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Identification of the Structural and Functional Boundaries of the Multidrug Resistance Protein 1 Cytoplasmic Loop 3

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Departments of Biochemistry and Pathology and Molecular Medicine and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada K7L 3N6, and Department of Medicine, The Upstate Medical University, The State University of New York, Syracuse, New York 13210
Cite this: Biochemistry 2003, 42, 48, 14099–14113
Publication Date (Web):November 12, 2003
https://doi.org/10.1021/bi035333y
Copyright © 2003 American Chemical Society

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    Abstract

    Multidrug resistance protein (MRP) 1 is a member of the ABCC branch of the ATP binding cassette (ABC) transporter superfamily that can confer resistance to natural product chemotherapeutic drugs and transport a variety of conjugated organic anions, as well as some unconjugated compounds in a glutathione- (GSH-) dependent manner. In addition to the two tandemly repeated polytopic membrane-spanning domains (MSDs) typical of ABC transporters, MRP1 and its homologues MRP2, -3, -6, and -7 contain a third NH2-terminal MSD. The cytoplasmic loop (CL3) connecting this MSD, but apparently not the MSD itself, is required for MRP1 leukotriene C4 (LTC4) transport activity, substrate binding and appropriate trafficking of the protein to the basolateral membrane. We have used a baculovirus dual-expression system to produce various functionally complementing fragments of MRP1 in insect Sf21 cells to precisely define the region in CL3 that is required for activity and substrate binding. Using a parallel approach in polarized MDCK-I cells, we have also defined the region of CL3 that is required for basolateral trafficking. The CL3 NH2- and COOH-proximal functional boundaries have been identified as Cys208 and Asn260, respectively. Cys208 also corresponds to the NH2-proximal boundary of the region required for basolateral trafficking in MDCK-I cells. However, additional residues downstream of the CL3 COOH-proximal functional boundary extending to Lys270 were found to be important for basolateral localization. Finally, we show that regions in CL3 necessary for LTC4 binding and transport are also required for binding of the photoactivatable GSH derivative azidophenacyl-GSH.

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     This work was supported by a grant from the National Cancer Institute of Canada with funds from the Terry Fox Foundation. C.J.W. is the recipient of an Ontario Graduate Scholarship. S.P.C.C. is the Canada Research Chair in Cancer Biology, and R.G.D. is the Stauffer Professor of Basic Oncology at Queen's University.

     Department of Biochemistry, Queen's University.

    §

     Cancer Research Institute, Queen's University.

     SUNY.

     Department of Pathology and Molecular Medicine, Queen's University.

    *

     To whom correspondence should be addressed:  Tel 613-533-2981; fax 613-533-6830; e-mail [email protected].

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