Revealing the Regulation Effect of Surface Charge at Aromatic Interface to Dynamic Conformational Changes of α-Synuclein at Early Aggregation Stage

Abstract

The aggregation of α-synuclein (α-syn) is strongly influenced by membrane interfaces, but the mechanism of transition from monomers to oligomers at early aggregation stage is not clear. Here, we investigate the adsorption and structure changes of α-syn on oppositely charged aromatic interfaces through in-situ surface-enhanced infrared absorption (SEIRA) spectroscopy and nano-IR technique. The results show that the synergy of electrostatic and hydrophobic interactions leads to a “fast-slow” two-step aggregation pathway on negatively charged interface. Surface adsorption induces the formation of an extended helix structure and subsequently partial helix unwinding in NAC region, which enables the hydrophobic stacking between nearby NAC regions. Stable antiparallel β-sheet rich aggregates are gradually emerging as further interactions of monomers with the fast formed “first layer”. Monomers electrostatically adsorb on positively charged interface by C-terminus with NAC region and N-terminus stretched in solvent, which serve as an aggregation core and induce further adsorption and gradual formation of aggregates with C-terminus exposure. Our results demonstrate the modulation of surface charge and synergy of electrostatic and hydrophobic interactions on the interaction modes and aggregation pathways, which provide insights into dynamic conformation changes of α-syn at early aggregation stage and imply the important role of spatial-temporal heterogeneity of membranes in α-synucleinopathies.

Keywords

α-Synuclein / Interface / Early aggregation / IR spectroscopy / Surface analysis / Analytical methods / Proteins / Dynamic monitoring

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2024 SIOC, CAS, Shanghai, & WILEY-VCH GmbH