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J Biol Chem, Vol. 274, Issue 34, 24014-24022, August 20, 1999
Dual Targeting Property of the N-terminal Signal Sequence of
P4501A1
TARGETING OF HETEROLOGOUS PROTEINS TO ENDOPLASMIC RETICULUM AND
MITOCHONDRIA
Shripad V.
Bhagwat ,
Gopa
Biswas ,
Hindupur K.
Anandatheerthavarada ,
Sankar
Addya ,
William
Pandak¶, and
Narayan G.
Avadhani
From the Department of Animal Biology and the Mari
Lowe Center for Comparative Oncology, School of Veterinary Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania 19104-6047 and
¶ Section of Gastroenterology, McGuire Veterans Administration
Medical Center, and Medical College of Virginia, Virginia Commonwealth
University, Richmond, Virginia 23298-0711
Recent studies from our laboratory showed that
the -naphthoflavone-inducible cytochrome P4501A1 is targeted to both
the endoplasmic reticulum (ER) and mitochondria. In the present study,
we have further investigated the ability of the N-terminal signal
sequence (residues 1-44) of P4501A1 to target heterologous proteins,
dihydrofolate reductase, and the mature portion of the rat P450c27 to
the two subcellular compartments. In vitro transport and
in vivo expression experiments show that N-terminally fused
1-44 signal sequence of P4501A1 targets heterologous proteins to both
the ER and mitochondria, whereas the 33-44 sequence strictly functions
as a mitochondrial targeting signal. Site-specific mutations show that
positively charged residues at the 34th and 39th positions are critical
for mitochondrial targeting. Cholesterol 27-hydroxylase activity of the
ER-associated 1-44/1A1-CYP27 fusion protein can be reconstituted with
cytochrome P450 reductase, but the mitochondrial associated fusion
protein is functional with adrenodoxin + adrenodoxin reductase. Consistent with these differences, the fusion protein in the two organelle compartments exhibited distinctly different membrane topology. The results on the chimeric nature of the N-terminal signal
of P4501A1 coupled with interaction with different electron transport
proteins suggest a co-evolutionary nature of some of the xenobiotic
inducible microsomal and mitochondrial P450s.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.
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