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Journal of Lipid Research, Vol. 47, 1714-1724, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Interactions between fatty acids and -synuclein

Christian Lücke¹, Donald L. Gantz, Elena Klimtchuk and James A. Hamilton²

Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118

Published, JLR Papers in Press, May 10, 2006.

¹ Present address of C. Lücke: Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle, Germany.

² To whom correspondence should be addressed. e-mail: jhamilt{at}bu.edu

-Synuclein (S) is an amyloidogenic neuronal protein associated with several neurodegenerative disorders. Although unstructured in solution, S forms -helices in the presence of negatively charged lipid surfaces. Moreover, S was shown to interact with FAs in a manner that promotes protein aggregation. Here, we investigate whether S has specific FA binding site(s) similar to fatty acid binding proteins (FABPs), such as the intracellular FABPs. Our NMR experiments reveal that FA addition results in i) the simultaneous loss of S signal in both ¹H and ¹³C spectra and ii) the appearance of a very broad FA ¹³C-carboxyl signal. These data exclude high-affinity binding of FA molecules to specific S sites, as in FABPs. One possible mode of binding was revealed by electron microscopy studies of oleic acid bilayers at pH 7.8; these high-molecular-weight FA aggregates possess a net negative surface charge because they contain FA anions, and they were easily disrupted to form smaller particles in the presence of S, indicating a direct protein-lipid interaction. We conclude that S is not likely to act as an intracellular FA carrier. Binding to negatively charged membranes, however, appears to be an intrinsic property of S that is most likely related to its physiological role(s) in the cell.

Abbreviations: Aß, amyloid ß-protein; S, -synuclein; DHA, docosahexaenoic acid (22:6 ^{4,7,10,13,16,19}); EM, electron microscopy; (I-) FABP, (intestinal) fatty acid binding protein; LA, linolenic acid (18:3 ^9,12,15); NAC, non-amyloid ß-protein component; OA, oleic acid (18:1 ⁹); PLA₂, phospholipase A₂; TOCSY, total correlation spectroscopy; 1D, one-dimensional; 2D, two-dimensional

Supplementary key words multidimensional nuclear magnetic resonance spectroscopy • electron microscopy • fatty acid binding • protein-lipid complexes • neurodegenerative disorder

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