RESUMO
Since the proposal of the brainstem axis theory, increasing research attention has been paid to the interactions between bacterial amyloids produced by intestinal flora and the amyloid ß-protein (Aß) related to Alzheimer's disease (AD), and it has been considered as the possible cause of AD. Therefore, phenol-soluble modulin (PSM) α3, the most virulent protein secreted by Staphylococcus aureus, has attracted much attention. In this work, the effect of PSMα3 with a unique cross-α fibril architecture on the aggregation of pathogenic Aß40 of AD was studied by extensive biophysical characterizations. The results proposed that the PSMα3 monomer inhibited the aggregation of Aß40 in a concentration-dependent manner and changed the aggregation pathway to form granular aggregates. However, PSMα3 oligomers promoted the generation of the ß-sheet structure, thus shortening the lag phase of Aß40 aggregation. Moreover, the higher the cross-α content of PSMα3, the stronger the effect of the promotion, indicating that the cross-α structure of PSMα3 plays a crucial role in the aggregation of Aß40. Further molecular dynamics (MD) simulations have shown that the Met1-Gly20 region in the PSMα3 monomer can be combined with the Asp1-Ala2 and His13-Val36 regions in the Aß40 monomer by hydrophobic and electrostatic interactions, which prevents the conformational conversion of Aß40 from the α-helix to ß-sheet structure. By contrast, PSMα3 oligomers mainly combined with the central hydrophobic core (CHC) and the C-terminal region of the Aß40 monomer by weak H-bonding and hydrophobic interactions, which could not inhibit the transition to the ß-sheet structure in the aggregation pathway. Thus, the research has unraveled molecular interactions between Aß40 and PSMα3 of different structures and provided a deeper understanding of the complex interactions between bacterial amyloids and AD-related pathogenic Aß.