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Originally published In Press as doi:10.1074/jbc.M203292200 on August 20, 2002

J. Biol. Chem., Vol. 277, Issue 43, 40583-40593, October 25, 2002
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Bimodal Targeting of Microsomal CYP2E1 to Mitochondria through Activation of an N-terminal Chimeric Signal by cAMP-mediated Phosphorylation*

Marie-Anne RobinDagger , Hindupur K. AnandatheerthavaradaDagger , Gopa BiswasDagger , Naresh Babu V. Sepuri§, Donna M. Gordon, Debkumar Pain, and Narayan G. AvadhaniDagger ||

From the Dagger  Department of Animal Biology and the Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the § Department of Biochemistry and Pharmacology, Thomas Jefferson University Medical School, Philadelphia, Pennsylvania 19107, and the  Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

Cytochrome P450 2E1 (CYP2E1) plays an important role in alcohol-induced toxicity and oxidative stress. Recently, we showed that this predominantly microsomal protein is also localized in rat hepatic mitochondria. In this report, we show that the N-terminal 30 amino acids of CYP2E1 contain a chimeric signal for bimodal targeting of the apoprotein to endoplasmic reticulum (ER) and mitochondria. We demonstrate that the cryptic mitochondrial targeting signal at sequence 21-31 of the protein is activated by cAMP-dependent phosphorylation at Ser-129. S129A mutation resulted in lower affinity for binding to cytoplasmic Hsp70, mitochondrial translocases (TOM40 and TIM44) and reduced mitochondrial import. S129A mutation, however, did not affect the extent of binding to the signal recognition particle and association with ER membrane translocator protein Sec61. Addition of saturating levels of signal recognition particle caused only a partial inhibition of CYP2E1 translation under in vitro conditions, and saturating levels of ER resulted only in partial membrane integration. cAMP enhanced the mitochondrial CYP2E1 (referred to as P450MT5) level but did not affect its level in the ER. Our results provide new insights on the mechanism of cAMP-mediated activation of a cryptic mitochondrial targeting signal and regulation of P450MT5 targeting to mitochondria.

* This work was supported in part by National Institutes of Health Grant GM-34883 (to N. G. A.) and GM-57067 (to D. P.).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.

|| To whom correspondence should be addressed. Tel.: 215-898-8819; E-mail: narayan@vet.upenn.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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