The N-terminal Acetylation of α-Synuclein Changes the Affinity for Lipid Membranes but not the Structural Properties of the Bound State.
De Simone, Alfonso
Nature Publishing Group
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Runfola, M., De Simone, A., Vendruscolo, M., Dobson, C. M., & Fusco, G. (2020). The N-terminal Acetylation of α-Synuclein Changes the Affinity for Lipid Membranes but not the Structural Properties of the Bound State.. Scientific reports, 10 (1), 204. https://doi.org/10.1038/s41598-019-57023-4
The aggregation of α-synuclein (αS), a protein abundant at presynaptic terminals, is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Emerging evidence indicates that the interaction of αS with lipid membranes defines both its physiological function and pathological effects. The characterisation of the modes of membrane binding by αS is therefore crucial to clarify the balance between normal and aberrant behaviour of this protein. Here we used solid-state nuclear magnetic resonance (ssNMR) spectroscopy to probe the nature of the N-terminally acetylated form of αS (NTAc-αS) bound to synaptic-like lipid vesicles. This post-translational modification is prevalent for the physiological form of αS and modulates the binding to lipid bilayers. By probing the structure, dynamics and membrane topology of NTAc- αS, we found that N-terminal acetylation does not alter significantly the conformational properties of the membrane-bound state of αS, despite increasing its propensity for binding. Taken together, our data and previous characterisations of the cytosolic state of NTAc-αS clarify that the role of N-terminal acetylation is to regulate the binding affinity of αS for synaptic vesicles without altering the structural properties of the bound state.
Synaptic Vesicles, Cell Membrane, Humans, Membrane Lipids, Lipid Bilayers, Protein Processing, Post-Translational, Protein Binding, Acetylation, alpha-Synuclein
This research is supported by Parkinson’s UK (G-1508, A.D., M.V., C.M.D and G.F.), the UK Medical Research Council (MR/N000676/1, A.D., M.V. and C.M.D.), the European Research Council (ERC) Consolidator Grant (CoG) ‘BioDisOrder” (819644, A.D.), The Centre for Misfolding Diseases of the University of Cambridge (C.M.D. and M.V.) and the St John’s College Fellowship (G.F.).
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External DOI: https://doi.org/10.1038/s41598-019-57023-4
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300379
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/