C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction

Authors: Janin Lautenschläger, Amberley D. Stephens, Giuliana Fusco, Florian Ströhl, Nathan Curry, Maria Zacharopoulou, Claire H. Michel, Romain Laine, Nadezhda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan J. Phillips, Alfonso De Simone, Clemens F. Kaminski, Gabriele S. Kaminski Schierle


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.

Source: Nature Communications, 2018; 9 (1)