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J. Biol. Chem., Vol. 280, Issue 26, 25103-25110, July 1, 2005

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Cleavage Site Selection within a Folded Substrate by the ATP-dependent Lon Protease^*

Gabriela Ondroviová, Tong Liu¶, Kamalendra Singh¶, Bin Tian¶, Hong Li¶, Oleksandr Gakh||**, Dusan Pereko, Jií Janata||, Zvi Granot, Joseph Orly, Eva Kutejová, and Carolyn K. Suzuki¶¶¶

From the Institute of Molecular Biology, Slovak Academy of Sciences, 845 51 Bratislava, Slovak Republic, ^¶University of Medicine and Dentistry of New Jersey (UMDNJ), New Jersey Medical School, Department of Biochemistry and Molecular Biology, Newark, New Jersey 07103, ^||Institute of Microbiology, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Czech Republic, and the Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

Mechanistic studies of ATP-dependent proteolysis demonstrate that substrate unfolding is a prerequisite for processive peptide bond hydrolysis. We show that mitochondrial Lon also degrades folded proteins and initiates substrate cleavage non-processively. Two mitochondrial substrates with known or homology-derived three-dimensional structures were used: the mitochondrial processing peptidase -subunit (MPP) and the steroidogenic acute regulatory protein (StAR). Peptides generated during a time course of Lon-mediated proteolysis were identified and mapped within the primary, secondary, and tertiary structure of the substrate. Initiating cleavages occurred preferentially between hydrophobic amino acids located within highly charged environments at the surface of the folded protein. Subsequent cleavages proceeded sequentially along the primary polypeptide sequence. We propose that Lon recognizes specific surface determinants or folds, initiates proteolysis at solvent-accessible sites, and generates unfolded polypeptides that are then processively degraded.

Received for publication, March 14, 2005 , and in revised form, May 2, 2005.

^* This study was supported by grants from the National Institutes of Health, the Basil O'Connor Scholars Award - March of Dimes, and the Foundation of UMDNJ (to C. K. S.); from the Slovak Grant Agency and the Science and Technology Assistance Agency (to E. K.); from the Twinning Program- National Science Foundation/National Academy of Sciences (to C. K. S. and E. K.); and from the Israel Science Foundation (to J. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains eight supplemental figures.

Both authors contributed equally to this work

^** Present address: Depts. of Pediatric and Adolescent Medicine and Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905.

To whom correspondence may be addressed. Tel.: 421-2-59307442; Fax: 421-2-59307416; E-mail: Eva.Kutejova{at}savba.sk.

^¶¶ To whom correspondence may be addressed. Tel.: 973-972-1555; Fax: 973-972-5594; E-mail: suzukick{at}umdnj.edu.

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