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(Received for publication, June 24, 1997, and in revised form, August 18, 1997)
From the S. C. Johnson Medical Research Center, Mayo Clinic
Arizona, Scottsdale, Arizona 85259
Human multidrug resistance protein (MRP) was
expressed at high levels in stably transfected baby hamster kidney
(BHK-21) cells. These cells exhibited a pattern of cross-resistance to
several different drugs typical of an MRP-mediated phenotype despite
the addition of 10 histidine residues at the C terminus to facilitate purification. Consistent with this functional evidence of the presence
of MRP at the surface of these transfectants, strong signals were
detected by immunoblotting and immunofluorescence using a specific
monoclonal antibody to MRP. There was intense uniform staining of the
cell surface as well as weaker staining of intracellular membranes.
MRP-containing membranes were solubilized in 1%
N-dodecyl-
Volume 272, Number 49,
Issue of December 5, 1997
pp. 30962-30968
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
ATPase Activity of Purified Multidrug Resistance-associated
Protein
-D-maltoside in the presence of
0.4% sheep brain phospholipids. Two sequential affinity purification
steps on Ni-NTA agarose and wheat germ agglutinin agarose provided
substantial enrichment, and contaminating bands were not detected.
ATPase activity of the purified protein was assayed in the presence of the phospholipids, which had been maintained throughout all
purification steps. ATP was hydrolyzed in proportion to the amount of
purified protein assayed, and typical Michaelis-Menten behavior was
exhibited, yielding estimations of Km of ~3.0
mM and Vmax of 0.46 µmol
mg
1 min1. This activity was moderately
stimulated by the drugs that others have shown to be transported by
MRP-containing membrane vesicles. This stimulation was enhanced by
reduced glutathione as is its drug transport, and oxidized glutathione,
itself a substrate for transport, caused a strong stimulation. These
data describe the first purification of MRP and provide the first
direct evidence that the molecule possesses drug-stimulated ATPase
activity.
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