Ca2+ binding to alpha-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 Ca(2+)-regulated processes. A microdialysis technique was applied showing that alpha-synuclein binds Ca(2+) with an IC(50) of about 2-300 microm and in a reaction uninhibited by a 50-fold excess of Mg(2+). The Ca(2+)-binding site consists of a novel C-terminally localized acidic 32-amino acid domain also present in the homologue beta-synuclein, as shown by Ca(2+) binding to truncated recombinant and synthetic alpha-synuclein peptides. Ca(2+) binding affects the functional properties of alpha-synuclein. First, the ligand binding of (125)I-labeled bovine microtubule-associated protein 1A is stimulated by Ca(2+) ions in the 1-500 microm range and is dependent on an intact Ca(2+) binding site in alpha-synuclein. Second, the Ca(2+) binding stimulates the proportion of (125)I-alpha-synuclein-containing oligomers. This suggests that Ca(2+) ions may both participate in normal alpha-synuclein functions in the nerve terminal and exercise pathological effects involved in the formation of Lewy bodies.
Nielsen
M S
MS
Department of Medical Biochemistry, University of Aarhus, DK-8000 Aarhus C, Denmark.
Vorum
H
H
Lindersson
E
E
Jensen
P H
PH
D001704:Biopolymers; D002118:Calcium / Q000378:metabolism*; D008024:Ligands; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein
D001704:Biopolymers; D008024:Ligands; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D002118:Calcium