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J. Biol. Chem., Vol. 283, Issue 24, 16895-16905, June 13, 2008
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Phosphorylation at Ser-129 but Not the Phosphomimics S129E/D Inhibits the Fibrillation of 
-Synuclein*
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From the
Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland, Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, New York, New York 10021, ¶Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Deutsche Forschungsgemeinschaft Research Center for the Molecular Physiology of the Brain, 37077 Göttingen, Germany, ||Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina, and **Harvard Center for Neurodegeneration and Repair, Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, Cambridge, Massachusetts 02139
-Synuclein (-syn) phosphorylation at serine 129 is characteristic of Parkinson disease (PD) and related -synulceinopathies. However, whether phosphorylation promotes or inhibits -syn aggregation and neurotoxicity in vivo remains unknown. This understanding is critical for elucidating the role of -syn in the pathogenesis of PD and for development of therapeutic strategies for PD. To better understand the structural and molecular consequences of Ser-129 phosphorylation, we compared the biochemical, structural, and membrane binding properties of wild type -syn to those of the phosphorylation mimics (S129E, S129D) as well as of in vitro phosphorylated -syn using a battery of biophysical techniques. Our results demonstrate that phosphorylation at Ser-129 increases the conformational flexibility of -syn and inhibits its fibrillogenesis in vitro but does not perturb its membrane-bound conformation. In addition, we show that the phosphorylation mimics (S129E/D) do not reproduce the effect of phosphorylation on the structural and aggregation properties of -syn in vitro. Our findings have significant implications for current strategies to elucidate the role of phosphorylation in modulating protein structure and function in health and disease and provide novel insight into the underlying mechanisms that govern -syn aggregation and toxicity in PD and related -synulceinopathies.
Received for publication, January 29, 2008 , and in revised form, March 13, 2008.
* This work was supported, in whole or in part, by National Institutes of Health Grant AG019391 (from NIA). This work was also supported by the Swiss Federal Institute of Technology Lausanne (to H. A. L., K. E. P., and A. W. S.), Swiss National Science Foundation Grant 310000-110027 (to H. A. L.), by the Max Planck society (to M. Z. and C. O. F.), a Deutsche Forschungsgemeinschaft Heisenberg scholarship to M. Z. (ZW 71/2-1 and 3-1), Agencia de Promocion Cientifica y Tecnologica, Fundación Antorchas (to C. O. F.), Alexander von Humboldt Foundation (to C. O. F.), and the Irma T. Hirschl Foundation, and a gift from Herbert and Ann Siegel (to D. E.). 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. 1-9.
1 A member of the New York Structural Biology Center, supported by National Institutes of Health Grant GM66354.
2 To whom correspondence should be addressed: LMNN, EPFL, CH-1015 Lausanne, Switzerland. Tel.: 41-21-69-39691 or 41-21-69-31812; Fax: 41-21-693-96-65; E-mail: hilal.lashuel{at}epfl.ch.
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