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J. Biol. Chem., Vol. 277, Issue 6, 4232-4239, February 8, 2002
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From the Departments of Lipid peroxidation products have signaling
functions and at higher concentrations are toxic and may trigger cell
death. The compounds are metabolized predominantly by glutathione
S-transferases exemplified by mGSTA4-4, an enzyme
highly efficient in glutathione conjugation of 4-hydroxyalkenals, and
possessing glutathione peroxidase activity toward phospholipid
hydroperoxides. mGSTA4-4 belongs to the predominant group of
"canonical" glutathione S-transferases that are soluble
and generally localized in the cytoplasm. The intracellular
localization of mGSTA4-4 was examined in hepatocytes of normal mouse
liver and in transfected HepG2 cells by fluorescence microscopy and
digital deconvolution. mGSTA4-4 was found to be predominantly localized
at or near the plasma membrane in transfected HepG2 cells, as well as
in hepatocytes endogenously expressing the protein. In
vitro, mGSTA4-4 associated with liposomes, and this interaction
was potentiated when the liposomes contained negatively charged
phospholipids. Mutating lysine 115 to glutamic acid resulted in
a loss of the plasma membrane targeting of mGSTA4-4 as well as in a
significant reduction of its binding to liposomes in vitro.
These data suggest preferential targeting of mGSTA4-4 to the plasma
membrane that may contain the major substrate(s) for this enzyme.
Lysine 115 is critically important for the membrane association of
mGSTA4-4, most likely by entering into an electrostatic interaction
with negatively charged phospholipid headgroups.
Membrane Association of Glutathione S-Transferase
mGSTA4-4, an Enzyme That Metabolizes Lipid Peroxidation
Products*
,
,, and§§
Internal Medicine and
Biochemistry & Molecular Biology,
University of Arkansas for Medical Sciences, and Central Arkansas
Veterans Healthcare System, Little Rock, Arkansas 72205; the
§ Department of Internal Medicine, University of Texas
Medical School, Houston, Texas 77030; the ¶ Department of Human
Biological Chemistry & Genetics, University of Texas Medical Branch,
Galveston, Texas 77555; and the ** Department of Chemistry
and Biochemistry, University of Texas at Arlington, Arlington, Texas
76019
*
This work was supported in part by National Institutes of
Health Grants K08-DK02557 (to A. J.), CA77495 (to S. A.), CA27967 and
EY04396 (to Y. C. A), and ES07804 (to P. Z.).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.
Present address: Dept. of Pharmacology, University of
Pittsburgh, Pittsburgh, PA 15267.
§§
To whom correspondence should be addressed: Central Arkansas
Veterans Healthcare System Medical Research (151/LR), 4300 West 7th
St., Little Rock, AR 72205. Tel.: 501-257-4843; Fax: 501-257-4822; E-mail: zimniakpiotr@uams.edu.
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