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Originally published In Press as doi:10.1074/jbc.M111534200 on February 11, 2002

J. Biol. Chem., Vol. 277, Issue 18, 15303-15308, May 3, 2002
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Caspase-mediated Parkin Cleavage in Apoptotic Cell Death*

Søren KahnsDagger , Simon Lykkebo§, Lene Diness Jakobsen§, Morten S. Nielsen§, and Poul Henning Jensen§

From the § Department of Medical Biochemistry, Building 170 and the Dagger  Institute of Molecular and Structural Biology, University of Aarhus, DK-8000 Aarhus-C, Denmark

The parkin protein is important for the survival of the neurons that degenerate in Parkinson's disease as demonstrated by disease-causing lesions in the parkin gene. The Chinese hamster ovary and the SH-SY5Y cell line stably expressing recombinant human parkin combined with epitope-specific parkin antibodies were used to investigate the proteolytic processing of human parkin during apoptosis by immunoblotting. Parkin is cleaved during apoptosis induced by okadaic acid, staurosporine, and camptothecin, thereby generating a 38-kDa C-terminal fragment and a 12-kDa N-terminal fragment. The cleavage was not significantly affected by the disease-causing mutations K161N, G328E, T415N, and G430D and the polymorphism R366W. Parkin and its 38-kDa proteolytic fragment is preferentially associated with vesicles, thereby indicating that cleavage is a membrane-associated event. The proteolysis is sensitive to inhibitors of caspases. The cleavage site was mapped by site-directed mutagenesis of potential aspartic residues and revealed that mutation of Asp-126 alone abrogated the parkin cleavage. The tetrapeptide aldehyde LHTD-CHO, representing the amino acid sequence N-terminal to the putative cleavage site was an efficient inhibitor of parkin cleavage. This suggests that parkin function is compromised in neuropathological states associated with an increased caspase activation, thereby further adding to the cellular stress.

* This study was supported by Danish Medical Research Grant 9902995, 5th Frame Work Program Grant Protage QLK6-CT-1999-02193, The Danish Parkinson Foundation, The Lundbeck Foundation, and The Novo Nordic Foundation.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.: 45-89-422-856; Fax: 45-86-131-160; E-mail: phj@biokemi.au.dk.

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