Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity.
Woodhams, Philippa J
Lashuel, Hilal A
Phillips, Jonathan J
De Simone, Alfonso
Springer Science and Business Media LLC
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Stephens, A. D., Zacharopoulou, M., Moons, R., Fusco, G., Seetaloo, N., Chiki, A., Woodhams, P. J., et al. (2020). Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity.. Nat Commun, 11 (1), 2820. https://doi.org/10.1038/s41467-020-16564-3
As an intrinsically disordered protein, monomeric alpha-synuclein (aSyn) occupies a large conformational space. Certain conformations lead to aggregation prone and non-aggregation prone intermediates, but identifying these within the dynamic ensemble of monomeric conformations is difficult. Herein, we used the biologically relevant calcium ion to investigate the conformation of monomeric aSyn in relation to its aggregation propensity. We observe that the more exposed the N-terminus and the beginning of the NAC region of aSyn are, the more aggregation prone monomeric aSyn conformations become. Solvent exposure of the N-terminus of aSyn occurs upon release of C-terminus interactions when calcium binds, but the level of exposure and aSyn's aggregation propensity is sequence and post translational modification dependent. Identifying aggregation prone conformations of monomeric aSyn and the environmental conditions they form under will allow us to design new therapeutics targeted to the monomeric protein.
Humans, Calcium, Protein Conformation, Structure-Activity Relationship, Phosphorylation, Kinetics, Mutation, Mutant Proteins, alpha-Synuclein, Benzothiazoles, Proton Magnetic Resonance Spectroscopy, Protein Aggregates
G.S.K.S. acknowledges funding from the Wellcome Trust, the UK Medical Research Council (MRC), Alzheimer Research UK (ARUK), and Infinitus China Ltd. A. DS. Acknowledges funding from the European Research Grant 819644 "BioDisOrder". A.D.S. and M.Z. acknowledge Alzheimer Research UK for travel grants. M.Z. acknowledges funding from Newnham College (Cambridge) and the George and Marie Vergottis Foundation (Cambridge Trust) and the British Biophysical Society (BSS) for travel grants. P.J.W acknowledges EPSRC funding (EP/L016087/1).
Wellcome Trust (065807/Z/01/Z)
Medical Research Council (MR/N012453/1)
Wellcome Trust (203249/Z/16/Z)
Medical Research Council (MR/K02292X/1)
Alzheimer's Research UK (ARUK-PG2013-14)
Engineering and Physical Sciences Research Council (EP/L016087/1)
External DOI: https://doi.org/10.1038/s41467-020-16564-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/304535