Calcium binding at the C-terminus of α-synuclein modulates synaptic vesicle interaction
St George-Hyslop, P
De Simone, A
Kaminski Schierle, GS
Nature Publishing Group
© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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 presynaptic 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
J.L. was supported by a research fellowship from the Deutsche Forschungsgemeinschaft (DFG; award LA 3609/2-1). M.Z. acknowledges funding from the Eugenides Foundation. C.F.K. acknowledges funding from the UK Engineering and Physical Sciences Research Council (EPSRC). A.DS. acknowledges funding from the UK Medical Research Council (MRC, MR/N000676/1). A.DS. and G.F. acknowledge funding from Parkinson's UK (G-1508). G.S.K. and C.F.K. acknowledge funding from the Wellcome Trust, the UK Medical Research Council (MRC), Alzheimer Research UK (ARUK), and Infinitus China Ltd. J.L. and A.D.S. acknowledge Alzheimer Research UK (ARUK) travel grants.
This is the author accepted manuscript. The final version is available from Nature Publishing Group via the DOI in this record.
Published online 19 February 2018.