Aggregation of amyloidogenic proteins is considered a major mechanism behind the development of numerous protein aggregation diseases including Alzheimer’s. However, there are serious complications with translating current knowledge on amyloid aggregation in vitro to understanding the aggregation process in vivo. If the critical concentration for the spontaneous aggregation of Aβ peptide in vitro is in the micromolar range, physiological concentrations of Aβ are in the low nanomolar range making impossible amyloids to assemble. We have discovered recently that surface plays a role of catalyst allowing the self-assembly of amyloid aggregates to occur at physiologically relevant concentrations. We proposed a model in which the monomers transiently immobilized on the surfaces work as nuclei for the next aggregation step. The model was verified by experimental time-dependent AFM measurements. Additionally, single-molecule time-lapse AFM studies of aggregation of amyloid proteins on supported phospholipid bilayer revealed a strong effect of the membrane composition on the surface aggregation catalysis. We combined experimental studies involving single-molecule time-lapse AFM imaging with all-atom molecular dynamic simulations to characterize the on-surface self-assembly process of amyloid proteins. MD simulations show that the surface-protein interactions induce a conformational transition of the monomer facilitating binding of another molecule. Importantly, even transient interactions of amyloid beta protein with the membrane bilayer facilitate sampling of the energy profile allowing for the monomer to adopt the beta-sheet rich conformations responsible for the assembly of conformationally stable oligomers. The model explaining a critical role of cell surfaces in the early stages of the disease-prone self-assembly of amyloidogenic proteins is proposed and will be discussed.

Molecular mechanisms of proteins self-assembly in aggregates by the on-surface catalysis pathway

ACS Spring Meeting 2021

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