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J. Biol. Chem., Vol. 280, Issue 17, 16619-16624, April 29, 2005

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-Synuclein and Parkin Contribute to the Assembly of Ubiquitin Lysine 63-linked Multiubiquitin Chains^*

Ellen W. Doss-Pepe, Li Chen, and Kiran Madura

From the Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Mutations in -synuclein, Parkin, and UCH-L1 cause heritable forms of Parkinson disease. Unlike -synuclein, for which no precise biochemical function has been elucidated, Parkin functions as a ubiquitin E3 ligase, and UCH-L1 is a deubiquitinating enzyme. The E3 ligase activity of Parkin in Parkinson disease is poorly understood and is further obscured by the fact that multiubiquitin chains can be formed through distinct types of linkages that regulate diverse cellular processes. For instance, ubiquitin lysine 48-linked multiubiquitin chains target substrates to the proteasome, whereas ubiquitin lysine 63-linked chains control ribosome function, protein sorting and trafficking, and endocytosis of membrane proteins. It is notable in this regard that ubiquitin lysine 63-linked chains promote the degradation of membrane proteins by the lysosome. Because both Parkin and -synuclein can regulate the activity of the dopamine transporter, we investigated whether they influenced ubiquitin lysine 63-linked chain assembly. These studies revealed novel biochemical activities for both Parkin and -synuclein. We determined that Parkin functions with UbcH13/Uev1a, a dimeric ubiquitin-conjugating enzyme, to assemble ubiquitin lysine 63-linked chains. Our results and the results of others indicate that Parkin can promote both lysine 48- and lysine 63-linked ubiquitin chains. -Synuclein also stimulated the assembly of lysine 63-linked ubiquitin chains. Because UCH-L1, a ubiquitin hydrolase, was recently reported to form lysine 63-linked conjugates, it is evident that three proteins that are genetically linked to Parkinson disease can contribute to lysine 63 multiubiquitin chain formation.

Received for publication, December 2, 2004 , and in revised form, February 16, 2005.

^* This work was supported by National Institutes of Health Public Health Service Grant AG01047 (to E. W. D.-P.) and Grants NS044081 and CA83875 (to K. M.). 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.

To whom correspondence may be addressed: Dept. of Biochemistry, Robert Wood Johnson Medical School, 683 Hoes Lane, Rm. 372, Piscataway, NJ 08854. Tel.: 732-235-4595; Fax: 732-235-4783; E-mail: dosspeew{at}umdnj.edu. To whom correspondence may be addressed: Dept. of Biochemistry, Robert Wood Johnson Medical School, 683 Hoes Lane, Rm. 383, Piscataway, NJ 08854. Tel.: 732-235-5602; Fax: 732-235-4783; E-mail: maduraki{at}umdnj.edu.

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