Ca2+ binding to α-synuclein regulates ligand binding and oligomerization

alpha -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 alpha -synuclein filaments. The synaptic neurotransmitter release is primarily dependent on Ca2+-regulated processes. A microdialysis technique was applied showing that alpha -synuclein binds Ca2+ with an IC,, of about 2-300 muM 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 beta -synuclein, as shown by Ca2+ binding to truncated recombinant and synthetic alpha -synuclein peptides. Ca2+ binding affects the functional properties of alpha -synuclein, First, the ligand binding of I-125-labeled bovine microtubule-associated protein 1A is stimulated by Ca2+ ions in the 1-500 muM. range and is dependent on an intact Ca2+ binding site in alpha -synuclein. Second, the Ca2+ binding stimulates the proportion of I-125-alpha -synuclein-containing oligomers, This suggests that Ca2+ ions may both participate in normal alpha -synuclein functions in the nerve terminal and exercise pathological effects involved in the formation of Lewy bodies.