NDLI: Functional Multidrug Resistance Protein (MRP1) Lacking the N-terminal Transmembrane Domain

Content Provider	Journal of Biological Chemistry (JBC)
Author	Bakos, Éva Evers, Raymond Szakács, Gergely Tusnády, Gábor E. Welker, Ervin Szabó, Katalin Haas, Marcel De Deemter, Liesbeth Van Borst, Piet Váradi, András Sarkadi, Balázs
Abstract	The human multidrug resistance protein (MRP1) causes drug resistance by extruding drugs from tumor cells. In addition to an MDR-like core, MRP1 contains an N-terminal membrane-bound region (TMD0) connected to the core by a cytoplasmic linker (L0). We have studied truncated MRP1 versions containing either the MDR-like core alone or the core plus linker L0, produced in the baculovirus-insect (Sf9) cell system. Their function was examined in isolated membrane vesicles. Full-length MRP1 showed ATP-dependent, vanadate-sensitive accumulation of leukotriene C4 and N-ethylmaleimide glutathione. In addition, leukotriene C4-stimulated, vanadate-dependent nucleotide occlusion was detected. The MDR-like core was virtually inactive. Co-expression of the core with the N-terminal region including L0 fully restored MRP1 function. Unexpectedly, a truncated MRP1 mutant lacking the entire TMD0 region but still containing L0 behaved like wild-type MRP1 in vesicle uptake and nucleotide trapping experiments. We also expressed the MRP1 constructs in polarized canine kidney derived MDCKII cells. Like wild-type MRP1, the MRP1 protein without the TMD0 region was routed to the lateral plasma membrane and transported dinitrophenyl glutathione and daunorubicin. The TMD0L0 and the MRP1 minus TMD0L0 remained in an intracellular compartment. Taken together, these experiments strongly suggest that the TMD0 region is neither required for the transport function of MRP1 nor for its proper routing to the plasma membrane.
Related Links	http://www.jbc.org/content/273/48/32167.abstract
Ending Page	32175
Starting Page	32167
Page Count	9
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	48
Volume Number	273
DOI	10.1074/jbc.273.48.32167
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1998-11-27
Access Restriction	Open
Subject Keyword	Human multidrug transporter P-glycoprotein (MDR1 Pgp) ATP binding cassette (ABC) Dinitrophenyl S-glutathione (DNP-GS) Reduced glutathione (GSH) Oxidized glutathione (GSSG) Enhanced chemiluminescence (ECL) Leukotriene C4 (LTC4) Madin-Darby canine kidney (MDCK) Canalicular multispecific organic anion transporter (cMOAT) Monoclonal antibody (mAb) Human multidrug resistance (-associated) protein (MRP) N-ethylmaleimideS-glutathione (NEM-GS) Spodoptera frugiperda ovarian cells (Sf9 cells) Transmembrane domain (TMD) 4-morpholinepropanesulfonic acid. (MOPS) MEMBRANES AND BIOENERGETICS
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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