Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity

Amberley D. Stephens, Maria Zacharopoulou, Rani Moons, Giuliana Fusco, Neeleema Seetaloo, Anass Chiki, Philippa J. Woodhams, Ioanna Mela, Hilal A. Lashuel, Jonathan J. Phillips, Alfonso Simone, Frank Sobott and Gabriele S. Kaminski Schierle ()
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Amberley D. Stephens: University of Cambridge, Philippa Fawcett Drive
Maria Zacharopoulou: University of Cambridge, Philippa Fawcett Drive
Rani Moons: University of Antwerp
Giuliana Fusco: University of Cambridge
Neeleema Seetaloo: University of Exeter
Anass Chiki: Ecole Polytechnique Fédérale de Lausanne
Philippa J. Woodhams: University of Cambridge, Philippa Fawcett Drive
Ioanna Mela: University of Cambridge, Philippa Fawcett Drive
Hilal A. Lashuel: Ecole Polytechnique Fédérale de Lausanne
Jonathan J. Phillips: University of Exeter
Alfonso Simone: Imperial College London
Frank Sobott: University of Antwerp
Gabriele S. Kaminski Schierle: University of Cambridge, Philippa Fawcett Drive

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16564-3

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DOI: 10.1038/s41467-020-16564-3

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