PROTEIN STRUCTURE AND FOLDING
Ca2+ Binding to α-Synuclein Regulates Ligand Binding and Oligomerization*

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α-Synuclein is a protein normally involved in presynaptic vesicle homeostasis. It participates in the development of Parkinson's disease, in which the nerve cell lesions, Lewy bodies, accumulate α-synuclein filaments. The synaptic neurotransmitter release is primarily dependent on Ca2+-regulated processes. A microdialysis technique was applied showing that α-synuclein binds Ca2+ with an IC50 of about 2–300 μm and in a reaction uninhibited by a 50-fold excess of Mg2+. The Ca2+-binding site consists of a novel C-terminally localized acidic 32-amino acid domain also present in the homologue β-synuclein, as shown by Ca2+binding to truncated recombinant and synthetic α-synuclein peptides. Ca2+ binding affects the functional properties of α-synuclein. First, the ligand binding of 125I-labeled bovine microtubule-associated protein 1A is stimulated by Ca2+ ions in the 1–500 μm range and is dependent on an intact Ca2+ binding site in α-synuclein. Second, the Ca2+ binding stimulates the proportion of125I-α-synuclein-containing oligomers. This suggests that Ca2+ ions may both participate in normal α-synuclein functions in the nerve terminal and exercise pathological effects involved in the formation of Lewy bodies.

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Published, JBC Papers in Press, April 18, 2001, DOI 10.1074/jbc.M101181200

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This study was supported by the Danish Parkinson Foundation, The Danish Medical Research Council Grants 9802803 and 9902995, and the Aarhus University Research Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.