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MBC in Press, published online ahead of print March 16, 2005
Mol. Biol. Cell 10.1091/mbc.E04-12-1113

A more recent version of this article appeared on May 1, 2005
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Submitted on December 23, 2004
Revised on March 1, 2005
Accepted on March 2, 2005

Role of the NH2-Terminal Membrane Spanning Domain of MRP1/ABCC1 in Protein Processing and Trafficking

Christopher J. Westlake,*{dagger} Susan P.C. Cole,{dagger}{ddagger} and Roger G. Deeley{dagger}{ddagger}

Departments of *Biochemistry and {ddagger}Pathology and Molecular Medicine and the {dagger}Cancer Research Institute, Queen’s University, Kingston, Ontario, Canada K7L 3N6

Monitoring Editor: Jean Gruenberg

Multidrug Resistance Protein 1 (MRP1/ABCC1) transports organic anionic conjugates and confers resistance to cytotoxic xenobiotics. In addition to two membrane spanning domains (MSDs) typical of most 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 when compared with other ABCC proteins.

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




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