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Originally published In Press as doi:10.1074/jbc.M206896200 on October 17, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49495-49503, December 20, 2002
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Multiple Membrane-associated Tryptophan Residues Contribute to the Transport Activity and Substrate Specificity of the Human Multidrug Resistance Protein, MRP1*

Koji KoikeDagger , Curtis J. OleschukDagger §, Anass HaimeurDagger ||, Sharon L. OlsenDagger **, Roger G. DeeleyDagger , and Susan P. C. ColeDagger §Dagger Dagger

From the Dagger  Cancer Research Laboratories and § Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario K7L 3N6, Canada

The multidrug resistance protein, MRP1, is a clinically important ATP-binding cassette transporter in which the three membrane-spanning domains (MSDs), which contain up to 17 transmembrane (TM) helices, and two nucleotide binding domains (NBDs) are configured MSD1-MSD2-NBD1-MSD3-NBD2. In tumor cells, MRP1 confers resistance to a broad spectrum of drugs, but in normal cells, it functions as a primary active transporter of organic anions such as leukotriene C4 and 17beta -estradiol 17beta -(D-glucuronide). We have previously shown that mutation of TM17-Trp1246 eliminates 17beta -estradiol 17beta -(D-glucuronide) transport and drug resistance conferred by MRP1 while leaving leukotriene C4 transport intact. By mutating the 11 remaining Trp residues that are in predicted TM segments of MRP1, we have now determined that five of them are also major determinants of MRP1 function. Ala substitution of three of these residues, Trp445 (TM8), Trp553 (TM10), and Trp1198 (TM16), eliminated or substantially reduced transport levels of five organic anion substrates of MRP1. In contrast, Ala substitutions of Trp361 (TM7) and Trp459 (TM9) caused a more moderate and substrate-selective reduction in MRP1 function. More conservative substitutions (Tyr and Phe) of the Trp445, Trp553, and Trp1198 mutants resulted in substrate selective retention of transport in some cases (Trp445 and Trp1198) but not others (Trp553). Our findings suggest that the bulky polar aromatic indole side chain of each of these five Trp residues contributes significantly to the transport activity and substrate specificity of MRP1.

* This work was supported by Canadian Institutes for Health Research (CIHR) Grant MOP-10519.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a CIHR doctoral award and an Ontario Graduate Scholarship.

|| Recipient of a CIHR postdoctoral fellowship.

** Supported by a fellowship from the International Agency for Cancer Research.

Dagger Dagger Recipient of a Canada Research Chair and Senior Scientist of Cancer Care Ontario. To whom correspondence should be addressed: Cancer Research Laboratories, 3rd Floor, Botterell Hall, Queen's University, Kingston, Ontario, Canada. Tel.: 613-533-2636; Fax: 613-533-6830; E-mail: coles@post.queensu.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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