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

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Title: C-terminal calcium binding of alpha-synuclein modulates synaptic vesicle interaction
Authors: 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
Item Type: Journal Article
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.
Issue Date: 19-Feb-2018
Date of Acceptance: 19-Jan-2018
URI: http://hdl.handle.net/10044/1/64017
DOI: 10.1038/s41467-018-03111-4
ISSN: 2041-1723
Publisher: Nature Research
Start Page: 1
End Page: 13
Journal / Book Title: Nature Communications
Volume: 9
Issue: 1
Copyright Statement: © 2018 The Author(s). 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/.
Sponsor/Funder: Medical Research Council (MRC)
Parkinson's UK
Funder's Grant Number: MR/N000676/1
G-1508
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SATURATION-TRANSFER DIFFERENCE
HUMAN SERUM-ALBUMIN
A-BETA-PEPTIDE
PARKINSONS-DISEASE
NMR-SPECTROSCOPY
STRUCTURAL BASIS
GAMMA-SYNUCLEIN
LIPID VESICLES
KNOCKOUT MICE
PROTEIN
Animals
Binding Sites
Calcium
Cell Line
Humans
In Vitro Techniques
Lipid Metabolism
Microscopy, Electron, Transmission
Nuclear Magnetic Resonance, Biomolecular
Presynaptic Terminals
Protein Aggregates
Protein Binding
Rats
Rats, Sprague-Dawley
Synaptic Vesicles
Synaptosomes
alpha-Synuclein
Presynaptic Terminals
Synaptic Vesicles
Cell Line
Synaptosomes
Animals
Humans
Rats
Rats, Sprague-Dawley
Calcium
Microscopy, Electron, Transmission
Nuclear Magnetic Resonance, Biomolecular
Binding Sites
Protein Binding
Lipid Metabolism
alpha-Synuclein
In Vitro Techniques
Protein Aggregates
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
SATURATION-TRANSFER DIFFERENCE
HUMAN SERUM-ALBUMIN
A-BETA-PEPTIDE
PARKINSONS-DISEASE
NMR-SPECTROSCOPY
STRUCTURAL BASIS
GAMMA-SYNUCLEIN
LIPID VESICLES
KNOCKOUT MICE
PROTEIN
Publication Status: Published
Article Number: ARTN 712
Online Publication Date: 2018-02-19
Appears in Collections:Faculty of Natural Sciences