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J. Biol. Chem., Vol. 283, Issue 24, 16906-16914, June 13, 2008

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The Parkinson Disease-associated Leucine-rich Repeat Kinase 2 (LRRK2) Is a Dimer That Undergoes Intramolecular Autophosphorylation^*

Elisa Greggio¹, Ibardo Zambrano, Alice Kaganovich, Alexandra Beilina, Jean-Marc Taymans², Veronique Daniëls³, Patrick Lewis⁴, Shushant Jain⁵, Jinhui Ding^¶, Ali Syed, Kelly J. Thomas, Veerle Baekelandt, and Mark R. Cookson

From the Cell Biology and Gene Expression Unit and the ^¶Bioinformatics Facility, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda Maryland 20892 and the Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and apparently sporadic Parkinson disease. LRRK2 is a multidomain protein kinase with autophosphorylation activity. It has previously been shown that the kinase activity of LRRK2 is required for neuronal toxicity, suggesting that understanding the mechanism of kinase activation and regulation may be important for the development of specific kinase inhibitors for Parkinson disease treatment. Here, we show that LRRK2 predominantly exists as a dimer under native conditions, a state that appears to be stabilized by multiple domain-domain interactions. Furthermore, an intact C terminus, but not N terminus, is required for autophosphorylation activity. We identify two residues in the activation loop that contribute to the regulation of LRRK2 autophosphorylation. Finally, we demonstrate that LRRK2 undergoes intramolecular autophosphorylation. Together, these results provide insight into the mechanism and regulation of LRRK2 kinase activity.

Received for publication, October 22, 2007 , and in revised form, April 3, 2008.

^* This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the NIA. 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 supplemental text and a supplemental figure.

² A postdoctoral fellow of the Flemish Fund for Scientific Research (FWO Vlaanderen).

³ A research assistant of the Flemish Fund for Scientific Research (FWO Vlaanderen).

⁴ Present address: Dept. of Molecular Neuroscience and Rita Lila Weston Laboratories, Institute of Neurology, Queen Square, London WC1N 3BG UK.

⁵ Present address: Dept. of Clinical Genetics, Section of Medical Genomics, Vrije Universiteit Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands.

¹ To whom correspondence should be addressed: Laboratory of Neurogenetics, NIA, National Institutes of Health, Bldg. 35, Rm. 1A1012, MSC 3707, 35 Convent Dr., Bethesda, MD 20982-3707. Tel.: 301-451-3831; Fax: 301-451-7295; E-mail: greggio{at}mail.nih.gov.

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