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.
C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction / Lautenschlager, J., Stephens, A.D., Fusco, G., Strohl, F., Curry, N., Zacharopoulou, M., Michel, C.H., Laine, R., Nespovitaya, N., Fantham, M., Pinotsi, D., Zago, W., Fraser, P., Tandon, A., St George-Hyslop, P., Rees, E., Phillips, J.J., De Simone, A., Kaminski, C.F., Schierle, G.S.K.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 9:1(2018). [10.1038/s41467-018-03111-4]
C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction
Fusco G.;De Simone A.;
2018
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
