherapy. Studies using model cell lines have demonstrated that overexpression of some members of the ATP-binding cassette (ABC) transporter superfamily, such as ABCC1, causes enhanced efflux and, thus, decreased accumulation of multiple anticancer drugs, which leads to increased cell survival. Unlike most other ABC transporters, ABCC1 has an additional membrane-spanning domain (MSD0) with a putative extracellular amino terminus of 32 amino acids. However, the function of MSD0 and the role of the extracellular amino terminus are largely unknown. In this study, we examined the structural folding and the function of the amino terminus. We found that it has a U-shaped folding with the bottom of the U-structure facing cytoplasm and both ends in extracellular space. We also found that this U-shaped amino terminus probably functions as a gate to regulate the drug transport activity of human ABCC1.

Received for publication, April 12, 2006 , and in revised form, July 18, 2006.

^* This work was supported in part by National Institutes of Health Grants CA94961 and CA120221 and by Department of Defense Grant DAMD170010297. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported, in part, by National Institutes of Health National Research Service Award T32 HL07910.

² To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, IUCC, Indiana University School of Medicine, 1044 W. Walnut St., R4-166, Indianapolis, IN 46202. Tel.: 317-278-4503; Fax: 317-274-8046; E-mail: jianzhan{at}iupui.edu.

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