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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.

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