Journal Article

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

Woodhams, Philippa J., Fusco, Giuliana, Schierle, Gabriele S. Kaminski, Lashuel, Hilal A., Stephens, Amberley D., Moons, Rani, Chiki, Anass, Mela, Ioanna, Phillips, Jonathan J., Seetaloo, Neeleema, De Simone, Alfonso, Sobott, Frank, Zacharopoulou, Maria

2020

Overview

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. In Parkinson’s disease (PD) the monomeric protein alpha-synuclein (aSyn) misfolds and aggregates into insoluble fibrils. Here the authors use NMR measurements and hydrogen–deuterium exchange mass spectrometry and find that the more solvent exposed the N-terminus of aSyn is, the more aggregation prone its conformation becomes, and further show how PD mutations and post translational modifications influence the extent of the N-terminus solvent exposure.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 140/131 / 631/1647/296 / 631/45/535/878 / 631/57/2269 / 692/699/375/365/1718 / 82/58 / 82/80 / 82/83 / Agglomeration / alpha-Synuclein - chemistry / alpha-Synuclein - metabolism / Benzothiazoles - metabolism / C-Terminus / Calcium / Calcium - metabolism / Calcium ions / Deuterium / Environmental conditions / Exposure / Fibrils / Humanities and Social Sciences / Humans / Intermediates / Kinetics / Mass spectrometry / Mass spectroscopy / Movement disorders / multidisciplinary / Mutant Proteins - chemistry / Mutant Proteins - metabolism / Mutation / Mutation - genetics / N-Terminus / Neurodegenerative diseases / NMR / Nuclear magnetic resonance / Parkinson's disease / Phosphorylation / Protein Aggregates / Protein Conformation / Protein folding / Proteins / Proton Magnetic Resonance Spectroscopy / Science / Science (multidisciplinary) / Solvents / Structure-Activity Relationship / Synuclein / Translation