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J. Biol. Chem., Vol. 282, Issue 34, 24905-24914, August 24, 2007

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On the Oligomeric State of DJ-1 Protein and Its Mutants Associated with Parkinson Disease

A COMBINED COMPUTATIONAL AND IN VITRO STUDY^*

Fernando E. Herrera^||1, Silvia Zucchelli^¶||1, Aneta Jezierska^||12, Zeno Scotto Lavina^¶||, Stefano Gustincich^¶||3, and Paolo Carloni^||4

From the International School for Advanced Studies, INFM DEMOCRITOS, ^||SISSA Unit, Italian Institute of Technology, Via Beirut 2-4, 34014 Trieste, Italy and the Sector of Neurobiology, and the ^¶Giovanni Armenise-Harvard Foundation Laboratory, AREA Science Park, Basovizza, 34012 Trieste, Italy

Mutations in the DJ-1 protein are present in patients suffering from familial Parkinson disease. Here we use computational methods and biological assays to investigate the relationship between DJ-1 missense mutations and the protein oligomeric state. Molecular dynamics calculations suggest that: (i) the structure of DJ-1 wild type (WT) in aqueous solution, in both oxidized and reduced forms, is similar to the crystal structure of the reduced form; (ii) the Parkinson disease-causing M26I variant is structurally similar to the WT, consistent with the experimental evidence showing the protein is a dimer as WT; (iii) R98Q is structurally similar to the WT, consistent with the fact that this is a physiological variant; and (iv) the L166P monomer rapidly evolves toward a conformation significantly different from WT, suggesting a change in its ability to oligomerize. Our combined computational and experimental approach is next used to identify a mutant (R28A) that, in contrast to L166P, destabilizes the dimer subunit-subunit interface without significantly changing secondary structure elements.

Received for publication, February 2, 2007 , and in revised form, April 19, 2007.

^* This work was supported in part by Telethon Grant GGP06268, IIT, GRAND, and the Giovanni Armenise-Harvard Foundation. 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 Figs. S1 and S2 and supplemental Tables S1–S3.

¹ These authors contributed equally to this work.

² On leave from the University of Wroclaw, Faculty of Chemistry, 50-383 Wroclaw, Poland. Supported in part by the Wrocaw Centre for Networking and Supercomputing, Academic Computer Center CYFRONET-KRAKÓ_W Grant KBN/SGI/UWrocl/078/2001, and the Pozna Supercomputing and Networking Center.

³ To whom correspondence may be addressed: International School for Advanced Studies AREA Science Park, S.S. 14, Km 163.5, Basovizza, 34012 Trieste, Italy. Tel.: 39-040-3756505; Fax: 39-040-3756502; E-mail: gustinci{at}sissa.it. ⁴ To whom correspondence may be addressed: International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy. Tel.: 39-040-3787407; Fax: 39-040-3787528; E-mail: carloni{at}sissa.it.

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