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J. Biol. Chem., Vol. 281, Issue 14, 9251-9259, April 7, 2006

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Binding of -Synuclein Affects the Lipid Packing in Bilayers of Small Vesicles^*

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

The intracellular deposition of fibrillar aggregates of -synuclein is a characteristic feature of Parkinson disease. Alternatively, as a result of its unusual conformational plasticity, -synuclein may fold into an amphipathic helix upon contact with a lipid-water interface. Using spin label ESR and fluorescence spectroscopy, we show here that -synuclein affects the lipid packing in small unilamellar vesicles. The ESR hyperfine splittings of spin-labeled phospholipid probes revealed that -synuclein induces chain ordering at carbon 14 of the acyl chains below the chain melting phase transition temperature but not in the liquid crystalline state of electroneutral vesicle membranes. Binding of -synuclein leads to an increase in the temperature and cooperativity of the phase transition according to the fluorescence anisotropy of the hydrophobic polyene 1,6-diphenylhexatriene and of the fluorescence emission maxima of the amphiphilic probe 6-dodecanoyl-2-dimethylaminonaphthalene. Binding parameters were obtained from the fluorescence anisotropy measurements in combination with our previous determinations by titration calorimetry (Nuscher, B., Kamp, F., Mehnert, T., Odoy, S., Haass, C., Kahle, P. J., and Beyer, K. (2004) J. Biol. Chem. 279, 21966–21975). We also show that -synuclein interacts with vesicle membranes containing sphingomyelin and cholesterol. We propose that the protein is capable of annealing defects in curved vesicle membranes, which may prevent synaptic vesicles from premature fusion.

Received for publication, November 16, 2005 , and in revised form, February 1, 2006.

^* The work was supported by Deutsche Forschungsgemeinschaft Grant SFB 596 (Teilprojekt B10). 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.

¹ To whom correspondence should be addressed: Lehrstuhl fur Stoffwechselbiochmie, Universität München, Schillerstr. 44, 80336 München, Germany. Tel.: 49-89-218-075-470; Fax: 49-89-218-075-415; E-mail: kbeyer{at}med.uni-muenchen.de.

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