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Vol. 16, Issue 5, 2483-2492, May 2005

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Role of the NH₂-terminal Membrane Spanning Domain of Multidrug Resistance Protein 1/ABCC1 in Protein Processing and Trafficking

Christopher J. Westlake ^* , Susan P.C. Cole  , and Roger G. Deeley  

^* Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6; Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada K7L 3N6; and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada K7L 3N6

Submitted December 23, 2004; Revised March 1, 2005; Accepted March 2, 2005
Monitoring Editor: Jean Gruenberg

Multidrug resistance protein (MRP)1/ABCC1 transports organic anionic conjugates and confers resistance to cytotoxic xenobiotics. In addition to two membrane spanning domains (MSDs) typical of most ATP-binding cassette (ABC) transporters, MRP1 has a third MSD (MSD0) of unknown function. Unlike some topologically similar ABCC proteins, removal of MSD0 has minimal effect on function, nor does it prevent MRP1 from trafficking to basolateral membranes in polarized cells. However, we find that independent of cell type, the truncated protein accumulates in early/recycling endosomes. Using a real-time internalization assay, we demonstrate that MSD0 is important for MRP1 retention in, or recycling to, the plasma membrane. We also show that MSD0 traffics independently to the cell surface and promotes membrane localization of the core-region of MRP1 when the two protein fragments are coexpressed. Finally, we demonstrate that MSD0 becomes essential for trafficking of MRP1 when the COOH-terminal region of the protein is mutated. These studies demonstrate that MSD0 and the COOH-terminal region contain redundant trafficking signals, which only become essential when one or the other region is missing or is mutated. These data explain apparent differences in the trafficking requirement for MSD0 and the COOH-terminal region of MRP1 compared with other ABCC proteins.

Abbreviations used: ABC, ATP-binding cassette; CL, cytoplasmic loop; CFP, cyan fluorescent protein; ER, endoplasmic reticulum; HEK, human embryonic kidney; HRP, horseradish peroxidase; LTC₄, leukotriene C₄; MDCK, Madin-Darby canine kidney; MRP, multidrug resistance protein; MSD, membrane-spanning domain; SUR, sulfonylurea receptor; TB, transport buffer; TM, transmembrane; YFP, yellow fluorescent protein.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Roger G. Deeley (deeleyr{at}post.queensu.ca).

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