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The N-terminal Acetylation of α-Synuclein Changes the Affinity for Lipid Membranes but not the Structural Properties of the Bound State

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Runfola, Matteo 
De Simone, Alfonso 
Vendruscolo, Michele  ORCID logo
Dobson, Christopher M.  ORCID logo
Fusco, Giuliana 


Abstract: 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 and topological 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 the N-terminal acetylation is to regulate the binding affinity of αS for synaptic vesicles without altering the structural properties of the bound state.


Funder: Centre for Misfolding Diseases

Funder: Parkinson's UK

Funder: Cambridge University | St. John's College, University of Cambridge Centre for Misfolding Diseases


Article, /631/45/470/2284, /631/45/535/878, /82/6, article

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Scientific Reports

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Nature Publishing Group UK
RCUK | Medical Research Council (MRC) (MR/N000676/1)
Parkinson&apos (G-1508, G-1508)
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (819644)
RCUK | MRC | Medical Research Foundation (MR/N000676/1)