Lautenschlager, J; Stephens, AD; Fusco, G; Strohl, F; Curry, N; Zacharopoulou, M; Michel, CH; ... Schierle, GSK; + view all Lautenschlager, J; Stephens, AD; Fusco, G; Strohl, F; Curry, N; Zacharopoulou, M; Michel, CH; Laine, R; Nespovitaya, N; Fantham, M; Pinotsi, D; Zago, W; Fraser, P; Tandon, A; St George-Hyslop, P; Rees, E; Phillips, JJ; De Simone, A; Kaminski, CF; Schierle, GSK; - view fewer (2018) C-terminal calcium binding of alpha-synuclein modulates synaptic vesicle interaction. Nature Communications , 9 , Article 712. 10.1038/s41467-018-03111-4.

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Abstract

Alpha-synuclein is known to bind to small unilamellar vesicles (SUVs) via its N terminus, which forms an amphipathic alpha-helix upon membrane interaction. Here we show that calcium binds to the C terminus of alpha-synuclein, therewith increasing its lipid-binding capacity. Using CEST-NMR, we reveal that alpha-synuclein interacts with isolated synaptic vesicles with two regions, the N terminus, already known from studies on SUVs, and additionally via its C terminus, which is regulated by the binding of calcium. Indeed, dSTORM on synaptosomes shows that calcium mediates the localization of alpha-synuclein at the pre-synaptic terminal, and an imbalance in calcium or alpha-synuclein can cause synaptic vesicle clustering, as seen ex vivo and in vitro. This study provides a new view on the binding of alpha-synuclein to synaptic vesicles, which might also affect our understanding of synucleinopathies.

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