As an intrinsically disordered protein, monomeric alpha-synuclein (aSyn) constantly reconfigures and probes the conformational space. Under certain conditions, aSyn misfolds, aggregates, and forms amyloid fibrils, which are a hallmark of Parkinson's disease (PD). Certain aSyn monomeric conformations lead to aggregation-prone and non-aggregation prone intermediates, but identifying these within the dynamic ensemble of monomeric conformations is difficult. We use the biologically relevant calcium ion to investigate the conformation of monomeric aSyn in relation to its aggregation propensity, with a combination of biophysical techniques, such as aggregation kinetics assays and hydrogen-deuterium exchange mass spectrometry (HDX-MS). 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-dependent. Thus, understanding aggregation-prone conformations of monomeric aSyn, and the environmental conditions they form under, could potentially allow us to design new therapeutics targeted to the monomeric protein, to stabilise aSyn in non-aggregation prone conformations, by either preserving long-range interactions between the N- and C-termini or by protecting the N-terminus from exposure.

Extent of N-terminus exposure by altered long-range interactions of monomeric alpha-synuclein determines its aggregation propensity

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.