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J. Biol. Chem., Vol. 279, Issue 21, 21966-21975, May 21, 2004

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-Synuclein Has a High Affinity for Packing Defects in a Bilayer Membrane

A THERMODYNAMICS STUDY^*

Brigitte Nuscher, Frits Kamp, Thomas Mehnert, Sabine Odoy, Christian Haass, Philipp J. Kahle, and Klaus Beyer

From the Laboratory of Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilian University, 80336 Munich, Germany

A number of neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the intracellular deposition of fibrillar aggregates that contain a high proportion of -synuclein (S). The interaction with the membrane-water interface strongly modulates folding and aggregation of the protein. The present study investigates the lipid binding and the coil-helix transition of S, using titration calorimetry, differential scanning calorimetry, and circular dichroism spectroscopy. Titration of the protein with small unilamellar vesicles composed of zwitterionic phospholipids below the chain melting temperature of the lipids yielded exceptionally large exothermic heat values. The sigmoidal titration curves were evaluated in terms of a simple model that assumes saturable binding sites at the vesicle surface. The cumulative heat release and the ellipticity were linearly correlated as a result of simultaneous binding and helix folding. There was no heat release and folding of S in the presence of large unilamellar vesicles, indicating that a small radius of curvature is necessary for the S-membrane interaction. The heat release and the negative heat capacity of the protein-vesicle interaction could not be attributed to the coil-helix transition of the protein alone. We speculate that binding and helix folding of S depends on the presence of defect structures in the membrane-water interface, which in turn results in lipid ordering in the highly curved vesicular membranes. This will be discussed with regard to a possible role of the protein for the stabilization of synaptic vesicle membranes.

Received for publication, January 30, 2004 , and in revised form, March 12, 2004.

^* 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 should be addressed: Institut für Stoffwechselbiochemie, Ludwig Maximilians Universität, Schillerstr. 44, 80336 München, Germany. Tel.: 49-89-599-6470; Fax: 49-89-599-6415; E-mail: kbeyer{at}med.uni-muenchen.de.

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