C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction.
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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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2041-1723
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Alzheimer's Research UK (ARUK-PG2013-14)
Biotechnology and Biological Sciences Research Council (BB/H023917/1)
Engineering and Physical Sciences Research Council (EP/H018301/1)
Medical Research Council (G0902243)
Wellcome Trust (203249/Z/16/Z)