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J. Biol. Chem., Vol. 277, Issue 46, 44268-44277, November 15, 2002
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From the Department of Pharmacology and Toxicology, Walther
Oncology Center/Walther Cancer Institute and the Indiana University
Cancer Center, Indiana University School of Medicine,
Indianapolis, Indiana 46202
Multidrug resistance-associated protein 1 (MRP1)
is a member of the ATP-binding cassette membrane transport
superfamily and is responsible for multidrug resistance in cancer
cells. Currently, there are nine known human MRPs. Distinct from many
other members of the ATP-binding cassette superfamily, human MRP1 and
four other MRPs have an additional membrane-spanning domain (MSD) with
a putative extracellular amino terminus. The functional significance of
this additional MSD (MSD1) is currently unknown. To understand the role
of MSD1 in human MRP1 structure and function, we studied the
amino-terminal 33 amino acids. We found that the amino terminus of
human MRP1 has two cysteine residues (Cys7 and
Cys32) that are conserved among the five human MRPs that
have MSD1. Mutation analyses of the two cysteines in human MRP1
revealed that the Cys7 residue is critical for the
MRP1-mediated drug resistance and leukotriene C4
transport activity. On the other hand, mutation of Cys32
reduced only moderately the MRP1 function. The effect of
Cys7 mutation on MRP1 activity appears to be due to the
5-7-fold decrease in the maximal transport rate
Vmax. We also found that mutation of
Cys7 changed the amino-terminal conformation of MRP1. This
conformational change is likely responsible for the decrease in
Vmax of LTC4 transport mediated by
the mutant MRP1. Based on these studies, we conclude that the amino
terminus of human MRP1 is important and that the Cys7
residue plays a critical role in maintaining the proper structure and
function of human MRP1.
Structural and Functional Consequences of Mutating Cysteine
Residues in the Amino Terminus of Human Multidrug
Resistance-associated Protein 1*
*
This work was supported in part by National Institutes of
Health Grants CA64539 and GM59475 and by Department of Defense Grant DAMD170010297.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 Career Investigator Award from the American Lung
Association. To whom correspondence should be addressed: Dept. of
Pharmacology and Toxicology, IUCC, Indiana University School of
Medicine, 1044 W. Walnut St., R4-166, Indianapolis, IN 46202. Tel.: 317-278-4503; Fax: 317-274-8046; E-mail:
jianzhan@iupui.edu.
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